Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

Out-of-hospital cardiac arrests in the older population in Ireland.

INTRODUCTION: Age influences survival from an out-of-hospital cardiac arrest (OHCA) but it is unclear to what extent. Improved understanding of the impact of increasing age may be helpful in improving decision making on who should receive attempted resuscitation to optimise outcomes and minimise inappropriate end-of-life management. Our aim is to describe the demographics, characteristics and outcomes following resuscitation attempts in OHCA patients aged 70 years and older in Ireland. METHODS: Data were extracted from the national OHCA Register. Patient and event characteristics were compared across three age categories (70-79; 80-89; ≥90 years). Multivariable logistic regression was used to determine the predictors of the primary outcome (survival to hospital discharge). RESULTS: A total of 2281 patients aged 70 years and older were attended by emergency medical services and had resuscitation attempted between 2012 and 2014. Overall survival to hospital discharge was 2.9%. For those aged 70-79 years, 80-89 years, 90 years and older survival to hospital discharge in each age group was 4.0%, 1.8% and 1.4%, respectively. Older age (adjusted OR (AOR) 0.95 95% CI 0.90 to 0.99) and having an arrest in the subjects own home (AOR 0.14 95% CI 0.07 to 0.28) were independent predictor associated with reduced odds of survival to hospital discharge. An initial shockable rhythm (AOR 17.9. 95% CI 8.19 to 39.2) and having a bystander witnessed OHCA (AOR 3.98. 95% CI 1.38 to 11.50) were independent predictors associated with increased odds of survival to hospital discharge. CONCLUSION: In those aged 70 years and older, the rate of survival to hospital discharge declined with increasing age group. Younger age, an initial shockable rhythm and witnessed arrest were independent predictors of survival to hospital discharge.

Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.

Out-of-hospital cardiac arrest attended by ambulance services in Ireland: first 2†years' results from a nationwide registry.

BACKGROUND: National data collection provides information on out-of-hospital cardiac arrest (OHCA) incidence, management and outcomes that may not be generalisable from smaller studies. This retrospective cohort study describes the first 2 years' results from the Irish National Out-of-Hospital Cardiac Arrest Register (OHCAR). METHODS: Data on OHCAs attended by emergency medical services (EMS) where resuscitation was attempted (EMS-treated) were collected from ambulance services and entered onto OHCAR. Descriptive analysis of the study population was performed, and regression analysis was performed on the subgroup of adult patients with a bystander-witnessed event of presumed cardiac aetiology and an initial shockable rhythm (Utstein group). RESULTS: 3701 EMS-treated OHCAs were recorded for the study period (1 January 2012-31 December 2013). Incidence was 39/100 000 population/year. In the Utstein group (n=577), compared with the overall group, there was a higher proportion of male patients, public event location, bystander cardiopulmonary resuscitation (CPR) and early defibrillation. Median EMS call-response interval was similar in both groups. A higher proportion of patients in the Utstein group achieved return of spontaneous circulation (35% vs 17%) and survival to hospital discharge (22% vs 6%). After multivariate adjustment for the Utstein group, the following variables were found to be independent predictors of the outcome survival to hospital discharge: public event location (OR 3.1 (95% CI 1.9 to 5.0)); bystander CPR (2.4 (95% CI 1.2 to 4.9)); EMS response of 8 min or less (2.2 (95% CI 1.3 to 3.6)). CONCLUSIONS: This study highlights the role of nationwide registries in quantifying, monitoring and benchmarking OHCA incidence and outcome, providing baseline data upon which service improvement effects can be measured.

Urban overdose hotspots: a 12-month prospective study in Dublin ambulance services.

BACKGROUND: Opioid overdose (OD) is the primary cause of death among drug users globally. Personal and social determinants of overdose have been studied before, but the environmental factors lacked research attention. Area deprivation or presence of addiction clinics may contribute to overdose. OBJECTIVES: The objective of the study is to examine the baseline incidence of all new ODs in an ambulance service and their relationship with urban deprivation and presence of addiction services. METHODS: A prospective chart review of prehospital advanced life support patients was performed on confirmed OD calls. Demographic, geographic, and clinical information, that is, presentation, treatment, and outcomes, was collected for each call. The census data were used to calculate deprivation. Geographical information software mapped the urban deprivation and addiction services against the overdose locations. RESULTS: There were 469 overdoses, 13 of which were fatal; most were male (80%), of a young age (32 years), with a high rate of repeated overdoses (26%) and common polydrug use (9.6%). Most occurred in daytime (275) and on the streets (212). Overdoses were more likely in more affluent areas (r = .15; P < .05) and in a 1000-m radius of addiction services. Residential overdoses were in more deprived areas than street overdoses (mean difference, 7.8; t170 = 3.99; P < .001). Street overdoses were more common in the city center than suburbs (χ(2)(1) = 33.04; P < .001). CONCLUSIONS: The identified clusters of increased incidence-urban overdose hotspots-suggest a link between environment characteristics and overdoses. This highlights a need to establish overdose education and naloxone distribution in the overdose hotspots.

A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression.

Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.

Smoking-associated gene expression alterations in nasal epithelium reveal immune impairment linked to lung cancer risk.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, 40% of which occur more than 15 years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk remain unclear. We thus set out to examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data and to explore the mechanisms of the persisting risk in former smokers. METHODS: We analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking statuses. We developed a computational model to assess smoking-associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. RESULTS: We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune- and interferon-related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. CONCLUSIONS: Our results provide initial evidence for germline-mediated personalized smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

Accelerated waning of the humoral response to COVID-19 vaccines in obesity.

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.

Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.

Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers.

INTRODUCTION: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. METHODS: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. RESULTS: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPα, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). CONCLUSIONS: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.

Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.

The recent whole-genome scan for breast cancer has revealed the FGFR2 (fibroblast growth factor receptor 2) gene as a locus associated with a small, but highly significant, increase in the risk of developing breast cancer. Using fine-scale genetic mapping of the region, it has been possible to narrow the causative locus to a haplotype of eight strongly linked single nucleotide polymorphisms (SNPs) spanning a region of 7.5 kilobases (kb) in the second intron of the FGFR2 gene. Here we describe a functional analysis to define the causative SNP, and we propose a model for a disease mechanism. Using gene expression microarray data, we observed a trend of increased FGFR2 expression in the rare homozygotes. This trend was confirmed using real-time (RT) PCR, with the difference between the rare and the common homozygotes yielding a Wilcox p-value of 0.028. To elucidate which SNPs might be responsible for this difference, we examined protein-DNA interactions for the eight most strongly disease-associated SNPs in different breast cell lines. We identify two cis-regulatory SNPs that alter binding affinity for transcription factors Oct-1/Runx2 and C/EBPbeta, and we demonstrate that both sites are occupied in vivo. In transient transfection experiments, the two SNPs can synergize giving rise to increased FGFR2 expression. We propose a model in which the Oct-1/Runx2 and C/EBPbeta binding sites in the disease-associated allele are able to lead to an increase in FGFR2 gene expression, thereby increasing the propensity for tumour formation.

The Dublin cardiac arrest registry: temporal improvement in survival from out-of-hospital cardiac arrest reflects improved pre-hospital emergency care.

AIMS: Out-of-hospital cardiac arrest (OOHCA) survival remains poor, estimated at 3-7%. We aim to describe the incidence of OOHCA, survival from OOHCA, and the impact of improved pre-hospital care on survival from OOHCA. METHODS AND RESULTS: A retrospective registry was established using multi-source information to assess survival from cardiac arrest following the introduction of several improvements in pre-hospital emergency medical care from 2003. Survival from OOHCA, from asystole/pulseless electrical activity, and from ventricular tachycardia/ventricular fibrillation was estimated. Adjusted per 100 000 population annual incidence rates from national population census data were calculated. Mean and median emergency medical services (EMS) response times to OOHCA calls were assessed. A total of 962 OOHCAs occurred from 1 January 2003 until 31 December 2008. Sixty-nine per cent (69%, n = 664) were male. Seventy-two per cent (72%, n = 693) occurred at home with 28% occurring in a public venue. Of these public venues, 33.9% (91 of 268) had an automated external defibrillator available. Bystander cardiopulmonary resuscitation (CPR) was in progress when emergency services arrived in 11% (n = 106) of the cases. Nineteen per cent (19.4%, n = 187) had a known prior cardiac history or chest pain prior to circulatory collapse. Overall survival to hospital discharge improved significantly from 2.6 to 11.3%, P = 0.001. Survival from ventricular fibrillation (VF) to hospital admission, rose from 28.6 to 86.3%, P = 0.001. Survival to hospital discharge from VF improved from 21.4 to 33%, P = 0.007. Mean EMS response times to the scene of arrest decreased from 9.18 to 8.34 min. Emergency medical services scene time, reflecting acute pre-hospital medical care, rose from 14.46 to 18.12 min. The adjusted incidence of OOHCA for our catchment population declined from 109.4 to 88.2 per 100,000 population between 2003 and 2008. CONCLUSIONS: The incidence of OOHCA has declined but importantly, survival to hospital discharge has improved dramatically. Reduction in ambulance response time, resulting in earlier initiation of basic and advanced life support and earlier defibrillation, was associated with an increase in the proportion of victims found in VF rather than asystole and likely accounted for most of the improvement. Further improvements in response times and public education to improve bystander CPR rates should remain a priority.

Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response.

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

DNA Repair Biomarker for Lung Cancer Risk and its Correlation With Airway Cells Gene Expression.

BACKGROUND: Improving lung cancer risk assessment is required because current early-detection screening criteria miss most cases. We therefore examined the utility for lung cancer risk assessment of a DNA Repair score obtained from OGG1, MPG, and APE1 blood tests. In addition, we examined the relationship between the level of DNA repair and global gene expression. METHODS: We conducted a blinded case-control study with 150 non-small cell lung cancer case patients and 143 control individuals. DNA Repair activity was measured in peripheral blood mononuclear cells, and the transcriptome of nasal and bronchial cells was determined by RNA sequencing. A combined DNA Repair score was formed using logistic regression, and its correlation with disease was assessed using cross-validation; correlation of expression to DNA Repair was analyzed using Gene Ontology enrichment. RESULTS: DNA Repair score was lower in case patients than in control individuals, regardless of the case's disease stage. Individuals at the lowest tertile of DNA Repair score had an increased risk of lung cancer compared to individuals at the highest tertile, with an odds ratio (OR) of 7.2 (95% confidence interval [CI] = 3.0 to 17.5; P < .001), and independent of smoking. Receiver operating characteristic analysis yielded an area under the curve of 0.89 (95% CI = 0.82 to 0.93). Remarkably, low DNA Repair score correlated with a broad upregulation of gene expression of immune pathways in patients but not in control individuals. CONCLUSIONS: The DNA Repair score, previously shown to be a lung cancer risk factor in the Israeli population, was validated in this independent study as a mechanism-based cancer risk biomarker and can substantially improve current lung cancer risk prediction, assisting prevention and early detection by computed tomography scanning.

Extent of differential allelic expression of candidate breast cancer genes is similar in blood and breast.

INTRODUCTION: Normal gene expression variation is thought to play a central role in inter-individual variation and susceptibility to disease. Regulatory polymorphisms in cis-acting elements result in the unequal expression of alleles. Differential allelic expression (DAE) in heterozygote individuals could be used to develop a new approach to discover regulatory breast cancer susceptibility loci. As access to large numbers of fresh breast tissue to perform such studies is difficult, a suitable surrogate test tissue must be identified for future studies. METHODS: We measured differential allelic expression of 12 candidate genes possibly related to breast cancer susceptibility (BRCA1, BRCA2, C1qA, CCND3, EMSY, GPX1, GPX4, MLH3, MTHFR, NBS1, TP53 and TRXR2) in breast tissue (n = 40) and fresh blood (n = 170) of healthy individuals and EBV-transformed lymphoblastoid cells (n = 19). Differential allelic expression ratios were determined by Taqman assay. Ratio distributions were compared using t-test and Wilcoxon rank sum test, for mean ratios and variances respectively. RESULTS: We show that differential allelic expression is common among these 12 candidate genes and is comparable between breast and blood (fresh and transformed lymphoblasts) in a significant proportion of them. We found that eight out of nine genes with DAE in breast and fresh blood were comparable, as were 10 out of 11 genes between breast and transformed lymphoblasts. CONCLUSIONS: Our findings support the use of differential allelic expression in blood as a surrogate for breast tissue in future studies on predisposition to breast cancer.

Reliability, Validity and Utility of Inertial Sensor Systems for Postural Control Assessment in Sport Science and Medicine Applications: A Systematic Review.

BACKGROUND: Recent advances in mobile sensing and computing technology have provided a means to objectively and unobtrusively quantify postural control. This has resulted in the rapid development and evaluation of a series of wearable inertial sensor-based assessments. However, the validity, reliability and clinical utility of such systems is not fully understood. OBJECTIVES: This systematic review aims to synthesise and evaluate studies that have investigated the ability of wearable inertial sensor systems to validly and reliably quantify postural control performance in sports science and medicine applications. METHODS: A systematic search strategy utilising the PRISMA guidelines was employed to identify eligible articles through ScienceDirect, Embase and PubMed databases. In total, 47 articles met the inclusion criteria and were evaluated and qualitatively synthesised under two main headings: measurement validity and measurement reliability. Furthermore, studies that investigated the utility of these systems in clinical populations were summarised and discussed. RESULTS: After duplicate removal, 4374 articles were identified with the search strategy, with 47 papers included in the final review. In total, 28 studies investigated validity in healthy populations, and 15 studies investigated validity in clinical populations; 13 investigated the measurement reliability of these sensor-based systems. CONCLUSIONS: The application of wearable inertial sensors for sports science and medicine postural control applications is an evolving field. To date, research has primarily focused on evaluating the validity and reliability of a heterogeneous set of assessment protocols, in a laboratory environment. While researchers have begun to investigate their utility in clinical use cases such as concussion and musculoskeletal injury, most studies have leveraged small sample sizes, are of low quality and use a variety of descriptive variables, assessment protocols and sensor-mounting locations. Future research should evaluate the clinical utility of these systems in large high-quality prospective cohort studies to establish the role they may play in injury risk identification, diagnosis and management. This systematic review was registered with the International Prospective Register of Systematic Reviews on 10 August 2018 (PROSPERO registration: CRD42018106363): https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=106363 .

Capturing concussion related changes in dynamic balance using the Quantified Y Balance Test - a case series of six elite rugby union players.

Concussion is one of the most common injuries reported across a myriad of sports. Recent evidence suggests that individuals may possess sensorimotor deficits beyond clinical recovery, predisposing them to further injury. This preliminary prospective case series aimed to determine if an inertial sensor instrumented Y balance test can capture changes in dynamic balance, regardless of apparent `clinical recovery', in six concussed elite rugby union players. The findings from this case series demonstrate that the inertial sensor-based measures can detect clinically meaningful changes in dynamic balance performance, not captured by the traditional clinical scoring methods, 48-hours post-injury and at the point of `clinical recovery' (return to play). Further research should investigate the role such instrumented dynamic balance assessments may play in the management of sports-related concussion.

Evaluating the use of machine learning in the assessment of joint angle using a single inertial sensor.

INTRODUCTION: Joint angle measurement is an important objective marker in rehabilitation. Inertial measurement units may provide an accurate and reliable method of joint angle assessment. The objective of this study was to assess whether a single sensor with the application of machine learning algorithms could accurately measure hip and knee joint angle, and investigate the effect of inertial measurement unit orientation algorithms and person-specific variables on accuracy. METHODS: Fourteen healthy participants completed eight rehabilitation exercises with kinematic data captured by a 3D motion capture system, used as the reference standard, and a wearable inertial measurement unit. Joint angle was calculated from the single inertial measurement unit using four machine learning models, and was compared to the reference standard to evaluate accuracy. RESULTS: Average root-mean-squared error for the best performing algorithms across all exercises was 4.81° (SD = 1.89). The use of an inertial measurement unit orientation algorithm as a pre-processing step improved accuracy; however, the addition of person-specific variables increased error with average RMSE 4.99° (SD = 1.83°). CONCLUSIONS: Hip and knee joint angle can be measured with a good degree of accuracy from a single inertial measurement unit using machine learning. This offers the ability to monitor and record dynamic joint angle with a single sensor outside of the clinic.