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Abstract Background Pharmacogenomics (PGx) constitutes an important part of personalized medicine and has several clinical applications. PGx role in clinical practice is known, however, it has not been widely adopted yet. In this study, we aim to investigate the perspectives of Greek physicians regarding the implementation of PGx testing in clinical practice and the key issues associated with it. Methods Fourteen interviews were conducted with physicians of various specialties for which PGx applications are available. A semi-structured interview guide was utilized based on the Consolidated Framework for Implementation Research (CFIR) context and the Diffusion of Innovation model. Transcripts were coded independently and compared by two members of the research team. Descriptive statistics were generated using Microsoft Excel. Results Six main themes emerged: awareness and use of PGx testing; source of information; key stakeholders of the PGx supply chain, their interactions and change agents; clinical benefit and significance of PGx testing; barriers and lack of reimbursement; and recommendations to boost the PGx adoption rate. Most respondents were aware of PGx applications, but only three had already recommended PGx testing. Peer-reviewed journals along with clinical guidelines were regarded as the most used source of information while stakeholders of the PGx supply chain were discussed. PGx was considered that promote patient-centered care, enhance medication clinical effectiveness, decrease the risk of side effects, and reduce healthcare costs. Lack of reimbursement, scarcity of resources, and high PGx cost were the foremost barriers affecting PGx adoption. Conclusions It was concluded that if case PGx testing is reimbursed and physicians’ training is reinforced, PGx implementation will be boosted and improved shortly.

Abstract Background The measurement properties of the falls efficacy scale have not been evaluated in patients on hemodialysis. This study determined the inter- and intrarater reliability, standard error of measurement, minimal detectable change, and limits of agreements of the falls efficacy scale in patients on hemodialysis. Methods A cross-sectional study was conducted with 65 patients (57.5 ± 13.9 years, 63.1% male) on hemodialysis. The fear of falling was assessed by two previously trained raters using the falls efficacy scale. The intraclass correlation coefficient, standard error of measurement, minimal detectable change, and Bland–Altman plot were calculated to assess the inter- and intrarater reliability of the falls efficacy scale. Results The interrater intraclass correlation coefficient was 0.91, and the intrarater intraclass correlation coefficient was 0.78, representing excellent interrater and good intrarater reliability. The standard error of measurement for inter- and intrarater assessments were 2.99 and 4.46, and the minimal detectable change for inter- and intrarater assessments were 9.26 and 12.33, respectively. The interrater mean difference score was 0.26 (95% limits of agreement: − 8.01 to 8.53), and the intrarater mean difference score was − 1.06 (95% limits of agreement: − 13.39 to 11.27). Conclusion In patients on hemodialysis, the falls efficacy scale showed excellent and good inter- and intrarater reliability, respectively. Additionally, standard error of measurement, minimal detectable change, and limits of agreements of the falls efficacy scale score were satisfactory.

Abstract This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54–63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18–29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18–45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5–21) sessions. At baseline, 90–100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62–83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants’ reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement. Trial registration NCT04872933. Date of first registration 05/05/2021.

Pharmacogenomics (PGx) is a rapidly changing field of genomics in which healthcare professionals play an important role in its implementation in the clinical setting, however PGx level of adoption remains low. This study aims to investigate the attitude, self-confidence, level of knowledge, and their impact on health sciences undergraduate students’ intentions to adopt PGx in clinical practice using a questionnaire developed based on the Theory of Planned Behavior (TPB). A model was proposed and a questionnaire was developed that was distributed to 467 undergraduate students of all academic years from four different departments of the University of Sharjah (UoS) including medical, dental, nursing, and pharmacy students from September 2022 to November 2022. Descriptive statistics along with factor analysis and regression analysis were conducted. The proposed model had a good internal consistency and fit. Attitude was the factor with the greatest impact on student’s intentions followed by self-confidence and barriers. The level of knowledge had a meaningless impact. The majority of students shared a positive attitude and were aware of PGx benefits. Almost 60% of the respondents showed a high level of knowledge, while 50% of them were confident of implementing PGx in their clinical practice. Many students were prone to adopt PGx in their future careers. PGx testing cost and the lack of reimbursement were the most important barriers. Overall, students shared a positive intention and were prone to adopt PGx. In the future, it would be important to investigate the differences between gender, year of studies, and area of studies studies and their impact on students’ intentions.

Summary: Background: Pharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology, demonstrating a beneficial effect of PGx-guided treatment in reducing adverse drug reactions, there are very few such studies in psychiatry, none of which spans across all main psychiatric indications, namely schizophrenia, major depressive disorder and bipolar disorder. In this study we aim to investigate the clinical effectiveness of PGx-guided treatment (occurrence of adverse drug reactions, hospitalisations and re-admissions, polypharmacy) and perform a cost analysis of the intervention. Methods: We report our findings from a multicenter, large-scale, prospective study of pre-emptive genome-guided treatment named as PREemptive Pharmacogenomic testing for preventing Adverse drug REactions (PREPARE) in a large cohort of psychiatric patients (n = 1076) suffering from schizophrenia, major depressive disorder and bipolar disorder. Findings: We show that patients with an actionable phenotype belonging to the PGx-guided arm (n = 25) present with 34.1% less adverse drug reactions compared to patients belonging to the control arm (n = 36), 41.2% less hospitalisations (n = 110 in the PGx-guided arm versus n = 187 in the control arm) and 40.5% less re-admissions (n = 19 in the PGx-guided arm versus n = 32 in the control arm), less duration of initial hospitalisations (n = 3305 total days of hospitalisation in the PGx-guided arm from 110 patients, versus n = 6517 in the control arm from 187 patients) and duration of hospitalisation upon readmission (n = 579 total days of hospitalisation upon readmission in the PGx-guided arm, derived from 19 patients, versus n = 928 in the control arm, from 32 patients respectively). It was also shown that in the vast majority of the cases, there was less drug dose administrated per drug in the PGx-guided arm compared to the control arm and less polypharmacy (n = 124 patients prescribed with at least 4 psychiatric drugs in the PGx-guided arm versus n = 143 in the control arm) and smaller average number of co-administered psychiatric drugs (2.19 in the PGx-guided arm versus 2.48 in the control arm. Furthermore, less deaths were reported in the PGx-guided arm (n = 1) compared with the control arm (n = 9). Most importantly, we observed a 48.5% reduction of treatment costs in the PGx-guided arm with a reciprocal slight increase of the quality of life of patients suffering from major depressive disorder (0.935 versus 0.925 QALYs in the PGx-guided and control arm, respectively). Interpretation: While only a small proportion (∼25%) of the entire study sample had an actionable genotype, PGx-guided treatment can have a beneficial effect in psychiatric patients with a reciprocal reduction of treatment costs. Although some of these findings did not remain significant when all patients were considered, our data indicate that genome-guided psychiatric treatment may be successfully integrated in mainstream healthcare. Funding: European Union Horizon 2020.

The exponential growth of the aged population worldwide is followed by an increase in the prevalence of age-related disorders. Oxidative stress plays central role in damage accumulation during ageing and cell senescence. Thus, a major target of today’s anti-ageing research has been focused on antioxidants counteracting senescence. In the current work, six novel 5,7,8-trimethyl-1,4-benzoxazine/catechol or resorcinol hybrids were synthesized connected through a methoxymethyl-1,2,3-triazolyl or a 1,2,3-triazoly linker. The compounds were evaluated for their antioxidant capacity in a cell-free system and for their ability to reduce intracellular ROS levels in human skin fibroblasts, both young (early-passage) and senescent. The most efficient compounds were further tested in these cells for their ability to induce the expression of the gene heme oxygenase-1 (ho-1), known to regulate redox homeostasis, and cellular glutathione (GSH) levels. Overall, the two catechol derivatives were found to be more potent than the resorcinol analogues. Furthermore, these two derivatives were shown to act coordinately as radical scavengers, ROS inhibitors, ho-1 gene expression inducers, and GSH enhancers. Interestingly, one of the two catechol derivatives was also found to enhance human skin fibroblast viability. The properties of the synthesized compounds support their potential use in cosmetic applications, especially in products targeting skin ageing.

Abstract Background Non-specific acute low back pain (LBP) is a common health problem that may be accompanied by muscle spasm and decreased mobility. The combination of non-steroidal anti-inflammatory drugs and muscle relaxants represents an advantageous therapeutic option, however, available data on their combined use are conflicting. This prospective, randomized, single-blind, two-parallel-group trial assessed the efficacy of a single intramuscular (IM) injection of the fixed-dose combination (FDC) diclofenac (75 mg)-thiocolchicoside (4 mg/4 ml) product (test treatment) compared to diclofenac (75 mg/3 ml) alone (reference treatment) for the symptomatic relief of acute LBP. Tolerability and safety were also assessed as secondary variables. Methods One hundred thirty-four patients were enrolled (safety population) and randomly allocated to the combination or single-agent regimen. Pain intensity and muscle spasm, assessed respectively by the patient-reported visual analogue scale and investigator-performed finger-to-floor distance test, were determined prior to the injection as well as 1 and 3 h post-injection in 123 patients (per-protocol population). The patients were blinded to treatment. Safety was assessed up to 24 h post-injection. Results The test treatment was superior in both alleviating the pain intensity and reducing the finger-to-floor distance at both 1 (p 30% reduction in pain intensity at 1 and 3 h with the test treatment (p = 0.037 and p

Abstract Background Cardiovascular diseases and especially Acute Coronary Syndrome (ACS) constitute a major health issue impacting millions of patients worldwide. Being a leading cause of death and hospital admissions in many European countries including Spain, it accounts for enormous amounts of healthcare expenditures for its management. Clopidogrel is one of the oldest antiplatelet medications used as standard of care in ACS. Methods In this study, we performed an economic evaluation study to estimate whether a genome-guided clopidogrel treatment is cost-effective compared to conventional one in a large cohort of 243 individuals of Spanish origin suffering from ACS and treated with clopidogrel. Data were derived from the U-PGx PREPARE clinical trial. Effectiveness was measured as survival of individuals while study data on safety and efficacy, as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. Results Based on our findings, PGx-guided treatment group is cost-effective. PGx-guided treatment demonstrated to have 50% less hospital admissions, reduced emergency visits and almost 13% less ADRs compared to the non-PGx approach with mean QALY 1.07 (95% CI, 1.04–1.10) versus 1.06 (95% CI, 1.03–1.09) for the control group, while life years for both groups were 1.24 (95% CI, 1.20–1.26) and 1.23 (95% CI, 1.19–1.26), respectively. The mean total cost of PGx-guided treatment was 50% less expensive than conventional therapy with clopidogrel [€883 (95% UI, €316–€1582), compared to €1,755 (95% UI, €765–€2949)]. Conclusion These findings suggest that PGx-guided clopidogrel treatment represents a cost-effective option for patients suffering from ACS in the Spanish healthcare setting.

Abstract Background Physical activity and emotional self-management has the potential to enhance health-related quality of life (HRQoL), but few people with chronic kidney disease (CKD) have access to resources and support. The Kidney BEAM trial aims to evaluate whether an evidence-based physical activity and emotional wellbeing self-management programme (Kidney BEAM) leads to improvements in HRQoL in people with CKD. Methods This was a prospective, multicentre, randomised waitlist-controlled trial, with health economic analysis and nested qualitative studies. In total, three hundred and four adults with established CKD were recruited from 11 UK kidney units. Participants were randomly assigned to the intervention (Kidney BEAM) or a wait list control group (1:1). The primary outcome was the between-group difference in Kidney Disease Quality of Life (KDQoL) mental component summary score (MCS) at 12 weeks. Secondary outcomes included the KDQoL physical component summary score, kidney-specific scores, fatigue, life participation, depression and anxiety, physical function, clinical chemistry, healthcare utilisation and harms. All outcomes were measured at baseline and 12 weeks, with long-term HRQoL and adherence also collected at six months follow-up. A nested qualitative study explored experience and impact of using Kidney BEAM. Results 340 participants were randomised to Kidney BEAM (n = 173) and waiting list (n = 167) groups. There were 96 (55%) and 89 (53%) males in the intervention and waiting list groups respectively, and the mean (SD) age was 53 (14) years in both groups. Ethnicity, body mass, CKD stage, and history of diabetes and hypertension were comparable across groups. The mean (SD) of the MCS was similar in both groups, 44.7 (10.8) and 45.9 (10.6) in the intervention and waiting list groups respectively. Conclusion Results from this trial will establish whether the Kidney BEAM self management programme is a cost-effective method of enhancing mental and physical wellbeing of people with CKD. Trial Registration NCT04872933. Registered 5th May 2021.

Abstract Background Physical frailty is a major health concern among people receiving haemodialysis (HD) for stage-5 chronic kidney disease (CKD-5). Wearable accelerometers are increasingly being recommended to objectively monitor activity levels in CKD-5 and recent research suggests they may also represent an innovative strategy to evaluate physical frailty in vulnerable populations. However, no study has yet explored whether wearable accelerometers may be utilised to assess frailty in the context of CKD-5-HD. Therefore, we aimed to examine the diagnostic performance of a research-grade wearable accelerometer in evaluating physical frailty in people receiving HD. Methods Fifty-nine people receiving maintenance HD [age = 62.3 years (SD = 14.9), 40.7% female] participated in this cross-sectional study. Participants wore a uniaxial accelerometer (ActivPAL) for seven consecutive days and the following measures were recorded: total number of daily steps and sit-to-stand transitions, number of daily steps walked with cadence

Abstract Background Pharmacists’ contribution to pharmacogenomics (PGx) implementation in clinical practice is vital, but a great proportion of them are not aware of PGx and its applications. This highlights the university education’s crucial role to prepare pharmacists to face future challenges in such a constantly evolving and demanding environment. Objectives Our study aims to examine pharmacy students’ training satisfaction, knowledge, self-confidence and attitudes towards PGx on their intentions for postgraduate training in PGx and personalised medicine (PM). Methods An initial model on students’ intention to pursue postgraduate training in PGx and PM and its predicting factors, based on the Theory of Planned Behaviour (TPB), was proposed. Based on it, a questionnaire was developed and distributed to 346 pharmacy students of all study years, capturing the selected factors influencing students’ intentions to postgraduate training in PGx and PM, as well as their demographics. Structural equation modelling (SEM) analysis was employed to determine the effects of both the examined factors and demographics on students’ intentions. Results Students did not consider themselves adequately prepared for using PGx in clinical practice. Their attitudes towards PGx implementation were the most important factor influencing their intentions to pursue postgraduate training in PGx and PM. Other factors such as self-confidence and training satisfaction also affected students’ intentions, but to a lower extent. Students of the last two study years (40% of the whole sample) and male (36%) students stated to be less willing to pursue PGx-related studies in the future. Only 10% of the participants claimed to have undergone a recent PGx or genetic test, but this did not affect their intentions. Conclusion There is an important gap in pharmacy school curriculum regarding PGx and PM training which coupled with the slow rate of PGx and PM implementation into clinical practice seems to restrain students’ aspiration to further expand their knowledge and horizons in terms of PGx and PM.

Abstract Objective to assess the effects of cilostazol on pain-free walking distance in PAD patients with IC at 3 and 6 months in a real world, prospective, observational study. We included 1015 PAD patients presenting with IC (71.3% men, 93.5% white, mean age 69.2 ± 8.7 years). Patients were followed up for 6 months by their physicians. Results Cilostazol significantly increased pain-free walking distance by a median of 285 and 387 m at 3 and 6 months, respectively (p

Over 80% of the global population addresses their primary healthcare needs using traditional medicine based on medicinal plants. Consequently, there’s a rising demand for these plants for both household and industrial use at local, regional, national, and international levels. However, wild harvesting has negatively impacted natural ecosystems. Cultivating medicinal species has been proposed as a conservation strategy to alleviate this pressure. Yet, in this age of global climate change concerns, smallholder farmers’ views on the benefits of such cultivation clash with the uncertainties of climate change impacts, amplifying their anxieties. In this context, the climate change dependence of ex situ cultivation of ten wild medicinal taxa with significant ethnopharmacological interest in Crete, Greece, were studied, projecting their potential habitat suitability under various future climate scenarios. The results demonstrated species-specific effects. Based on the potential cultivation area gains and losses, these effects can be categorized into three groups. We also outlined the spatial patterns of these gains and losses, offering valuable insights for regional management strategies benefiting individual practitioners.

COX-2-mediated prostaglandin E2 (PGE2) release from dying cancer cells contributes to cytotoxic therapy resistance. Here the authors show that cytotoxic drugs induce PGE2 release only in cancer cells with basal COX-2 activity and that pharmacological COX-2 inhibition can boost the efficacy of the combination of chemotherapy and PD-1 blockade.

IntroductionA multi-site randomized controlled trial was carried out between 2015 and 2019 to evaluate the impacts on quality of life of an intradialytic exercise programme for people living with chronic kidney disease. This included a qualitative process evaluation which gave valuable insights in relation to feasibility of the trial and of the intervention in the long-term. These can inform future clinical Trial design and evaluation studies.MethodsA constructivist phenomenological approach underpinned face-to-face, semi-structured interviews. Purposive recruitment ensured inclusion of participants in different arms of the PEDAL Trial, providers with different roles and trial team members from seven Renal Units in five study regions. Following ethical review, those willing took part in one interview in the Renal Unit. Audio-recorded interviews were transcribed (intelligent verbatim) and inductively thematically analyzed.ResultsParticipants (n = 65) (Intervention arm: 26% completed; 13% who did not; Usual care arm: 13%; 46% women; 54% men; mean age 60 year) and providers (n = 39) were interviewed (23% PEDAL Trial team members). Three themes emerged: (1) Implementing the Intervention; (2) Implementing the trial; and (3) Engagement of the clinical team. Explanatory theory named “the Ideal Scenario” was developed, illustrating complex interactions between different aspects of intervention and trial implementation with the clinical context. This describes characteristics likely to optimize trial feasibility and intervention sustainability in the long-term. Key aspects of this relate to careful integration of the trial within the clinical context to optimize promotion of the trial in the short-term and engagement and ownership in the long-term. Strong leadership in both the clinical and trial teams is crucial to ensure a proactive and empowering culture.ConclusionNovel explanatory theory is proposed with relevance for Implementation Science. The “Ideal Scenario” is provided to guide trialists in pre-emptive and ongoing risk analysis relating to trial feasibility and long-term intervention implementation. Alternative study designs should be explored to minimize the research-to-practice gap and optimize the likelihood of informative findings and long-term implementation. These might include Realist Randomized Controlled Trials and Hybrid Effectiveness-Implementation studies.

Abstract Background There is an increasing interest worldwide in investigating healthcare stakeholders’ perceptions and intentions to adopt pharmacogenomics (PGx) into clinical practice. However, the existing inquiries based on well-established theories and models that interpret their intentions to implement PGx are scarce. This study is the first that examines the impact of selected factors on health science students’ intention to adopt genetic testing applications using the technology acceptance model while it compares two different cultural groups: Greeks (Europe; Christian) and Malays (Asia; Muslim). Results Malay students were more persuaded about benefits of genomics for drug management compared to their Greek counterparts. However, participants from both countries appear to be particularly convinced about the benefits of genomics on disease management. Moreover, students from both countries considered the potential misuse of genetic information by corporate or government bodies as their most important concern; Greek students appeared to be considerably less worried than Malay about other probable hazards such as the deficient protection of privacy and confidentiality, which could be attributed to their religious background. Participants from both samples expressed very positive attitudes towards genetic research and testing and their favourable intentions to adopt genetic testing for personal use. Exploratory factors analysis and path analysis yielded quite similar results for both samples. Path analysis revealed that the factors of attitudes, concerns, drug management benefits and disease management benefits significantly influenced students’ intentions to adopt genetic testing for personal use, with attitudes being the most inspirational factor with rather high impact, while training did not seem to affect participant’s intentions. The squared multiple correlation of both models was quite satisfactory reaching to 0.55 for the Malaysian sample. Conclusion Similarities in the results of the two groups along with the relevant validity and reliability tests indicate that the proposed model is a good fit for future studies to interpret stakeholders’ intentions to adopt genetic testing. Therefore, it can provide a promising and reliable basis for future model development to explain the relationships between intentions to adopt genetic testing and its predictors.

Giannis Mountzios,1 Sofia Lampaki,2 Georgia-Angeliki Koliou,3 Athanassios Vozikis,4 Ioannis Kontogiorgos,4 Panagiotis Papantoniou,4 Margarita-Ioanna Koufaki,4 Eleni Res,5 Anastasios Boutis,6 Athina Christopoulou,7 Nicoleta Pastelli,8 Anastasios Grivas,9 Gerasimos Aravantinos,10 Efthalia Lalla,11 Georgios Oikonomopoulos,12 Anna Koumarianou,13 Dionisios Spyratos,2 Dimitrios Bafaloukos Snr,14 Georgios Rigakos,15 Pavlos Papakotoulas,6 George Fountzilas,16– 18 Helena Linardou19 1Fourth Department of Medical Oncology and Clinical Trials Unit Henry Dunant Hospital Center, Athens, Greece; 2Pulmonary Department, Lung Cancer Oncology Unit, Aristotle University of Thessaloniki, G. Papanicolaou Hospital, Thessaloniki, Greece; 3Section of Biostatistics, Hellenic Cooperative Oncology Group, Athens, Greece; 4Laboratory of Health Economics and Management, Department of Economics, University of Piraeus, Piraeus, Greece; 5Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece; 6First Department of Clinical Oncology, Theagenio Hospital, Thessaloniki, Greece; 7Medical Oncology Unit, S. Andrew Hospital, Patras, Greece; 8Department of Pathology, G. Papanicolaou Hospital, Thessaloniki, Greece; 9Second Department of Internal Medicine, Agios Savvas Cancer Hospital, Athens, Greece; 10Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece; 11Third Department of Clinical Oncology, Theagenio Hospital, Thessaloniki, Greece; 12Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece; 13Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 14First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece; 15Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece; 16Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece; 17Aristotle University of Thessaloniki, Thessaloniki, Greece; 18Department of Medical Oncology, German Oncology Center, Limassol, Cyprus; 19Fourth Oncology Department, Metropolitan Hospital, Athens, GreeceCorrespondence: Giannis MountziosFourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Messoghion Av. 107, Athens, 11526, GreeceTel +2106972000Email gmountzios@gmail.comPurpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking.Materials and Methods: This was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered.Results: A total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37– 91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9– 51.4), the median PFS was 14.3 months (95% CI 12.2– 16.4), and the median OS was 29 months (95% CI 25.6– 33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5– 18.5) and 28.1 months (95% CI 21.1– 32.6), respectively. The mean expenditure for the treatment of each patient equals € 25,333.68; with € 21,865.06 being attributed to drug acquisition costs, € 3325.35 to monitoring costs and € 143.27 to adverse event treatment-related costs.Conclusion: Long-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC.Clinical Trial Registration: Clinicaltrials.gov NCT04640870.Keywords: lung cancer, epidermal growth factor receptor, EGFR, afatinib, molecular epidemiology, cost-effectiveness

Abstract Background Frailty is associated with multiple adverse outcomes in stage-5 chronic kidney disease (CKD-5) and upwards of one third of people receiving haemodialysis (HD) are frail. While many frailty screening methods are available in both uremic and non-uremic populations, their implementation in clinical settings is often challenged by time and resource constraints. In this study, we explored the diagnostic accuracy of time-efficient screening tools in people receiving HD. Methods A convenience sample of 76 people receiving HD [mean age = 61.1 years (SD = 14), 53.9% male] from three Renal Units were recruited for this cross-sectional study. Frailty was diagnosed by means of the Fried phenotype. Physical performance-based screening tools encompassed handgrip strength, 15-ft gait speed, timed up and go (TUG), and five-repetition sit to stand (STS-5) tests. In addition, participants completed the SF-36 Health Survey, the short-form international physical activity questionnaire and the Tinetti falls efficacy scale (FES) as further frailty-related measures. Outcome measures included the area under the curve (AUC), sensitivity, specificity, positive (PPV) and negative predictive values (NPV). The diagnostic performance of screening tools in assessing fall-risk was also investigated. Results Overall, 36.8% of participants were classified as frail. All the examined instruments could significantly discriminate frailty status in the study population. Gait speed [AUC = 0.89 (95%CI: 0.81–0.98), sensitivity = 75%, specificity = 93%] and TUG [AUC = 0.90 (95%CI: 0.80–0.99), sensitivity = 89%, specificity = 85%] exhibited the highest diagnostic accuracy. There was a significant difference in gait speed AUC (20%, p = 0.013) between participants aged 65 years or older (n = 36) and those under 65 years of age (n = 40), with better discriminating performance in the younger sub-group. The Tinetti FES was the only instrument showing good diagnostic accuracy (AUCs≥0.80) for both frailty (sensitivity = 82%, specificity = 79%) and fall-risk (sensitivity = 82%, specificity = 71%) screening. Conclusions This cross-sectional study revealed that time- and cost-efficient walking performance measures can accurately be used for frailty-screening purposes in people receiving HD. While self-selected gait speed had an excellent performance in people under 65 years of age, TUG may be a more suitable screening method for elderly patients (≥65 years). The Tinetti FES may be a clinically useful test when physical testing is not achievable.

Background and Aims No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterized fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. Methods We undertook immunohistochemistry, metabolic, signalling pathway and epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. Results Stricturing CD was characterized by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1 , HDAC2 , and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appeared 'metabolically primed' and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and TGFβ-independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. Conclusions Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype and metabolic priming characterize SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Background Stage 5 chronic kidney disease (CKD-5) patients on haemodialysis (HD) are at high risk of accidental falls. Previous research has shown that frailty is one of the primary contributors to the increased risk of falling in this clinical population. However, HD patients often present with abnormalities of cardiovascular function such as baroreflex impairment and orthostatic dysregulation of blood pressure (BP) which may also be implicated in the aetiology of falling. Therefore, we aimed to explore the relative importance of frailty and cardiovascular function as potential exercise-modifiable predictors of falls in these patients. Methods Ninety-three prevalent CKD-5 patients on HD from three Renal Units were recruited for this prospective cohort study, which was conducted between October 2015 and August 2018. At baseline, frailty status was assessed using the Fried’s frailty phenotype, while physical function was evaluated through timed up and go (TUG), five repetitions chair sit-to-stand (CSTS-5), objectively measured physical activity, and maximal voluntary isometric strength. Baroreflex and haemodynamic function at rest and in response to a 60° head-up tilt test (HUT-60°) were also assessed by means of the Task Force Monitor. The number of falls experienced was recorded once a month during 12 months of follow-up. Results In univariate negative binomial regression analysis, frailty (RR: 4.10, 95%CI: 1.60–10.51, p = 0.003) and other physical function determinants were associated with a higher number of falls. In multivariate analysis however, only worse baroreflex function (RR: 0.96, 95%CI: 0.94–0.99, p = 0.004), and orthostatic decrements of BP to HUT-60° (RR: 0.93, 95%CI: 0.87–0.99, p = 0.033) remained significantly associated with a greater number of falls. Eighty falls were recorded during the study period and the majority of them (41.3%) were precipitated by dizziness symptoms, as reported by participants. Conclusions This prospective study indicates that cardiovascular mechanisms implicated in the short-term regulation of BP showed a greater relative importance than frailty in predicting falls in CKD-5 patients on HD. A high number of falls appeared to be mediated by a degree of cardiovascular dysregulation, as evidenced by the predominance of self-reported dizziness symptoms. Trial registration ClinicalTrials.gov (trial registration ID: NCT02392299; date of registration: March 18, 2015).

Abstract This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, and is an update of a previous version written in 2009. It aims to provide guidance on how to look after patients and how to run dialysis units, and provides standards which units should in general aim to achieve. We would not advise patients to interpret the guideline as a rulebook, but perhaps to answer the question: “what does good quality haemodialysis look like?” The guideline is split into sections: each begins with a few statements which are graded by strength (1 is a firm recommendation, 2 is more like a sensible suggestion), and the type of research available to back up the statement, ranging from A (good quality trials so we are pretty sure this is right) to D (more like the opinion of experts than known for sure). After the statements there is a short summary explaining why we think this, often including a discussion of some of the most helpful research. There is then a list of the most important medical articles so that you can read further if you want to – most of this is freely available online, at least in summary form. A few notes on the individual sections: 1.This section is about how much dialysis a patient should have. The effectiveness of dialysis varies between patients because of differences in body size and age etc., so different people need different amounts, and this section gives guidance on what defines “enough” dialysis and how to make sure each person is getting that. Quite a bit of this section is very technical, for example, the term “eKt/V” is often used: this is a calculation based on blood tests before and after dialysis, which measures the effectiveness of a single dialysis session in a particular patient.2.This section deals with “non-standard” dialysis, which basically means anything other than 3 times per week. For example, a few people need 4 or more sessions per week to keep healthy, and some people are fine with only 2 sessions per week – this is usually people who are older, or those who have only just started dialysis. Special considerations for children and pregnant patients are also covered here.3.This section deals with membranes (the type of “filter” used in the dialysis machine) and “HDF” (haemodiafiltration) which is a more complex kind of dialysis which some doctors think is better. Studies are still being done, but at the moment we think it’s as good as but not better than regular dialysis.4.This section deals with fluid removal during dialysis sessions: how to remove enough fluid without causing cramps and low blood pressure. Amongst other recommendations we advise close collaboration with patients over this.5.This section deals with dialysate, which is the fluid used to “pull” toxins out of the blood (it is sometimes called the “bath”). The level of things like potassium in the dialysate is important, otherwise too much or too little may be removed. There is a section on dialysate buffer (bicarbonate) and also a section on phosphate, which occasionally needs to be added into the dialysate.6.This section is about anticoagulation (blood thinning) which is needed to stop the circuit from clotting, but sometimes causes side effects.7.This section is about certain safety aspects of dialysis, not seeking to replace well-established local protocols, but focussing on just a few where we thought some national-level guidance would be useful.8.This section draws together a few aspects of dialysis which don’t easily fit elsewhere, and which impact on how dialysis feels to patients, rather than the medical outcome, though of course these are linked. This is where home haemodialysis and exercise are covered. There is an appendix at the end which covers a few aspects in more detail, especially the mathematical ideas. Several aspects of dialysis are not included in this guideline since they are covered elsewhere, often because they are aspects which affect non-dialysis patients too. This includes: anaemia, calcium and bone health, high blood pressure, nutrition, infection control, vascular access, transplant planning, and when dialysis should be started.

Background: Whether or not clinically implementable exercise interventions in haemodialysis patients improve quality of life remains unknown. Objectives: The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial evaluated the clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on quality of life compared with usual care for haemodialysis patients. Design: We conducted a prospective, multicentre randomised controlled trial of haemodialysis patients from five haemodialysis centres in the UK and randomly assigned them (1 : 1) using a web-based system to (1) intradialytic exercise training plus usual-care maintenance haemodialysis or (2) usual-care maintenance haemodialysis. Setting: The setting was five dialysis units across the UK from 2015 to 2019. Participants: The participants were adult patients with end-stage kidney disease who had been receiving haemodialysis therapy for > 1 year. Interventions: Participants were randomised to receive usual-care maintenance haemodialysis or usual-care maintenance haemodialysis plus intradialytic exercise training. Main outcome measures: The primary outcome of the study was change in Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score (from baseline to 6 months). Cost-effectiveness was determined using health economic analysis and the EuroQol-5 Dimensions, five-level version. Additional secondary outcomes included quality of life (Kidney Disease Quality of Life Short Form, version 1.3, generic multi-item and burden of kidney disease scales), functional capacity (sit-to-stand 60 and 10-metre Timed Up and Go tests), physiological measures (peak oxygen uptake and arterial stiffness), habitual physical activity levels (measured by the International Physical Activity Questionnaire and Duke Activity Status Index), fear of falling (measured by the Tinetti Falls Efficacy Scale), anthropometric measures (body mass index and waist circumference), clinical measures (including medication use, resting blood pressure, routine biochemistry, hospitalisations) and harms associated with intervention. A nested qualitative study was conducted. Results: We randomised 379 participants; 335 patients completed baseline assessments and 243 patients (intervention, n = 127; control, n = 116) completed 6-month assessments. The mean difference in change in physical component summary score from baseline to 6 months between the intervention group and control group was 2.4 arbitrary units (95% confidence interval –0.1 to 4.8 arbitrary units; p = 0.055). Participants in the intervention group had poor compliance (49%) and very poor adherence (18%) to the exercise prescription. The cost of delivering the intervention ranged from £463 to £848 per participant per year. The number of participants with harms was similar in the intervention (n = 69) and control (n = 56) groups. Limitations: Participants could not be blinded to the intervention; however, outcome assessors were blinded to group allocation. Conclusions: On trial completion the primary outcome (Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score) was not statistically improved compared with usual care. The findings suggest that implementation of an intradialytic cycling programme is not an effective intervention to enhance health-related quality of life, as delivered to this cohort of deconditioned patients receiving haemodialysis. Future work: The benefits of longer interventions, including progressive resistance training, should be confirmed even if extradialytic delivery is required. Future studies also need to evaluate whether or not there are subgroups of patients who may benefit from this type of intervention, and whether or not there is scope to optimise the exercise intervention to improve compliance and clinical effectiveness. Trial registration: Current Controlled Trials ISRCTN83508514. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.

Abstract Background The achievement and improvement of skills in musical techniques to reach the highest levels of performance may expose music students to a wide range of playing-related musculoskeletal disorders (PRMDs). In order to establish effective solutions for PRMDs and to develop future preventive measures, it is fundamental to firstly identify the main risk factors that play a significant role in the development of musculoskeletal conditions and symptoms. The aim of the study is to identify those factors associated with increased risk of PRMDs among music students. A further goal is to characterise this population and describe the clinical features of PRMDs, as well as to determine the evolving course of PRMDs in music students during their training. Methods One hundred and ninety schools have been invited to participate in this study, sixty of which have already confirmed officially their support for the investigation’s recruitment procedures, by means of a subsequent distribution of the link to a web-based questionnaire to their student groups (total potential student numbers available: n = 12,000 [based on ~ 200 students per school on average, and 60 volunteering schools]; expected number of students: n = 3000 [based on a 25% response rate from the 12,000 students attending the 60 volunteering schools]). The web-based questionnaire includes questions about any PRMD that students have experienced during their training, and different potential risk factors (i.e. lifestyle and physical activity, practice habits, behaviour toward prevention and health history, level of stress, perfectionism, fatigue and disability). Overall recurrence or new onsets of PRMDs will be assessed at 6 and 12 months after the first data collection to investigate and record the development of new incidents within a period of a year and to enable characterisation of the nature and the evolving course of PRMDs. Discussion To the best of our knowledge, no other longitudinal studies on risk factors for PRMDs among music students have been conducted so far. Therefore, this study can be considered as an opportunity to begin filling the gaps within current research in this field and to generate new knowledge within musical contexts in education and employment. Trial registration ClinicalTrials.gov (NCT03622190), registration date 09/08/2018.

Climate change is affecting species distribution and ecosystem form and function. Forests provide a range of ecosystem services, and understanding their vulnerability to climate change is important for designing effective adaptation strategies. Species Distribution Modelling (SDM) has been extensively used to derive habitat suitability maps under current conditions and project species distribution shifts under climate change. In this study, we model the current and future habitat suitability of the dominant tree species in Greece (Abies cephalonica, Abies borisii-regis, Pinus brutia, Pinus halepensis, Pinus nigra, Quercus ilex, Quercus pubescens, Quercus frainetto and Fagus sylvatica), based on species-specific presence data from the EU-Forest database, enhanced with data from Greece that is currently under-represented in terms of tree species occurrence points. By including these additional presence data, areas with relatively drier conditions for some of the study species were included in the SDM development, yielding a potentially lower vulnerability under climate change conditions. SDMs were developed for each taxon using climate and soil data at a resolution of ~1 km2. Model performance was assessed under current conditions and was found to adequately simulate potential distributions. Subsequently, the models were used to project the potential distribution of each species under the SSP1-2.6 and SSP5-8.5 scenarios for the 2041–2070 and 2071–2100 time periods. Under climate change scenarios, a reduction in habitat-suitable areas was predicted for most study species, with higher elevation taxa experiencing more pronounced potential habitat shrinkages. An exception was the endemic A. cephalonica and its sister species A. borisii-regis, which, although currently found at mid and high elevations, seem able to maintain their potential distribution under most climate change scenarios. Our findings suggest that climate change could significantly affect the distribution and dynamics of forest ecosystems in Greece, with important ecological, economic and social implications, and thus adequate mitigation measures should be implemented.

Τα μέχρι τώρα ερευνητικά δεδομένα δείχνουν κάποια σύνδεση της εκφοβιστικής συμπεριφοράς με το κάπνισμα, αλλά δεν δίνουν μια σαφή εικόνα αναφορικά με την εμπλοκή των εφήβων μαθητών/ριών στον σχολικό εκφοβισμό και το αν έχουν δοκιμάσει άλλες εξαρτησιογόνες ουσίες. Επιπλέον, η μειωμένη προσκόλληση στο σχολείο φαίνεται ότι συνδέεται τόσο με το αν οι συμμετέχοντες είχαν δοκιμάσει ουσίες όσο και με την εμπλοκή τους σε περιστατικά εκφοβισμού/θυματοποίησης. Ο κύριος στόχος της έρευνας αυτής ήταν να εξετάσει τη σχέση ανάμεσα στο κατά πόσο οι μαθητές/ριες είχαν δοκιμάσει ουσίες, τον σχολικό εκφοβισμό και την προσκόλληση στο σχολείο. Στην έρευνα συμμετείχαν 779 μαθητές/ριες (426 αγόρια, 353 κορίτσια) γυμνασίων και λυκείων του νομού Λάρισας. Το ερωτηματολόγιο που χρησιμοποιήθηκε αφορούσε το αν έχουν δοκιμάσει νόμιμες και παράνομες εξαρτησιογόνες ουσίες, την εμπλοκή τους σε περιστατικά εκφοβισμού/θυματοποίησης (κατηγοριοποίηση των μαθητών σε θύτες, θύματα, θύτες-θύματα και μη εμπλεκόμενους) και τον βαθμό προσκόλλησής τους στο σχολείο όπως αυτή μετριέται μέσα από τέσσερις παραμέτρους: τη δέσμευση απέναντι στο σχολείο, την αφοσίωση στο σχολείο, την εμπλοκή στις σχολικές δραστηριότητες και την πίστη στους κανόνες του σχολείου. Παρατηρήθηκε ότι όσο ισχυρότερη είναι η προσκόλληση των μαθητών/ριών με το σχολείο τόσο λιγότερο έχουν δοκιμάσει εξαρτησιογόνες ουσίες. Τα αποτελέσματα έδειξαν ότι οι θύτες και οι θύτες-θύματα είχαν δοκιμάσει εξαρτησιογόνες ουσίες περισσότερο από ό,τι τα θύματα και οι μη εμπλεκόμενοι/ες μαθητές/ριες σε περιστατικά εκφοβισμού/θυματοποίησης, ενώ καταγράφουν και χαμηλότερες τιμές στους τομείς της δέσμευσης και της αφοσίωσης. Δεν παρατηρείται στατιστικά σημαντική σχέση μεταξύ εκφοβισμού/θυματοποίησης και εμπλοκής στις σχολικές δραστηριότητες, ενώ σχετικά με την πίστη στους κανόνες του σχολείου οι υψηλότερες τιμές αφορούσαν τους/τις μη εμπλεκόμενους/ες και οι χαμηλότερες τον ρόλο «θύτης-θύμα». Τα αποτελέσματα σχολιάζονται υπό το πρίσμα των σύγχρονων ερευνητικών ευρημάτων στον τομέα του σχολικού εκφοβισμού/θυματοποίησης και προτείνονται κατευθυντήριες γραμμές για την αξιοποίησή τους σε προγράμματα παρέμβασης στον χώρο του σχολείου.

Musculoskeletal (MSK) conditions among professional musicians and music students are frequent and may have significant physical and psychosocial consequences on their lives and/or on their playing abilities. The Risk of Music Students (RISMUS) research project was set up in 2018 to longitudinally identify factors associated with increased risk of playing-related musculoskeletal disorders (PRMDs) in a large sample of music students enrolled in pan-European institutions. The aim of this cross-sectional study was to describe the prevalence of playing-related musculoskeletal disorders (PRMDs) in this novel population at baseline of the RISMUS project. A further goal was to begin to identify variables that might be associated with the self-reported presence of PRMDs among music students. Eight hundred and fifty students from fifty-six conservatories and music universities in Europe completed a web-based questionnaire on lifestyle and physical activity participation levels, musical practice habits, health history and PRMDs, psychological distress, perfectionism and fatigue. A total of 560 (65%) out of 850 participants self-reported a positive history of painful MSK conditions in the last 12 months, 408 (48%) of whom self-reported PRMDs. Results showed that coming from West Europe, being a first- or a second-year Masters student, having more years of experience and higher rates of perceived exertion after 45 minutes of practice without breaks were factors significantly associated with self-reported presence of PRMDs. According to the authors' knowledge, a large-scale multicentre study investigating prevalence and associated factors for PRMDs among music students at different stages of their education (from Pre-college to Masters levels) has not been conducted before. The high prevalence of PRMDs among music students, especially those studying at university-level, has been confirmed in this study and associated factors have been identified, highlighting the need for relevant targeted interventions as well as effective prevention and treatment strategies.