In the heat of the moment: the effects of extreme temperatures on the cognitive functioning of firefighters.

Exposure to high temperatures can have detrimental effects on cognitive processing and this is concerning for firefighters who routinely work in extreme temperatures. Whilst past research has studied the effects of heat on firefighter cognition, findings are mixed, and no work has measured the time course of cognitive recovery. This study compared working memory, vigilance, and cognitive flexibility of 37 firefighters before and after they engaged in a live-fire training exercise with temperatures exceeding 115 °C. To assess recovery, cognition was measured on exiting the fire, then 20- and 40-minutes post-fire. Results showed impaired vigilance and cognitive flexibility (increased errors, slower responses) immediately after the fire, but recovery at 20-minutes. These findings indicate that a live indoor fire negatively impacts cognitive processing, but this effect is relatively short-lived and return to baseline functioning is seen 20-minutes after exiting the fire. The findings could be used to inform re-entry and cooling decisions.

Acute heat stress may affect cognitive processing, posing a health and safety risk to firefighters. This study demonstrates impaired cognition following a firefighter training exercise in temperatures exceeding 115 °C. Cognition recovered as core body temperature returned to normal, providing evidence for a 20-minute cooling period following exposure to extreme heat.

Does resistance training ameliorate cancer-related fatigue in cancer survivors? A systematic review with meta-analysis.

PURPOSE: Cancer-related fatigue (CRF) is unrelenting. As neither rest nor sleep ameliorates cognitive, emotional, and physical symptoms, quality of life is diminished. This study examines resistance training (RT) effectiveness on CRF in cancer survivors. The secondary aims were to identify the dose-response relationship of RT frequency, intensity, and volume on CRF in different cancer survivor populations. MATERIALS AND METHODS: Systematic searches via numerous databases for RCTs were performed in June 2022. Patient-reported outcome measures (PROM), were analysed, pre-to-post intervention, using a random-effects model. The Physiotherapy Evidence Database (PEDro) scale informed methodological quality assessment. RESULTS: Eight studies were included (cancer survivors: breast (BCS) = 5; endometrial (ECS) = 1; prostate (PCS) = 2). Overall, RT interventions ≥ 6 weeks elicited large significant reductions in CRF for FACIT-F (SMD = 0.932, p = <0.001) and moderate significant reductions in CRF for PFS-R (SMD = -0.622, p = 0.004). CONCLUSION: Main findings indicate that RT ameliorates CRF, especially in BCS; however, individualised approaches should be advocated. Supervised training elicited the greatest positive outcomes, thus should be a pivotal part of the cancer rehabilitation pathway. Future studies should be adequately powered, undertake discrete analyses of different cancer types, and investigate chronic RT effects.

Cancer-related fatigue (CRF) is debilitating and distressing, leading to reduced quality of life and function in cancer survivors.Considerable heterogeneity exists in disease histology and clinical patient presentation.Individualised resistance training (RT) is an effective, safe, and accessible intervention to mitigat:e fatigue levels, thus aid function, most notably in breast cancer survivors.

The relationship between psychological, cognitive, and contextual factors and rehabilitation outcomes in Achilles tendinopathy: A prospective feasibility cohort study.

OBJECTIVES: This study aimed to investigate the feasibility of conducting a full-scale study investigating the influence of patient-related factors on rehabilitation outcomes in Achilles tendinopathy (AT). A secondary aim was to investigate preliminary relationships between patient-related factors and clinical outcomes at 12- and 26- weeks. DESIGN: feasibility cohort. SETTING: Australian healthcare settings. METHODS: Participants with AT receiving physiotherapy in Australia were recruited via treating physiotherapists and online. Data were collected online at baseline, 12- and 26-weeks. Progression criteria for a full-scale study were recruitment rate of ≥10 per month, conversion rate ≥20%, and response rate to questionnaires ≥80%. The relationship between patient-related factors and clinical outcomes was investigated using Spearman's rho correlation coefficient. RESULTS: The average recruitment rate was 5/month, conversion rate was 97%, and response rate to questionnaires was ≥97% at all timepoints. There was a fair to moderate correlation (rho = 0.225 to 0.683) between patient-related factors and clinical outcomes at the 12-week, but no to weak correlation at the 26-week (rho = 0.002 to 0.284). CONCLUSIONS: Feasibility outcomes suggest a future full-scale cohort study is feasible with the caveat of utilizing strategies to improve recruitment rate. Preliminary bivariate correlations at 12-weeks warrant further investigations in larger studies.

Do extreme temperatures affect cognition? A short review of the impact of acute heat stress on cognitive performance of firefighters.

Research shows that exposure to high environmental temperatures can affect task performance. Theoretical explanations outline that heat is a source of stress that competes for limited-capacity resources, therefore if a task is resource-intensive, and/or if heat stress is extreme, performance will suffer. One occupation in which individuals complete demanding tasks and make difficult decisions, often in temperatures exceeding 200°C, is firefighting. Yet very little is currently known about the impact of heat stress on the cognitive functioning of firefighters. This short review summarizes the limited research in this area, focusing on studies that measured cognition of firefighters following a realistic training exercise. The findings are mixed with evidence that heat stress improves, impairs, and has no impact on cognitive functioning. While there are differences in the firefighting activities utilized, and the temperatures that participants were exposed to, it is argued that the varied findings can be attributed to the tasks used to assess cognitive processing, and the cognitive functions being measured. In accordance with the wider field of research, it is concluded that complex functioning, such as sustained attention, vigilance, and working memory is negatively impacted by acute exposure to extreme heat. Greater understanding of factors affecting cognition would inform safety practices and more research is needed to understand how and when heat stress may influence cognition in firefighting scenarios.

The effect of resistance training on functional capacity in middle-aged to elderly individuals with peripheral artery disease: a meta-analysis.

INTRODUCTION: Peripheral artery disease (PAD) is an ischemic disease of the lower limbs, caused by atherosclerotic plaques, leading to impairments in functional capacity and reduced quality of life. This meta-analysis aimed to assess the effect of 12-week and 24-week resistance training (RT) interventions on 6-minute walking distance (6WMD) and initial claudication distance (ICD) measured during a 6-minute walk test (6MWT). EVIDENCE ACQUISITION: A meta-analysis was conducted in accordance with PRISMA guidelines, with an electronic search conducted using the online database of PUBMED. Methodological quality of all included studies was completed using a modified version of the Newcastle Ottawa Scale (NOS). The effect sizes (ES) of 6MWD and ICD were calculated, with the 12-week and 24-week interventions analyzed separately. EVIDENCE SYNTHESIS: An initial literature search yielded 1973 results that were consequently reduced to 7 studies to be included in the final meta-analysis. The pooled effect size for 6MWD for 12-week and 24-week interventions was ES=0.189 [95% CI: -0.074 to 0.451] P=0.159 and ES=0.298 [95% CI: -0.036 to 0.631] P=0.080 respectively. For ICD, ES=0.498 [95% CI: 0.000 to 0.995] P=0.050 and ES: 1.106 [95% CI: 0.120 to 0.428] P=0.001 respectively. CONCLUSIONS: Short-term RT interventions have a positive effect on functional capacity in middle-aged to elderly individuals with PAD. There was a greater effect on ICD compared to 6MWD, with 24-week interventions showing larger effects for both measures. Improvements in functional capacity in such populations confers significant potential for positive health outcomes.

Comparisons of Core Temperature Between a Telemetric Pill and Heart Rate Estimated Core Temperature in Firefighters.

Background: Firefighters may experience high environmental temperatures or carry out intensive physical tasks, or both, which leads to increased core body temperature and risk of fatalities. Hence there is a need to remotely and non-invasively monitor core body temperature. Methods: Estimated (heart rate algorithm) and actual core body temperature (ingested telemetric pill) measures were collected simultaneously for comparison during training exercises on 44 firefighter volunteers. Results: Prediction of core body temperature varied, with no specific identifiable pattern between the algorithm values and directly measured body core temperatures. Group agreement of Lin's Concordance of 0.74 (95% Upper 0.75, lower CI 0.73), was deemed poor. Conclusion: From individual agreement data Lin's Concordance was variable (Min 0.11, CI 0.13-0.01; Max 0.83, CI 0.86-0.80), indicating that the heart rate algorithm approach was not suitable for core body temperature monitoring in this population group, especially at the higher more critical core body temperatures seen.

The acute effects of higher versus lower load duration and intensity on morphological and mechanical properties of the healthy Achilles tendon: a randomized crossover trial.

The Achilles tendon (AT) exhibits volume changes related to fluid flow under acute load which may be linked to changes in stiffness. Fluid flow provides a mechanical signal for cellular activity and may be one mechanism that facilitates tendon adaptation. This study aimed to investigate whether isometric intervention involving a high level of load duration and intensity could maximize the immediate reduction in AT volume and stiffness compared with interventions involving a lower level of load duration and intensity. Sixteen healthy participants (12 males, 4 females; age 24.4±9.4 years, body mass 70.9±16.1 kg, height 1.7±0.1 m) performed three isometric interventions of varying levels of load duration (2 s and 8 s) and intensity (35% and 75% maximal voluntary isometric contraction) over a 3 week period. Freehand 3D ultrasound was used to measure free AT volume (at rest) and length (at 35%, 55% and 75% of maximum plantarflexion force) pre- and post-interventions. The slope of the force-elongation curve over these force levels represented individual stiffness (N mm-1). Large reductions in free AT volume and stiffness resulted in response to long-duration high-intensity loading whilst less reduction was produced with a lower load intensity. In contrast, no change in free AT volume and a small increase in AT stiffness occurred with lower load duration. These findings suggest that the applied load on the AT must be heavy and sustained for a long duration to maximize immediate volume reduction, which might be an acute response that enables optimal long-term tendon adaptation via mechanotransduction pathways.

Hypocalcaemia in pharyngolaryngectomy: Preservation or autotransplantation of parathyroid glands.

OBJECTIVE: To describe transient and permanent hypocalcaemia following partial and total pharyngolaryngectomy with parathyroid gland preservation or autotransplantation. METHODS: Thirty patients underwent partial or total pharyngolaryngectomy by a single surgeon during the period 2009-2020. Intraoperative parathyroid gland preservation or autotransplantation (where the gland appeared devascularized) was routinely performed. Calcium levels performed on day 1, 3 months, and at 12 months postoperatively were collected. Rates of transient and permanent hypocalcaemia were calculated. RESULTS: A total of 13% of patients had transient hypocalcaemia, and 10% permanent hypocalcaemia. Rates of transient and permanent hypocalcaemia in total pharyngolaryngectomy were 14% and 14%, respectively. Partial pharyngectomy hypocalcaemia rates were 13% for transient and 0% for permanent. The majority of patients underwent salvage surgery for oncological resection, often following radiotherapy (63%). Ipsilateral hemithyroidectomy was preferred to total (57% vs 7%), with high rates of concurrent neck dissection (67%) and reconstruction (87%). CONCLUSION: This data supports preservation or autotransplantation of parathyroid glands as a means of reducing permanent postoperative hypocalcaemia. LEVEL OF EVIDENCE: Level IV, case series, retrospective.

Glutathione-coordinated metal complexes as substrates for cellular transporters.

Glutathione is the major thiol-containing species in both prokaryotes and eukaryotes and plays a wide variety of roles, including detoxification of metals by sequestration, reduction, and efflux. ABC transporters such as MRP1 and MRP2 detoxify the cell from certain metals by exporting the cations as a metal-glutathione complex. The ability of the bacterial Atm1 protein to efflux metal-glutathione complexes appears to have evolved over time to become the ABCB7 transporter in mammals, located in the inner mitochondrial membrane. No longer needed for the role of cellular detoxification, ABCB7 appears to be used to transport glutathione-coordinated iron-sulfur clusters from mitochondria to the cytosol.

Immediate and long-term effects of mechanical loading on Achilles tendon volume: A systematic review and meta-analysis.

The Achilles tendon (AT) may experience changes in dimensions related to fluid flow under load. The extent to which fluid flow involves redistribution within or flow out of the tendon is not known and could be determined by investigating volume changes. This study aimed to synthesize data on immediate and long-term effects of loading on tendon volume among people with a healthy AT and midportion Achilles tendinopathy (MAT). A secondary aim was to synthesise data from the included studies investigating parallel change in cross-sectional area and length. Systematic electronic search was performed in MEDLINE, EMBASE, CINAHL, AMED, and Scopus from inception until May 2020. Standardized mean differences (SMDs) were calculated for intervention-induced changes from baseline for all outcomes. Methodological quality was assessed using modified version of Newcastle Ottawa Scale (NOS). Twelve studies were included in meta-analysis. For healthy AT, there were negligible to small changes in volume following cross-country running (-0.33 [95% CI = -1.11 to 0.45] (P = 0.41)) and isometric exercise (0.01 [95% CI = -0.54 to 0.55] (P = 0.98)) and a large increase at the short-term with 12-week isometric protocol (0.88 [95% CI = -0.10 to1.86] (P = 0.08)). For MAT, there was an immediate large reduction in volume with isometric exercise (-1.24 [95% CI = -1.93 to -0.55] (P = 0.0004)), small increase with eccentric exercise (0.41 [95% CI = -0.18 to 1.01](P = 0.18)) and small reduction at the short-term with long-term interventions (-0.46 [95% CI = -0.87 to -0.05] (P = 0.03)). This meta-analysis suggests that healthy AT remain isovolumetric with acute interventions while MAT exhibit immediate and short-term volume reductions in response to different interventions.

Reliability of Human Achilles Tendon Stiffness Measures Using Freehand 3-D Ultrasound.

Achilles tendon (AT) stiffness is an important property of both human locomotor performance and injury mechanics. Freehand 3-D ultrasound (3-DUS) is a promising method for measuring stiffness of the Achilles tendon, particularly the free AT (2-6 cm proximal to calcaneus), which is commonly injured. The aim of this study was to investigate the test-retest reliability of freehand 3-DUS in measuring free AT stiffness in humans. The free Achilles tendon length of healthy participants (n = 10) was scanned on the same day on two consecutive occasions (1 h apart) during rest and isometric plantar flexion contractions at 20%, 40% and 60% of maximum force. The slope of the force-elongation curve over these force levels represented individual stiffness (N/mm). Relative reliability was assessed using the intra-class correlation coefficient (ICC), and absolute reliability was estimated with the standard error of measurement (SEM) and smallest detectable change. Systematic bias in stiffness measures was explored by comparing test and retest distributions and Bland-Altman plots. The test-retest reliability of free AT stiffness measured using freehand 3-DUS was excellent [ICC = 0.994, 95% confidence interval [CI]: 0.978-0.999)]. The mean stiffness values at test (361.83 N/mm [170.77]) and retest (364.98 N/mm [168.57]) did not significantly differ (p = 0.72), and the smallest detectable change was 52.14 N/mm. The Bland-Altman plot indicated the absence of systematic bias (95% CI: -22.18 to 15.88). Freehand 3-DUS provides reliable and precise measures of tendon stiffness and can be used to detect small changes in free AT stiffness in response to load or tendon pathology.

Early Detection of Alzheimer's Disease with Blood Plasma Proteins Using Support Vector Machines.

The successful development of amyloid-based biomarkers and tests for Alzheimer's disease (AD) represents an important milestone in AD diagnosis. However, two major limitations remain. Amyloid-based diagnostic biomarkers and tests provide limited information about the disease process and they are unable to identify individuals with the disease before significant amyloid-beta accumulation in the brain develops. The objective in this study is to develop a method to identify potential blood-based non-amyloid biomarkers for early AD detection. The use of blood is attractive because it is accessible and relatively inexpensive. Our method is mainly based on machine learning (ML) techniques (support vector machines in particular) because of their ability to create multivariable models by learning patterns from complex data. Using novel feature selection and evaluation modalities, we identified 5 novel panels of non-amyloid proteins with the potential to serve as biomarkers of early AD. In particular, we found that the combination of A2M, ApoE, BNP, Eot3, RAGE and SGOT may be a key biomarker profile of early disease. Disease detection models based on the identified panels achieved sensitivity (SN) > 80%, specificity (SP) > 70%, and area under receiver operating curve (AUC) of at least 0.80 at prodromal stage (with higher performance at later stages) of the disease. Existing ML models performed poorly in comparison at this stage of the disease, suggesting that the underlying protein panels may not be suitable for early disease detection. Our results demonstrate the feasibility of early detection of AD using non-amyloid based biomarkers.

Evolution of the human mitochondrial ABCB7 [2Fe-2S](GS)4 cluster exporter and the molecular mechanism of an E433K disease-causing mutation.

Iron-sulfur cluster proteins play key roles in a multitude of cellular processes. Iron-sulfur cofactors are assembled primarily in mitochondria and are then exported to the cytosol by use of an ABCB7 transporter. It has been shown that the yeast mitochondrial transporter Atm1 can export glutathione-coordinated iron-sulfur clusters, [2Fe-2S](SG)4, providing a source of cluster units for cytosolic iron-sulfur cluster assembly systems. This pathway is consistent with the endosymbiotic model of mitochondrial evolution where homologous bacterial heavy metal transporters, utilizing metal glutathione adducts, were adapted for use in eukaryotic mitochondria. Herein, the basis for endosymbiotic evolution of the human cluster export protein (ABCB7) is developed through a BLAST analysis of transporters from ancient proteobacteria. In addition, a functional comparison of native human protein, versus a disease-causing mutant, demonstrates a key role for residue E433 in promoting cluster transport. Dysfunction in mitochondrial export of Fe-S clusters is a likely cause of the disease condition X-linked sideroblastic anemia.

Defining the mechanism of the mitochondrial Atm1p [2Fe-2S] cluster exporter.

Iron-sulfur cluster proteins play key roles in a multitude of physiological processes; including gene expression, nitrogen and oxygen sensing, electron transfer, and DNA repair. Biosynthesis of iron-sulfur clusters occurs in mitochondria on iron-sulfur cluster scaffold proteins in the form of [2Fe-2S] cores that are then transferred to apo targets within metabolic or respiratory pathways. The mechanism by which cytosolic Fe-S cluster proteins mature to their holo forms remains controversial. The mitochondrial inner membrane protein Atm1p can transport glutathione-coordinated iron-sulfur clusters, which may connect the mitochondrial and cytosolic iron-sulfur cluster assembly systems. Herein we describe experiments on the yeast Atm1p/ABCB7 exporter that provide additional support for a glutathione-complexed cluster as the natural physiological substrate and a reflection of the endosymbiotic model of mitochondrial evolution. These studies provide insight on the mechanism of cluster transport and the molecular basis of human disease conditions related to ABCB7. Recruitment of MgATP following cluster binding promotes a structural transition from closed to open conformations that is mediated by coupling helices, with MgATP hydrolysis facilitating the return to the closed state.

Adaptation of Tendon Structure and Function in Tendinopathy With Exercise and Its Relationship to Clinical Outcome.

CONTEXT: Exercise is seen as the most evidence-based treatment for managing tendinopathy and although the type of exercise used to manage tendinopathy may induce adaptation in healthy tendons, it is not clear whether these adaptations occur in tendinopathy and if so whether they are associated with improved clinical outcomes. OBJECTIVE: The aim of the study was to synthesize available evidence for adaptation of the Achilles tendon to eccentric exercise and the relationship between adaptation (change in tendon thickness) and clinical outcomes among people with Achilles tendinopathy. EVIDENCE ACQUISITION: The search was performed in September 2018 in several databases. Studies investigating the response (clinical outcome and imaging on ultrasound/magnetic resonance imaging) of pathological tendons (tendinopathy, tendinosis, and partial rupture) to at least 12 weeks of eccentric exercise were included. Multiple studies that investigated the same interventions and outcome were pooled and presented in effect size estimates, mean difference, and 95% confidence intervals if measurement scales were the same, or standard mean difference and 95% confidence intervals if measurements scales were different. Where data could not be pooled the studies were qualitatively synthesized based on van Tulder et al. EVIDENCE SYNTHESIS: Eight studies met the inclusion and exclusion criteria and were included in the review. There was strong evidence that Achilles tendon thickness does not decrease in parallel with improved clinical outcomes. CONCLUSIONS: Whether a longer time to follow-up is more important than the intervention (ie, just the time per se) for a change in tendon thickness remains unknown. Future studies should investigate whether exercise (or other treatments) can be tailored to optimize tendon adaptation and function, and whether this relates to clinical outcomes.

Immediate and Short-Term Effects of Short- and Long-Duration Isometric Contractions in Patellar Tendinopathy.

OBJECTIVES: Isometric muscle contractions are used in the management of patellar tendinopathy to manage pain and improve function. Little is known about whether long- or short-duration contractions are optimal to improve pain. This study examined the immediate and short-term (4 weeks) effects of long- and short-duration isometric contraction on patellar tendon pain, and tendon adaptation. DESIGN: Repeated measures within groups. SETTING: Clinical primary care. PATIENTS: Participants (n = 16, males) with patellar tendinopathy. INTERVENTION: Short-duration (24 sets of 10 seconds) or long-duration (6 sets of 40 seconds) isometric knee extension loading (85% maximal voluntary contraction), for 4 weeks. MAIN OUTCOME MEASURE: Immediate change in pain with single-leg decline squat (SLDS) and hop, as well as change in pain and tendon adaptation [within-session anterior-posterior (AP) strain] were assessed over 4 weeks. RESULTS: Pain was significantly reduced after isometric loading on both SLDS (P < 0.01) and hop tests (P < 0.01). Pain and quadriceps function improved over the 4 weeks (P < 0.05). There was significant AP strain at each measurement occasion (P < 0.01). Although transverse strain increased across the training period from ∼14% to 22%, this was not significant (P = 0.08). CONCLUSIONS: This is the first study to show that short-duration isometric contractions are as effective as longer duration contractions for relieving patellar tendon pain when total time under tension is equalized. This finding provides clinicians with greater options in prescription of isometric loading and may be particularly useful among patients who do not tolerate longer duration contractions. The trend for tendon adaptation over the short 4-week study period warrants further investigation.

Breath-based non-invasive diagnosis of Alzheimer's disease: a pilot study.

Early detection of Alzheimer's disease (AD) will help researchers to better understand the disease and develop improved treatments. Recent developments have thus focused on identifying biomarkers for mild cognitive impairment due to AD (MCI) and AD during the preclinical phase. The aim of this pilot study is to determine whether exhaled volatile organic compounds (VOCs) can be used as a non-invasive method to distinguish controls from MCI, controls from AD and to determine whether there are differences between MCI and AD. The study used gas chromatography-ion mobility spectrometry (GC-IMS) techniques. Confounding factors, such as age, smoking habits, gender and alcohol consumption are investigated to demonstrate the efficacy of results. One hundred subjects were recruited including 50 controls, 25 AD and 25 MCI patients. The subject cohort was age- and gender-matched to minimise bias. Breath samples were analysed using a commercial GC-IMS instrument (G.A.S. BreathSpec, Dortmund, Germany). Data analysis indicates that the GC-IMS signal was consistently able to separate between diagnostic groups [AUC ± 95%, sensitivity, specificity], controls versus MCI: [0.77 (0.64-0.90), 0.68, 0.80], controls versus AD: [0.83 (0.72-0.94), 0.60, 0.96], and MCI versus AD: [0.70 (0.55-0.85), 0.60, 0.84]. VOC analysis indicates that six compounds play a crucial role in distinguishing between diagnostic groups. Analysis of possible confounding factors indicate that gender, age, smoking habits and alcohol consumption have insignificant influence on breath content. This pilot study confirms the utility of exhaled breath analysis to distinguish between AD, MCI and control subjects. Thus, GC-IMS offers great potential as a non-invasive, high-throughput, diagnostic technique for diagnosing and potentially monitoring AD in a clinical setting.

Maternal Mortality due to Eclampsia in Khyber Pakhtunkhwa: Identifying Underlying Risk Factors, and Care-seeking Behaviours.

OBJECTIVE: To identify the characteristics of women at risk of death due to eclampsia, and steps to improve maternal outcome. METHODS: This study is a part of a retrospective study conducted in 2016 and included Mansehra, Swabi, Haripur, Nowshera, Kohat, and Dera Ismail Khan districts of the Khyber Pakhtunkhwa province of Pakistan, and used information cited by a 2016 study to estimate the maternal mortality rate in the province based on data pertaining to the 2013-14 period. The Maternal Death from Informants / Maternal Death Follow-on Review method was applied to identify the magnitude, causes and circumstances of maternal deaths in the province. SPSS 21 was used for data analysis. RESULTS: Of the 958 cases of maternal death identified, 167(17%) were related to eclampsia. The median age of such women was 28 years (interquartile range: 11 years). Of them, 88 (53%) died undelivered, 48 (29%) had a live birth while 31 (18%) had a stillbirth or abortion. Mothers aged 25 years or above (p<0.01), primiparous (p<0.01) and those with a previous history of stillbirth (p<0.005) carried higher risk, while higher socioeconomic status had a protective effect (p<0.007). CONCLUSIONS: Eclampsia deaths can be prevented through Continuum of Care approach and by ensuring provision of basic health facilities across the board.

Machine-learning based identification of undiagnosed dementia in primary care: a feasibility study.

BACKGROUND: Up to half of patients with dementia may not receive a formal diagnosis, limiting access to appropriate services. It is hypothesised that it may be possible to identify undiagnosed dementia from a profile of symptoms recorded in routine clinical practice. AIM: The aim of this study is to develop a machine learning-based model that could be used in general practice to detect dementia from routinely collected NHS data. The model would be a useful tool for identifying people who may be living with dementia but have not been formally diagnosed. DESIGN & SETTING: The study involved a case-control design and analysis of primary care data routinely collected over a 2-year period. Dementia diagnosed during the study period was compared to no diagnosis of dementia during the same period using pseudonymised routinely collected primary care clinical data. METHOD: Routinely collected Read-encoded data were obtained from 18 consenting GP surgeries across Devon, for 26 483 patients aged >65 years. The authors determined Read codes assigned to patients that may contribute to dementia risk. These codes were used as features to train a machine-learning classification model to identify patients that may have underlying dementia. RESULTS: The model obtained sensitivity and specificity values of 84.47% and 86.67%, respectively. CONCLUSION: The results show that routinely collected primary care data may be used to identify undiagnosed dementia. The methodology is promising and, if successfully developed and deployed, may help to increase dementia diagnosis in primary care.

Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial.

BACKGROUND: Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. RESULTS: In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus, we measure interferon (IFN) status, anti-IL-6 drug exposure, and whole blood genome-wide gene expression at three time points. We show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point. We observe a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure and find many novel interactions that have not been previously described. Finally, we find transcription factor binding motifs interrupted by eQTL interaction SNPs, which point to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. CONCLUSIONS: This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.