Mapping high-grade glioma immune infiltration to 5-ALA fluorescence levels: TCGA data computation, classical histology, and digital image analysis.

PURPOSE: Resection of high-grade gliomas has been considerably improved by 5-aminolevulinic acid (5-ALA). However, not all neurobiological properties of 5-ALA are fully understood. Specifically, potential differences in immune infiltration have not been conclusively examined, despite recent reports that immune cells might play a role. Thus, we here provide a systematic mapping of immune infiltration of different 5-ALA fluorescence levels. METHODS: Tumor-associated macrophages (CD68, CD163), cytotoxic T cells (CD8), and regulatory T cells (FoxP3) were quantified via three methods. First, data from The Cancer Genome Atlas (TCGA) of 172 patients was examined for correlations between 5-ALA fluorescence-related mRNA expression signatures and immune markers. Second, as classical histology, 508 stained slides from 39 high-grade glioma patients were analysed semi-quantitatively by two independent reviewers, generating 1016 data points. Third, digital image analysis was performed with automated scanning and algorithm-based cell quantification. RESULTS: TCGA mRNA data from 172 patients showed a direct, significant correlation between 5-ALA signatures and immune markers (p < 0.001). However, we were not able to confirm this finding in the here studied initial set of 39 patient histologies where we found a comparable immune infiltration in different fluorescence levels. Digital image analysis correlated excellently with standard histology. CONCLUSION: With mapping the immune infiltration pattern of different 5-ALA categories, we are adding fundamental basic insights to the field of 5-ALA and glioma biology. The observation that a significant correlation in TCGA data did not fully translate to detectable differences in immune infiltration in first histology data warrants further investigation in larger cohorts.

Mental health in clinically referred children and young people before and during the Covid-19 pandemic.

The Covid-19 pandemic and mitigation approaches, including lockdowns and school closures, are thought to have negatively impacted children and young people's (CYP) mental health. However, the impact for clinically referred CYP is less clear. We investigated differences in the mental health of CYP referred to specialist Child and Adolescent Mental Health Services (CAMHS) before and since the onset of the pandemic. Using baseline data (self- and parent- completed Mood and Feelings Questionnaire and Strengths and Difficulties Questionnaire) from an ongoing RCT (STADIA; ISRCTN: 15748675) in England involving 5-17-year-olds with emotional difficulties recently referred to CAMHS (non-urgent referrals), with repeated cross-sectional comparisons of CYP (n = 1028) recruited during 5 different time  periods: (1) Before schools were closed (Group 1 (pre-pandemic); n = 308; 27.08.2019-20.03.2020). (2) Early pandemic period until schools fully re-opened, which included the first national lockdown, its easing and the summer holidays (Group 2 (in-pandemic); n = 183; 21.03.2020-31.08.2020). (3) The following school-term-schools fully re-opened and remained open, including during the second national lockdown (Group 3 (in-pandemic); n = 204; 01.09.2020-18.12.2020). (4) Schools closed as part of the third national lockdown (Group 4 (in-pandemic); n = 101; 05.01.2021-07.03.2021). (5) Schools re-opened and remained open, until the school summer holidays (Group 5 (in-pandemic); n = 232; 08.03.2021-16.07.2021). Most CYP scored above cutoff for emotional problems and depression, with three-quarters meeting criteria for a probable disorder ('caseness'). The groups did not differ on parent-rated mental health measures. However, self-rated emotional problems, depression, functional impairment and caseness appeared to be higher amongst participants recruited in the two periods following school re-openings. In particular, functional impairment and caseness were greater in Group 5 compared with Group 2. Although symptom severity or impairment did not change in the initial pandemic period, self-reported difficulties were greater during the periods after schools re-opened. This suggests possible greater stresses in the adjustment to re-starting school following recurrent lockdowns and school closures.

One size does not fit all: Impact of hand size on ease of use of instruments for minimally invasive surgery.

BACKGROUND: Consideration of ergonomic factors is important for the practice of safe and efficient minimally invasive surgery (MIS). Surgeons with smaller glove sizes have previously been reported to have increased difficulties with some minimally invasive instruments. We aim to investigate hand anthropometrics and their relationship to surgeon comfort when using MIS instruments. METHODS: Male and female surgeons from two centres were surveyed on their experience of handling MIS instruments and images obtained of the dorsal and palmar aspects of their dominant hand. Photographs of hands were transformed to calibrated coordinates to enable anthropometric measurements of finger length and width as well as palm width and hand span photogrammetrically. Surgeon-perceived discomfort, fatigue, pressure points and techniques to mitigate difficulty handling instruments were compared to hand measurements. RESULTS: Questionnaires were completed by 58 surgeons; 20 (34%) were consultants, 17 (29%) were women. Glove size ranged from 6 to 8 (median 7.5). Male participants had significantly larger hands than females in all measured dimensions. Female surgeons and those with smaller finger and hand dimensions were significantly more likely to experience difficulty or discomfort across a range of variables when using MIS instruments. CONCLUSIONS: Surgeons with smaller hands reported increased problems handling MIS instruments. This represents an issue of equity in surgery, with women being more significantly affected than men. Hand size varies greatly between surgeons and anthropometric variability should be considered in design of MIS instruments.

U can't touch this! Face touching behaviour whilst driving: implications for health, hygiene and human factors.

Analysis of thirty-one hours of video-data documenting 36 experienced drivers highlighted the prevalence of face-touching, with 819 contacts identified (mean frequency: 26.4 face touches/hour (FT/h); mean duration: 3.9-seconds). Fewer face-touches occurred in high primary workload conditions (where additional physical/cognitive demands were placed on drivers), compared to low workload (4.4 and 26.1 FT/h, respectively). In 42.5% of touches (or 11.2 FT/h), mucous membrane contact was made, with fingertips (33.1%) and thumbs (35.6%) most commonly employed. Individual behaviours differed (ranging from 5.1 to 90.7 FT/h), but there were no significant differences identified between genders, age-groups or hand used. Results are of relevance from an epidemiological/hygiene perspective within the context of the COVID-19 pandemic (and can therefore inform the design of practical solutions and encourage behavioural change to reduce the risk of self-inoculation while driving), but they also help to elucidate how habitual human behaviours are imbricated with the routine accomplishment of tasks.

Practitioner summary: The study highlights the propensity of face touching whilst driving through the analysis of on-road video datasets. Results have implications for the design of technological interventions (such as touchless interfaces and driver monitoring systems) and can inform awareness campaigns to reduce the risk of self-inoculation and infection transmission while driving.

Frontiers in human factors: integrating human factors and ergonomics to improve safety and quality in Latin American healthcare systems.

BACKGROUND: The importance of human factors/ergonomics (HFE) is well established in all high-reliability systems but only applied in the healthcare sector relatively recently. Across many sectors, low-/middle-income countries (LMICs) lag behind more economically developed countries in their application of this safety science, due to resource and, in some cases, awareness and expertise. Most previous applications of HFE related to occupational ergonomics rather than healthcare safety. METHODS: The paper details how the reputation of HFE is being developed within healthcare communities of Latin America (LatAm), through increasing awareness and understanding of its role as safety science in the healthcare sector. It starts by articulating the need for HFE and then provides examples from Mexico, Colombia and Peru. RESULTS: The practical examples for research and education illustrate a developing awareness of the relevance of HFE to the healthcare sectors in LatAm and an appreciation of its worth to improve health service quality and patient safety through healthcare community engagement. A new LatAm Network of HFE in Healthcare Systems (RELAESA) was formed in 2019, which has provided a platform for HFE advice during the COVID-19 pandemic. CONCLUSION: There is a real opportunity in LatAm and other LMIC health services to make more rapid and sustainable progress in healthcare-embedded HFE than has been experienced within healthcare services of more developed nations.

Health Care Professionals' Views on Using Remote Measurement Technology in Managing Central Nervous System Disorders: Qualitative Interview Study.

BACKGROUND: Remote measurement technologies (RMT) can be used to collect data on a variety of bio-behavioral variables, which may improve the care of patients with central nervous system disorders. Although various studies have explored their potential, prior work has highlighted a knowledge gap in health care professionals' (HCPs) perceptions of the value of RMT in clinical practice. OBJECTIVE: This study aims to understand HCPs' perspectives on using RMT in health care practice for the care of patients with depression, epilepsy, or multiple sclerosis (MS). METHODS: Semistructured interviews were conducted with 26 multidisciplinary primary and secondary care HCPs who care for patients with epilepsy, depression, or MS. Interviews were transcribed verbatim and analyzed using thematic analysis. RESULTS: A total of 8 main themes emerged from the analysis: (1) potential clinical value of RMT data; (2) when to use RMT in care pathways; (3) roles of health care staff who may use RMT data; (4) presentation and accessibility of data; (5) obstacles to successful use of RMT; (6) limits to the role of RMT; (7) empowering patients; and (8) considerations around alert-based systems. CONCLUSIONS: RMT could add value to the system of care for patients with central nervous system disorders by providing clinicians with graphic summaries of data in the patient record. Barriers of both technical and human nature should be considered when using these technologies, as should the limits to the benefits they can offer.

Promoting healthy teenage behaviour across three European countries through the use of a novel smartphone technology platform, PEGASO fit for future: study protocol of a quasi-experimental, controlled, multi-Centre trial.

BACKGROUND: Behaviour change interventions targeting physical activity, diet, sleep and sedentary behaviour of teenagers show promise when delivered through smartphones. However, to date there is no evidence of effectiveness of multicomponent smartphone-based interventions. Utilising a user-centred design approach, we developed a theory-based, multi-dimensional system, PEGASO Fit For Future (PEGASO F4F), which exploits sophisticated game mechanics involving smartphone applications, a smartphone game and activity sensors to motivate teenagers to take an active role in adopting and maintaining a healthy lifestyle. This paper describes the study protocol to assess the feasibility, usability and effectiveness (knowledge/awareness and behavioural change in lifestyle) of the PEGASO system. METHODS: We are conducting a quasi-experimental controlled cluster trial in 4 sites in Spain, Italy, and UK (England, Scotland) over 6 months. We plan to recruit 525, in a 2:1 basis, teenagers aged 13-16 years from secondary schools. The intervention group is provided with the PEGASO system whereas the comparison group continues their usual educational routine. Outcomes include feasibility, acceptance, and usability of the PEGASO system as well as between and within group changes in motivation, self-reported diet, physical activity, sedentary and sleeping behaviour, anthropometric measures and knowledge about a healthy lifestyle. DISCUSSION: PEGASO F4F will provide evidence into the cross-cultural similarities and differences in the feasibility, acceptability and usability of a multi-dimensional smartphone based behaviour change intervention for teenagers. The study will explore facilitating factors, challenges and barriers of engaging teenagers to adapt and maintain a healthy lifestyle when using smartphone technology. Positive results from this ICT based multi component intervention may have significant implications both at clinical level, improving teenagers health and at public health level since it can present an influential tool against the development of chronic disease during adulthood. TRIAL REGISTRATION: https://clinicaltrials.gov Registration number: NCT02930148, registered 4 October 2016.

Not again! Effect of previous test results, age group and reason for testing on (re-)infection with Chlamydia trachomatis in Germany.

BACKGROUND: Infection with Chlamydia trachomatis (Ct) is the most commonly reported sexually transmitted infection in Europe. In Germany, Ct screening is offered free of charge to pregnant women since 1995 and to women < 25 years of age since 2008. For symptomatic individuals, testing is covered by statutory health insurance. Study results have shown that repeat Ct infection occurs in 10-20% of previously infected women and men. Our aim was to describe persons tested for Ct and to investigate the determinants of (repeat) Ct infection in women and men in Germany. METHODS: We analysed Ct test results from men and women tested between 2008 and 2014 in laboratories participating in the German Chlamydia trachomatis Laboratory Sentinel surveillance. Reinfection was defined as at least 2 positive laboratory tests within more than 30 days. We performed logistic regression stratified by sex and, for women, reason for testing to determine the effect of previous test results and age group on subsequent test results. RESULTS: In total, 2,574,635 Ct tests could be attributed to 1,815,494 women and 123,033 men. 5% of women and 14% of men tested positive at least once. 15-19- and 20-24-year-old women tested positive at least once respectively in 6.8 and 6.0%, while men respectively in 16.6 and 21.2%. Altogether, 23.1% of tested women and 11.9% of tested men were tested repeatedly between 2008 and 2014. Among those who previously tested positive, reinfection occurred in 2.0% of women and 6.6% of men. Likelihood to be tested Ct positive was higher in women and men with a positive Ct test in the past compared to previously tested Ct negative, odds ratios 4.7 and 2.6 (p < 0.01) respectively. Odds ratios ranged by age group and test reason. CONCLUSION: A history of Ct infection increased the likelihood of infection with Ct in women and men taking into account the result of the previous test. Health education, safer sex and treatment of partners are necessary for women and men who have tested positive to prevent reinfection and complications and to interrupt the chain of transmission. To identify potential reinfection repeat testing after treatment should be performed.

Wearable technology in epilepsy: The views of patients, caregivers, and healthcare professionals.

PURPOSE: In recent years, digital technology and wearable devices applied to seizure detection have progressively become available. In this study, we investigated the perspectives of people with epilepsy (PWE), caregivers (CG), and healthcare professionals (HP). We were interested in their current use of digital technology as well as their willingness to use wearables to monitor seizures. We also explored the role of factors influencing engagement with technology, including demographic and clinical characteristics, data confidentiality, need for technical support, and concerns about strain or increased workload. METHODS: An online survey drawing on previous data collected via focus groups was constructed and distributed via a web link. Using logistic regression analyses, demographic, clinical, and other factors identified to influence engagement with technology were correlated with reported use and willingness to use digital technology and wearables for seizure tracking. RESULTS: Eighty-seven surveys were completed, fifty-two (59.7%) by PWE, 13 (14.4%) by CG, and 22 (25.3%) by HP. Responders were familiar with multiple digital technologies, including the Internet, smartphones, and personal computers, and the use of digital services was similar to the UK average. Moreover, age and disease-related factors did not influence access to digital technology. The majority of PWE were willing to use a wearable device for long-term seizure tracking. However, only a limited number of PWE reported current regular use of wearables, and nonusers attributed their choice to uncertainty about the usefulness of this technology in epilepsy care. People with epilepsy envisaged the possibility of understanding their condition better through wearables and considered, with caution, the option to send automatic emergency calls. Despite concerns around accuracy, data confidentiality, and technical support, these factors did not limit PWE's willingness to use digital technology. Caregivers appeared willing to provide support to PWE using wearables and perceived a reduction of their workload and anxiety. Healthcare professionals identified areas of application for digital technologies in their clinical practice, pending an appropriate reorganization of the clinical team to share the burden of data reviewing and handling. CONCLUSIONS: Unlike people who have other chronic health conditions, PWE appeared not to be at risk of digital exclusion. This study highlighted a great interest in the use of wearable technology across epilepsy service users, carers, and healthcare professionals, which was independent of demographic and clinical factors and outpaced data security and technology usability concerns.

The dichotomy of the application of a systems approach in UK healthcare the challenges and priorities for implementation.

There is increasing demand for a systems approach within national healthcare guidelines to provide a systematic and sustainable framework for improvements in patient safety. Supported by this is the growing body of evidence within Human Factors/Ergonomics (HFE) healthcare literature for the inclusion of this approach in health service design, provision and evaluation. This paper considers the current interpretation of this within UK healthcare systems and the dichotomy which exists in the challenge to implement a systems approach. Three case studies, from primary and secondary care, present a systems approach, offering a novel perspective of primary care and blood sampling. These provide practical illustrations of how HFE methods have been used in collaboration with healthcare staff to understand the system for the purpose of professional education, design and safety of clinical activities. The paper concludes with the challenge for implementation and proposes five roles for systems HFE to support patient safety. Practitioner Summary: healthcare is classified as a complex and dynamic system within this paper and as such HFE system methods are presented as desirable to understand the system, to develop HFE tools, to deliver education and integrate HFE within healthcare systems.

More holes than cheese. What prevents the delivery of effective, high quality and safe health care in England?

What prevents the delivery of effective, high quality and safe health care in the National Health Service (NHS) in England? This paper presents 760 challenges which 330 NHS staff reported as preventing the delivery of effective, high quality and safe care. Some problems have been known for over 25 years (staff shortages, finance and patient complexity) but other challenges raise questions about the commitment of the NHS to patient and staff safety. For example, Organisational Culture leading to 'stifling bureaucracy', 'odds stacked against smooth […] working' and Workload resulting in 'firefighting daily' and 'perpetual crisis mode'. The role of Human Factors/Ergonomics professional input (engagement with safety scientists) is discussed in the context of success stories and examples of Human Factors Integration from other safety critical industries (Defence, Nuclear and Rail). Practitioner Summary: 760 challenges to the quality, effectiveness and safety of health care were identified at Human Factors/Ergonomics taster workshops in England. These are used to challenge health care providers to think about a Human Factors Integration (HFI systems) approach for safety, well-being and performance for all people involved in providing and receiving health care.

RBP-Jκ-dependent Notch signaling is required for murine articular cartilage and joint maintenance.

OBJECTIVE: Osteoarthritis (OA) is a degenerative disease resulting in severe joint cartilage destruction and disability. While the mechanisms underlying the development and progression of OA are poorly understood, gene mutations have been identified within cartilage-related signaling molecules, implicating impaired cell signaling in OA and joint disease. The Notch pathway has recently been identified as a crucial regulator of growth plate cartilage development, and components are expressed in joint tissue. This study was undertaken to investigate a novel role for Notch signaling in joint cartilage development, maintenance, and the pathogenesis of joint disease in a mouse model. METHODS: We performed the first mouse gene study in which the core Notch signaling component, RBP-Jκ, was tissue specifically deleted within joints. The Prx1Cre transgene removed Rbpjk loxP-flanked alleles in mesenchymal joint precursor cells, while the Col2Cre(ERT2) transgene specifically deleted Rbpjk in postnatal chondrocytes. Murine articular chondrocyte cultures were also used to examine Notch regulation of gene expression. RESULTS: Loss of Notch signaling in mesenchymal joint precursor cells did not affect embryonic joint development in mice, but rather, resulted in an early, progressive OA-like pathology. Additionally, partial loss of Notch signaling in murine postnatal cartilage resulted in progressive joint cartilage degeneration and an age-related OA-like pathology. Inhibition of Notch signaling altered the expression of the extracellular matrix (ECM)-related factors type II collagen (COL2A1), proteoglycan 4, COL10A1, matrix metalloproteinase 13, and ADAMTS. CONCLUSION: Our findings indicate that the RBP-Jκ-dependent Notch pathway is a novel pathway involved in joint maintenance and articular cartilage homeostasis, a critical regulator of articular cartilage ECM-related molecules, and a potentially important therapeutic target for OA-like joint disease.

Using Shopping Data to Improve the Diagnosis of Ovarian Cancer: Computational Analysis of a Web-Based Survey.

BACKGROUND: Shopping data can be analyzed using machine learning techniques to study population health. It is unknown if the use of such methods can successfully investigate prediagnosis purchases linked to self-medication of symptoms of ovarian cancer. OBJECTIVE: The aims of this study were to gain new domain knowledge from women's experiences, understand how women's shopping behavior relates to their pathway to the diagnosis of ovarian cancer, and inform research on computational analysis of shopping data for population health. METHODS: A web-based survey on individuals' shopping patterns prior to an ovarian cancer diagnosis was analyzed to identify key knowledge about health care purchases. Logistic regression and random forest models were employed to statistically examine how products linked to potential symptoms related to presentation to health care and timing of diagnosis. RESULTS: Of the 101 women surveyed with ovarian cancer, 58.4% (59/101) bought nonprescription health care products for up to more than a year prior to diagnosis, including pain relief and abdominal products. General practitioner advice was the primary reason for the purchases (23/59, 39%), with 51% (30/59) occurring due to a participant's doctor believing their health problems were due to a condition other than ovarian cancer. Associations were shown between purchases made because a participant's doctor believing their health problems were due to a condition other than ovarian cancer and the following variables: health problems for longer than a year prior to diagnosis (odds ratio [OR] 7.33, 95% CI 1.58-33.97), buying health care products for more than 6 months to a year (OR 3.82, 95% CI 1.04-13.98) or for more than a year (OR 7.64, 95% CI 1.38-42.33), and the number of health care product types purchased (OR 1.54, 95% CI 1.13-2.11). Purchasing patterns are shown to be potentially predictive of a participant's doctor thinking their health problems were due to some condition other than ovarian cancer, with nested cross-validation of random forest classification models achieving an overall in-sample accuracy score of 89.1% and an out-of-sample score of 70.1%. CONCLUSIONS: Women in the survey were 7 times more likely to have had a duration of more than a year of health problems prior to a diagnosis of ovarian cancer if they were self-medicating based on advice from a doctor rather than having made the decision to self-medicate independently. Predictive modelling indicates that women in such situations, who are self-medicating because their doctor believes their health problems may be due to a condition other than ovarian cancer, exhibit distinct shopping behaviors that may be identifiable within purchasing data. Through exploratory research combining women sharing their behaviors prior to diagnosis and computational analysis of these data, this study demonstrates that women's shopping data could potentially be useful for early ovarian cancer detection.

Comparison of minimal detectable protoporphyrin IX concentrations with a loupe device and conventional 5-ALA fluorescence microscopy: an experimental study.

Significance: The 5-aminolevulinic acid (5-ALA) fluorescence technique is now widely applied for intraoperative visualization of specific central nervous system (CNS) tumors. Previous technical implementations of this technique have relied on specifically modified surgical microscopes to visualize intratumoral fluorescent protoporphyrin (PpIX). While this approach evidently allows for reliable intraoperative tumor visualization, it requires the availability of specifically modified surgical microscopes and their use even in cases where the operating neurosurgeon would prefer to use surgical loupes. Recently, a novel loupe device was introduced that is also capable of visualizing 5-ALA fluorescence. Aim: The aim of this study was therefore to compare the detected PpIX concentrations between the conventional fluorescence microscope and the novel loupe device. Approach: We used fluorescence phantoms of different PpIX concentrations for comparison between a conventional fluorescence microscope and the novel loupe device. For this purpose, we created fluorescence images using the excitation light sources of the conventional fluorescence microscope and the loupe device with both available background illumination modes (low and high). Subsequently, the minimal detectable PpIX concentrations according to each technique were determined by five independent neurosurgeons. Results: Using the conventional fluorescence microscope, the median minimal detectable PpIX concentration was 0.16 µg/ml (range: 0.15 to 0.17 µg/ml). By the loupe device, the median minimal detectable PpIX concentration was 0.12 µg/ml (range: 0.10 to 0.12 µg/ml) and 0.08 µg/ml (range: 0.07 to 0.08 µg/ml) for the high- and low-modes, respectively. Altogether, the minimal detectable PpIX concentrations were significantly lower using the loupe device compared to the conventional fluorescence microscope (p=0.007). Conclusions: Our data indicate that the novel loupe device is able to visualize 5-ALA fluorescence with high sensitivity and thus might serve as a powerful tool for visualization of specific CNS tumors in the future.

Flavin fluorescence lifetime and autofluorescence optical redox ratio for improved visualization and classification of brain tumors.

Purpose: Modern techniques for improved tumor visualization have the aim to maximize the extent of resection during brain tumor surgery and thus improve patient prognosis. Optical imaging of autofluorescence is a powerful and non-invasive tool to monitor metabolic changes and transformation in brain tumors. Cellular redox ratios can be retrieved from fluorescence emitted by the coenzymes reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD). Recent studies point out that the influence of flavin mononucleotide (FMN) has been underestimated. Experimental design: Fluorescence lifetime imaging and fluorescence spectroscopy were performed through a modified surgical microscope. We acquired 361 flavin fluorescence lifetime (500-580 nm) and fluorescence spectra (430-740 nm) data points on freshly excised different brain tumors: low-grade gliomas (N=17), high-grade gliomas (N=42), meningiomas (N=23), metastases (N=26) and specimens from the non-tumorous brain (N=3). Results: Protein-bound FMN fluorescence in brain tumors did increase with a shift toward a more glycolytic metabolism (R=-0.87). This increased the average flavin fluorescence lifetime in tumor entities with respect to the non-tumorous brain. Further, these metrics were characteristic for the different tumor entities and showed promise for machine learning based brain tumor classification. Conclusions: Our results shed light on FMN fluorescence in metabolic imaging and outline the potential for supporting the neurosurgeon in visualizing and classifying brain tumor tissue during surgery.

Examining the Use of Autonomous Systems for Home Health Support Using a Smart Mirror.

The home is becoming a key location for healthcare delivery, including the use of technology driven by autonomous systems (AS) to monitor and support healthcare plans. Using the example of a smart mirror, this paper describes the outcomes of focus groups with people with multiple sclerosis (MS; n = 6) and people who have had a stroke (n = 15) to understand their attitudes towards the use of AS for healthcare in the home. Qualitative data were analysed using a thematic analysis. The results indicate that the use of such technology depends on the level of adaptability and responsiveness to users' specific circumstances, including their relationships with the healthcare system. A smart mirror would need to support manual entry, responsive goal setting, the effective aggregation of data sources and integration with other technology, have a range of input methods, be supportive rather than prescriptive in messaging, and give the user full control of their data. The barriers to its adoption include a perceived lack of portability and practicality, a lack of accessibility and inclusivity, a sense of redundancy, feeling overwhelmed by multiple technological devices, and a lack of trust in data sharing. These results inform the development and deployment of future health technologies based on the lived experiences of people with health conditions who require ongoing care.

Heme Biosynthesis Factors and 5-ALA Induced Fluorescence: Analysis of mRNA and Protein Expression in Fluorescing and Non-fluorescing Gliomas.

Objective: The intraoperative visualization of adult-type diffuse gliomas with 5-aminolevulinic acid (5-ALA) induced fluorescence is widely used in the neurosurgical field. While visible 5-ALA induced fluorescence is found in the majority of high-grade gliomas, most low-grade gliomas lack visible fluorescence during surgery. Recently, the heme biosynthesis pathway was identified as crucial influencing factor for presence of visible fluorescence since it metabolizes 5-ALA to fluorescing Protoporphyrin IX (PpIX). However, the exact alterations within the heme biosynthesis pathway resulting in visible 5-ALA induced fluorescence in gliomas are still unclear. The aim of the present study was thus to compare the mRNA and protein expression of promising intramitochondrial heme biosynthesis enzymes/transporters in glioma tissue samples of different fluorescence behavior. Methods: A total of 19 strongly fluorescing and 21 non-fluorescing tissue samples from neurosurgical adult-type diffuse gliomas (WHO grades II-IV) were included in the current analysis. In these samples, we investigated the mRNA expression by quantitative real time PCR and protein expression using immunohistochemistry of the intramitochondrial heme biosynthesis enzymes Coproporphyrinogen Oxidase (CPOX), Protoporphyrinogen Oxidase (PPOX), Ferrochelatase (FECH), and the transporter ATP-binding Cassette Subfamily B Member 2 (ABCG2). Results: Regarding mRNA expression analysis, we found a significantly decreased ABCG2 expression in fluorescing specimens compared to non-fluorescing samples (p = 0.001), whereas no difference in CPOX, PPOX and FECH was present. With respect to protein expression, significantly higher levels of CPOX (p = 0.005), PPOX (p < 0.01) and FECH (p = 0.003) were detected in fluorescing samples. Similar to mRNA expression analysis, the protein expression of ABCG2 (p = 0.001) was significantly lower in fluorescing samples. Conclusion: Distinct alterations of the analyzed heme biosynthesis factors were found primarily on protein level. Our data indicate that heme biosynthesis pathway activity in general is enhanced in fluorescing gliomas with upregulation of PpIX generating enzymes and decreased ABCG2 mediated PpIX efflux outweighing the also increased further metabolization of PpIX to heme. Intramitochondrial heme biosynthesis factors thus constitute promising pharmacological targets to optimize intraoperative 5-ALA fluorescence visualization of usually non-fluorescing tumors such as low-grade gliomas.

Analysis of corticosteroid and antiepileptic drug treatment effects on heme biosynthesis mRNA expression in lower-grade gliomas: Potential implications for 5-ALA metabolization.

OBJECTIVES: Intraoperative visualization of gliomas with 5-aminolevulinic acid (5-ALA) induced fluorescence constitutes a powerful technique. While visible fluorescence is typically observed in high-grade gliomas, fluorescence is considerably less common in lower-grade gliomas (LGGs) WHO grade II&III. Whereas the exact mechanisms determining fluorescence in LGGs are not fully understood, metabolization of non-fluorescent 5-ALA to fluorescent Protoporphyrin IX by specific heme biosynthesis enzymes/transporters has been identified as relevant mechanism influencing fluorescence behavior. Furthermore, recent in-vitro studies have suggested preoperative treatment with corticosteroids and anti-epileptic drugs (AED) as potential factors influencing 5-ALA induced fluorescence. METHODS: The goal of this study was thus to investigate the effect of preoperative corticosteroid/AED treatment on heme biosynthesis mRNA expression in a clinically relevant patient population. For this purpose, we analyzed the mRNA expression levels of specific heme biosynthesis factors including ALAD, HMBS, UROS, UROD, CPOX, PPOX, FECH, ABCB6, ACG2, SLC15A1 and SLC15A2, ABCB1, ABCB10 in a cohort of LGGs from "The Cancer Genome Atlas". RESULTS: Altogether, 403 patients with available data on preoperative corticosteroid/AED treatment and heme biosynthesis mRNA expression were identified. Regarding corticosteroid treatment, no significant differences in expression of any of the 11 investigated heme biosynthesis factors were found. In contrast, a marginal yet statistically significant increase in SLC15A1 levels and decrease in ABCB6 levels were observed in patients with preoperative AED treatment. CONCLUSION: While no significant differences in heme biosynthesis mRNA expression were observed according to preoperative corticosteroid treatment, changes in SLC15A1 as well as ABCB6 expression were detected in patients treated with AED. However, since these alterations were minor and have opposing effects on 5-ALA metabolization, our findings do not support a distinct effect of AED and corticosteroid treatment on heme biosynthesis regulation in LGGs.