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Abstract Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Brugada Syndrome (BrS) is a cardiac arrhythmia disorder which can lead to sudden cardiac death. It is commonly associated with loss-of-function mutations in the SCN5A gene, encoding the alpha subunit of the sodium voltage-gated channel. We introduced the BrS associated mutation c.845G>A (p.R282H) in the SCN5A gene in a human induced pluripotent stem cell (hiPSC) line. We describe two lines, where the mutation is either in the same (cis) or opposite (trans) allele to the common polymorphism c.1673A>G (p.H558R). These hiPSC lines provide physiological models to study the role of this mutation and the effect of the polymorphism in BrS.

A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on INa in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on INa and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak INa of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Nav1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak INa density, or the INa voltage dependence of (in)activation. Importantly, the increase in the peak INa density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases INa density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore INa and cardiac conduction.

Abstract Background Thoracic Aortic Aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threatening vascular disorder due to the risk of aortic dissection and rupture. There is an urgent need to identify blood-borne biomarkers for the early detection of TAA. The goal of the present study was to identify potential protein biomarkers associated with TAAs, using proteomic analysis of aortic tissue and plasma samples. Methods Extracted proteins from 14 aneurysmal and 12 non-aneurysmal thoracic aortic tissue specimens as well as plasma samples from six TAA patients collected pre-and postoperatively and six healthy controls (HC), were analyzed by liquid chromatography-tandem mass spectrometry. Proteomic data were further processed and following filtering criteria, one protein was selected for verification and validation in a larger cohort of patients and controls using a targeted quantitative proteomic approach and enzyme-linked immunosorbent assay, respectively. Results A total of 1593 and 363 differentially expressed proteins were identified in tissue and plasma samples, respectively. Pathway enrichment analysis on the differentially expressed proteins revealed a number of dysregulated molecular pathways that might be implicated in aneurysm pathology including complement and coagulation cascades, focal adhesion, and extracellular matrix receptor interaction pathways. Alpha-2-HS glycoprotein (AHSG) was selected for further verification in 36 TAA and 21 HC plasma samples using targeted quantitative proteomic approach. The results showed a significantly decreased concentration of AHSG (p = 0.0002) in the preoperative plasma samples compared with HC samples. Further analyses using a larger validation dataset revealed that AHSG protein levels were significantly lower (p = 0.03) compared with HC. Logistic regression analysis on the validation dataset revealed males, advanced age, hypertension and hyperlipidaemia as significant risk factors for TAA. Conclusion AHSG concentrations distinguish plasma samples derived from TAA patients and controls. The findings of this study suggest that AHSG may be a potential biomarker for TAA that could lead to better diagnostic capabilities.

Abstract Background Multiple lumbar punctures have historically been a strategy to relieve headaches associated with idiopathic intracranial hypertension despite limited clinical evidence of long-term efficacy. Lumbar puncture is typically a straightforward procedure with minimal complications reported, however, serious complications can occur. Lumbar-puncture-related spinal hematomas are rare but can lead to irreversible paralysis. Case presentation We report a case of a 28-year-old Caucasian woman who was treated with multiple lumbar punctures to manage headache, thought to be attributed to idiopathic intracranial hypertension. The patient developed a lumbosacral epidural hematoma following a lumbar puncture, which led to incomplete cauda equina syndrome. Multiple lumbar punctures had been the long-term management for the patient’s chronic headaches associated with her diagnosis of idiopathic intracranial hypertension. She had no risks of an underlying coagulopathy. Following a lumbar puncture, she re-presented with lower back pain and bilateral paresthesia. Over the subsequent 48 hours, this progressed to urinary incontinence and saddle paresthesia. Imaging revealed an epidural hematoma, which was conservatively managed. She continued to report saddle paresthesia and urinary incontinence 7 months following the lumbar puncture. Between 1974 to 2022, our literature search found 41 case reports detailing lumbar-puncture-related spinal hematomas. It is an established but rare complication of lumbar puncture and there are limited studies looking at the incidence of its occurrence. Whilst coagulopathy has been found to be a risk factor, it is unclear if the gauge of the needle is relevant. Case evidence suggests there may be no significant difference in outcomes between surgical and conservative management of spinal hematomas. This case highlights that lumbar punctures can be invasive, with potentially serious complications. A lumbar puncture should therefore only be performed when clinically justified. Conclusions This case highlights a rare complication of lumbar puncture and emphasizes the importance of a risk–benefit discussion for each procedure. Spinal hematoma following lumbar puncture is a rare complication but with potentially devastating consequences. Within the setting of idiopathic intracranial hypertension, the evidence base for the long-term benefit of headache relief by repeat lumbar puncture is low.

Abstract Objectives Intracranial pressure (ICP) has been thought to vary diurnally. This study evaluates diurnal ICP measurements and quantifies changes in ICP occurring with changes in body posture in active idiopathic intracranial hypertension (IIH). Methods This prospective observational study utilized telemetric ICP monitoring in people with active IIH. Participants had the Raumedic p-Tel ICP intraparenchymal device (Raumedic, Hembrechts, Germany) surgically inserted. Changes in ICP in the supine position were evaluated. Then, the ICP was measured in the standing, sitting, supine, left lateral decubitus positions and with coughing and bending. Ultimately, changes in ICP over the course of 24 h were recorded. ISRCTN registration number 12678718. Results 15 women were included, mean (standard deviation) age 29.5 (9.5) years, body mass index 38.1 (6.2) kg/m2, and baseline mean ICP of 21.2 (4.8) mmHg (equivalent to 28.8 (6.5) cmCSF). Mean ICP rose with the duration in the supine position 1.2 (3.3) mmHg over 5-minutes (p = 0.175), 3.5 (2.8) mmHg over 30-minutes (p = 0.0002) and by a further 2.1 (2.2) mmHg over 3 h (p = 0.042). Mean ICP decreased by 51% when moving from the supine position to standing (21.2 (4.8) mmHg to 10.3 (3.7) mmHg respectively, p = 0.0001). Mean ICP increased by 13% moving from supine to the left lateral decubitus position (21.2 (4.8) mmHg to 24.0 (3.8) mmHg, p = 0.028). There was no significant difference in ICP measurements at any point during the daytime, or between 5-minute standing or supine recordings and prolonged ambulatory daytime and end of night supine recordings respectively. ICP, following an initial drop, increased progressively in conjunction with lying supine position from 23:00 h to 07:00 h by 34% (5.2 (1.9) mmHg, p = 0.026). Conclusion This analysis demonstrated that ICP does not appear to have a diurnal variation in IIH, but varies by position and duration in the supine position. ICP rose at night whilst the patient was continuously supine. Furthermore, brief standing and supine ICP measures in the day predicted daytime prolonged ambulatory measures and end of night peak ICP respectively. This knowledge gives reassurance that ICP can be accurately measured and compared at any time of day in an ambulant IIH patient. These are useful findings to inform clinical measurements and in the interpretation of ICP analyses in IIH. Trial registration ISTCRN (12678718).

The high percentage of energy consumption by fossil fuels in the building sector in combination with climate change across the globe increased the need to move into more sustainable building practices. Thus, the integration of sustainable strategies and active solar energy systems into the design process is becoming a tool for the reduction of the energy demand and improvement of the energy performance of existing and new buildings.This study investigates the energy performance of an existing residential apartment building in Limassol, Cyprus before and after its energy renovation, using a double skin façade combined with building integration of active solar energy systems. The proposed research starts with the analysis of the existing building energy performance, focusing on the energy loads for cooling, heating, and artificial lighting. Subsequently, the results of the existing situation are evaluated using digital energy simulations, and the process moves on to the renovation and energy upgrade of the building by integrating the aforementioned systems. Energy-Plus simulations are performed where the proposed systems’ contribution to the energy reduction is investigated including their energy reduction potential. The before and after simulations are compared, with the focus to prove whether the systems can be viable in terms of decreasing the energy demands of the building. Finally, a life cycle cost (LCC) analysis is performed, to determine the viability of the enterprise. The performed research proves that the application of the double façade, consisting of three main features — a building integrated photovoltaic system (BIPV), glazing system and rambling planting, can combine the positive effects of each individual system, if there is a combined systematic approach on the architectural design of the building envelope. The combination of the above led to a reduction of 83.5% in the energy consumption of the building, from 94,321 kWh of the existing situation to the 15,563 kWh of the proposed one. This reduction includes the contribution from BIPV system, which amounts to 26,706 kWh/ year of primary energy — thus covering the 63% of the proposed consumption of the building. On the other hand, the LCC analysis sums that a careful combination of bioclimatic design and active solar systems, can have a viable payback period, which in this case is 13 years.The overall aim of this research is to determine whether the use of a double skin façade combined with integrated active solar systems constitute an energy and cost-efficient solution for the viable refurbishment of an existing building in the south-eastern Mediterranean area.

BackgroundThe Mindfulness-Based Interventions: Teaching Assessment Criteria (MBI:TAC) is a widely used tool for assessing fidelity in mindfulness-based program (MBP) research and training. It also supports MBP teacher reflective and skill development. MBI:TAC assessors review MBP teaching and rate the teaching on 6 domains. The MBI:TAC yields individual domain and overall scores, using 6 levels of competence. Although the MBI:TAC is widely used in MBP research and training, research is at an early stage.ObjectiveWe developed and tested a method of training MBI:TAC assessors to use the tool reliably and examined interrater reliability of the tool.MethodsA total of 31 international senior MBP teachers were recruited to join an online training to build their skills in using the MBI:TAC. The training systematically and iteratively built familiarity and skills in assessing the 6 MBI:TAC domains. Qualitative and quantitative data on trainee's experience of the training were gathered. Interrater reliability in using the tool was tested each week of the training. At the end of the training, interrater reliability was tested by asking trainees to individually assess videos that they had not previously seen. Their ratings were compared to benchmark assessments, which had been established via consensus agreement between 4 expert users of the MBI:TAC.ResultsThe training was well received and appreciated, with some challenges experienced in applying the assessment methodology. Participants' ratings became progressively more in line with one another and the benchmark ratings during the training. At the end, interrater reliability was high (ranging from 0.67 to 1.0).ConclusionIt is possible for senior MBP trainers, coming from different regions in the world, to align toward common understandings of the elements of MBP teaching competence and program integrity. An assessor training methodology was tested, and the learning from this project has led to refinements for future delivery.

Naegleria fowleri is both a pathogenic and a free-living microbial eukaryote, responsible for the development of primary amoebic meningoencephalitis (PAM) in humans. PAM is a rapid, severe and fatal underestimated infectious disease, which has been reported in countries with warmer climates. The major drawbacks with PAM are the lack of effective therapies and delay in diagnosis. The current frontline treatment presents a low rate of recovery (5%) and severe adverse effects. For example, many drug candidates lack efficacy, since they do not effectively cross the blood-brain-barrier. Consequently, more effective drugs are urgently needed. Herein, we report a new in vitro method suitable for medium- and high-throughput drug discovery assays, using the closely related Naegleria gruberi as a model. We have subsequently used this method to screen a library of 1175 Food and Drug Administration-approved drugs. As a result, we present three drugs (camptothecin, pyrimethamine, and terbinafine) that can be repurposed, and are anticipated to readily cross the blood-brain-barrier with activity against Naegleria species in therapeutically achievable concentrations. Successively, we integrated several in vitro assays that resulted in identifying fast-acting and high amoebicidal drugs. In conclusion, we present a new approach for the identification of anti-Naegleria drugs along with three potential drug candidates for further development for the treatment of PAM.

Lineage differentiation and commitment is driven by transcription regulators and chromatin changes. Here the authors report daily profiling of chromatin accessibility and transcriptome changes during human erythropoiesis, relating these changes to lineage potential between erythropoiesis and megakaryopoieis.

Abstract Objective Headache is the predominant disabler in idiopathic intracranial hypertension (IIH). The aim was to characterise headache and investigate the association with intracranial pressure. Methods IIH:WT was a randomised controlled parallel group multicentre trial in the United Kingdom investigating weight management methods in IIH. Participants with active IIH (evidenced by papilloedema) and a body mass index (BMI) ≥35 kg/m2 were recruited. At baseline, 12 months and 24 months headache characteristics and quality of life outcome measures were collected and lumbar puncture measurements were performed. Results Sixty-six women with active IIH were included with a mean age of 32.0 years (SD ± 7.8), and mean body mass index of 43.9 ± 7.0 kg/m2. The headache phenotype was migraine-like in 90%. Headache severity correlated with ICP at baseline (r = 0.285; p = 0.024); change in headache severity and monthly headache days correlated with change in ICP at 12 months (r = 0.454, p = 0.001 and r = 0.419, p = 0.002 respectively). Cutaneous allodynia was significantly correlated with ICP at 12 months. (r = 0.479, p

Concrete sewer pipes can be corroded by the biogenic sulfuric acid (H2SO4) generated from microbiological activities in a process called biocorrosion or microbiologically induced corrosion (MIC). In this study, inhibitors that can reduce Acidithiobacillus thiooxidans growth and thus may reduce the accumulation of biofilm components responsible for the biodegradation of concrete were used. D-tyrosine, tetrakis hydroxymethyl phosphonium sulfate (THPS) and TiO2 nanoparticles were investigated as potential inhibitors of sulfur-oxidizing bacteria (SOB) growth. Results showed that most of the chemicals used can inhibit SOB growth at a concentration lower than 100 mg/L. TiO2 nanoparticles exhibited the highest biocide effect and potential biocorrosion mitigation activity, followed by D-tyrosine and THPS.

Abstract Background Headache is the dominant factor for quality of life related disability in idiopathic intracranial hypertension (IIH) and typically has migraine-like characteristics. There are currently no evidence-based therapeutics for headache in IIH, and consequently this is an important unmet clinical need. Case series We report a series of seven patients in whom headaches were the presenting feature of IIH and the headaches had migraine-like characteristics, as is typical in many IIH patients. Papilloedema settled (ocular remission) but headaches continued. These headaches responded markedly to erenumab, a monoclonal antibody targeted against the calcitonin gene related peptide (CGRP) receptor. Of note, there was a recurrence of raised ICP, as evidenced by a return of the papilloedema, however the headaches did not recur whilst treated with erenumab. Conclusions Those with prior IIH who have their headaches successfully treated with CGRP therapy, should remain under close ocular surveillance (particularly when weight gain is evident) as papilloedema can re-occur in the absence of headache. These cases may suggest that CGRP could be a mechanistic driver for headache in patients with active IIH.