Initial combination therapy with macitentan and tadalafil in patients with pulmonary arterial hypertension, with and without cardiac comorbidities.

AIMS: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. METHODS AND RESULTS: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. CONCLUSIONS: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.

The value of stereoscopic three-dimensional vision on dental students' performance in a virtual reality simulator.

PURPOSE/OBJECTIVES: The aim of this study was to quantitatively investigate the impact of stereoscopic three-dimensional (3D) vision on students' performance when compared with that of two-dimensional (2D) vision in a 3D virtual reality (VR) simulator. METHODS: Twenty-four dental students (second- and fourth-year BDS) were assigned to perform three operative tasks under 3D and 2D viewing conditions on a Virteasy (HRV) simulator. Groups were crossed over and all students performed the same tasks under the alternate viewing conditions. The performance was evaluated by (1) accuracy, (2) outside target area removal, and (3) tooth cutting time, automatically using the generated feedback. RESULTS: Twenty-one participants completed all sessions. The results revealed a statistically significant effect of 3D vision over 2D vision on students' performance in terms of accuracy (p = 0.035). Stereoscopic 3D vision showed significant effect on outside target area removal in the first task (p = 0.035). Tooth cutting time was the same under both conditions (p = 0.766). The findings revealed improvement in accuracy score and reduction in outside target area removal over the course of the experiment under both conditions. Comparing the difference in 3D effect in the early and advanced learning groups revealed no significant difference among the groups (p > 0.05). CONCLUSION: Utilizing stereoscopic 3D vision in the training session improved students' perception of depth which led to more accurate tooth cutting within the target area, and less outside target area removal. However, 3D shows a limited impact on task completion time.

Effects of Cardiopulmonary Rehabilitation on Cardiorespiratory Fitness and Clinical Symptom Burden in Long COVID: Results from the COVID-Rehab Randomized Controlled Trial.

OBJECTIVE: To investigate the effectiveness of an eight-week cardiopulmonary rehabilitation program on cardiorespiratory fitness (VO2peak) and key cardiopulmonary exercise test measures, quality of life, and symptom burden in individuals with Long COVID. DESIGN: Forty individuals with Long COVID (mean age 53 ± 11 years), were randomized into 2 groups: 1/ Rehabilitation group: centre-based individualized clinical rehabilitation program (8 weeks, 3 sessions per week of aerobic and resistance exercises, and daily inspiratory muscle training) and 2/ Control group: individuals maintained their daily habits during an eight-week period. RESULTS: There was a significant difference between groups in mean VO2peak improvement (p = 0.003). VO2peak improved significantly in the rehab group (+2.7 mL.kg.min 95%IC:+1.6 to +3.8 p < 0.001) compared to the control group (+0.3 mL.kg.min 95%IC:-0.8 to +1.3 p = 0.596), along withVE/VCO2 slope (p = 0.032) (-2.4 95%IC:-4.8 to +0.01 p = 0.049 and + 1.3 95%IC:-1.0 to +3.6 p = 0.272 respectively) and VO2 at first ventilatory threshold (p = 0.045). Furthermore, all symptom impact scales improved significantly in the rehabilitation group compared to the control group (p < 0.05). CONCLUSION: An individualized and supervised cardiopulmonary rehabilitation program was effective in improving cardiorespiratory fitness, ventilatory efficiency, and symptom burden in individuals with Long COVID. Careful monitoring of symptoms is important to appropriately tailor and adjust rehabilitation sessions.

[18F]FDG-PET/CT atypical response patterns to immunotherapy in non-small cell lung cancer patients: long term prognosis assessment and clinical management proposal.

AIM: To determine the long-term prognosis of immune-related response profiles (pseudoprogression and dissociated response), not covered by conventional PERCIST criteria, in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs). METHODS: 109 patients were prospectively included and underwent [18F]FDG-PET/CT at baseline, after 7 weeks (PETinterim1), and 3 months (PETinterim2) of treatment. On PETinterim1, tumor response was assessed using standard PERCIST criteria. In the event of PERCIST progression at this time-point, the study design provided for continued immunotherapy for 6 more weeks. Additional response patterns were then considered on PETinterim2: pseudo-progression (PsPD, subsequent metabolic response); dissociated response (DR, coexistence of responding and non-responding lesions), and confirmed progressive metabolic disease (cPMD, subsequent homogeneous progression of lesions). Patients were followed up for at least 12 months. RESULTS: Median follow-up was 21 months. At PETinterim1, PERCIST progression was observed in 60% (66/109) of patients and ICPI was continued in 59/66. At the subsequent PETinterim2, 14% of patients showed PsPD, 11% DR, 35% cPMD, and 28% had a sustained metabolic response. Median overall survival (OS) and progression-free-survival (PFS) did not differ between PsPD and DR (27 vs 29 months, p = 1.0; 17 vs 12 months, p = 0.2, respectively). The OS and PFS of PsPD/DR patients were significantly better than those with cPMD (29 vs 9 months, p < 0.02; 16 vs 2 months, p < 0.001), but worse than those with sustained metabolic response (p < 0.001). This 3-group prognostic stratification enabled better identification of true progressors, outperforming the prognostic value of standard PERCIST criteria (p = 0.03). CONCLUSION: [18F]FDG-PET/CT enables early assessment of response to immunotherapy. The new wsPERCIST ("wait and see") PET criteria proposed, comprising immune-related atypical response patterns, can refine conventional prognostic stratification based on PERCIST criteria. TRIAL REGISTRATION: HDH F20230309081206. Registered 20 April 2023. Retrospectively registered.

Sustainable oral healthcare: what is it and how do we achieve it?

In recent years, there has been an increase in interest in what environmental sustainability means for healthcare, including oral health and dentistry. To help facilitate discussions among key stakeholders in this area, the Scottish Dental Clinical Effectiveness Programme held a workshop in November 2022. The purpose of this workshop was to explore current thinking on the subject of sustainability as it relates to oral health and to help stakeholders identify how to engage with the sustainability agenda. This paper presents an overview of the presentations and discussions from the workshop and highlights potential avenues for future work and collaboration.

Optical Spin Waves.

Chirality is inherent to a broad range of systems, including solid-state and wave physics. The precession (chiral motion) of the magnetic moments in magnetic materials, forming spin waves, has various properties and many applications in magnetism and spintronics. We show that an optical analogue of spin waves can be generated in arrays of plasmonic nanohelices. Such optical waves arise from the interaction between twisted helix eigenmodes carrying spin and orbital angular momenta. We demonstrate that these optical spin waves are reflected at the interface between successive domains of enantiomeric nanohelices, forming a heterochiral lattice regardless of the wave propagation direction within the lattice. Optical spin waves may be applied in techniques involving photon spin, ranging from data processing and storage to quantum optics.

Characterizing phenotypic data of Peromyscus leucopus compared to C57BL/6J Mus musculus and diversity outbred (DO) Mus musculus.

Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.

Structural Optimization of Azacryptands for Targeting Three-Way DNA Junctions.

Transient melting of the duplex-DNA (B-DNA) during DNA transactions allows repeated sequences to fold into non-B DNA structures, including DNA junctions and G-quadruplexes. These noncanonical structures can act as impediments to DNA polymerase progression along the duplex, thereby triggering DNA damage and ultimately jeopardizing genomic stability. Their stabilization by ad hoc ligands is currently being explored as a putative anticancer strategy since it might represent an efficient way to inflict toxic DNA damage specifically to rapidly dividing cancer cells. The relevance of this strategy is only emerging for three-way DNA junctions (TWJs) and, to date, no molecule has been recognized as a reference TWJ ligand, featuring both high affinity and selectivity. Herein, we characterize such reference ligands through a combination of in vitro techniques comprising affinity and selectivity assays (competitive FRET-melting and TWJ Screen assays), functional tests (qPCR and Taq stop assays), and structural analyses (molecular dynamics and NMR investigations). We identify novel azacryptands TrisNP-amphi and TrisNP-ana as the most promising ligands, interacting with TWJs with high affinity and selectivity. These ligands represent new molecular tools to investigate the cellular roles of TWJs and explore how they can be exploited in innovative anticancer therapies.

Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight.

Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space.

Correlation between Matrix Metalloproteinase presence and caries surface appearance.

INTRODUCTION: Cariogenic bacterial acids dissolve the inorganic elements in dentine, leaving the dentine matrix exposed. Host-derived matrix metalloproteinases (MMPs) play an essential role in caries progression as they are significant regulators of extracellular matrix turnover and can degrade exposed collagen. This paper investigates the expression of MMP2 and MMP9 across various stages of caries in primary human teeth and relate this with a diagnosis recorded by The International Caries Detection and Assessment System (ICDAS). METHODS: Twenty-four sections (150um in thickness) from extracted teeth, clinically diagnosed using ICDAS, were immunohistochemically treated with monoclonal anti-MMP2 and anti-MMP9 antibodies. Positive staining was visualised by immunofluorescence using a VectorFluor Duet Double Labeling Kit. Images from triplicate samples for each ICDAS score were analysed using ImageJ software. Collagen degradation in caries lesions was detected using a hydroxyproline assay. RESULTS: MMPs were weakly detected in caries with ICDAS 1-2 scores, and an insignificant increase was detected in ICDAS 3. However, a significant increase in MMP expression was seen in caries with an ICDAS score of 4-6. There was a strong positive correlation between the ICDAS score and MMP2, [r(6) = .86, p = .002] and between ICDAS and MMP9, [r(6) = .82, p = .004]. Data were analysed using two-way ANOVA followed by Tukey multiple comparison test (*p < 0.05). CONCLUSION: The use of ICDAS to assess the severity of caries lesions and how this correlates with the presence of MMP in these lesions validates the modern approach to caries management with a minimally invasive concept.

Effect of liming on polycyclic aromatic hydrocarbons leaching from hydrocarbon-contaminated tectogenic industriosol.

Soil stabilization/solidification is commonly employed remediation method for contaminated soils. Until now, limited attention has been given to the application of quicklime in polycyclic aromatic hydrocarbons (PAHs) contaminated soil. We treated a tectogenic industriosol spiked with 50 mg kg-1 of four PAHs (12.5 mg kg-1 each of fluorene (FLU), phenanthrene (PHE), fluoranthene (FLT) and pyrene (PYR)) using three different liming agents at 1% (w:w): quicklime (CaO), hydrated lime (Ca(OH)2) and carbonate calcium (CaCO3). All treated samples were leached in water at a solid-liquid ratio of 10, with subsequent analysis of leached soil and leachates for PAHs content. Results revealed that the addition of liming agents led to a reduction in FLU and PHE concentrations in treated soil by 6.81 ± 2.47% and 28.88 ± 4.18%, respectively, compared to a not-treated sol. However, no significant impact was observed on the 4-cycles PAHs (FLT and PYR). The addition of liming agents also significantly decreased the amount of PAHs in the leachate, by 100% for FLU and PHE, and by 74.9 ± 17.5% and 72.3 ± 34.8%, for FLT and PYR, respectively, compared to not limed soil. Among the liming agents, quicklime was the most effective in reducing the amount of 4 cycles PAHs in the leachate. Various mechanisms, such as encapsulation, volatilization and oxidation could contribute to this observed reduction. Quicklime treatment at a concentration of 1% w:w in PAHs-contaminated soil emerges as a promising technique to effectively reduce PAHs concentration in soils and mitigate PAHs mobility through leaching. This study also sheds light on the possibility to limit CO2 emissions and resources exploitation to assure the remediation process, thereby enhancing its overall environmental sustainability.

From hunter-gatherers to food producers: New dental insights into the Nile Valley population history (Late Paleolithic-Neolithic).

OBJECTIVES: This study presents biological affinities between the last hunter-fisher-gatherers and first food-producing societies from the Nile Valley. We investigate odontometric and dental tissue proportion changes between these populations from the Middle Nile Valley and acknowledge the biological processes behind them. MATERIALS AND METHODS: Dental remains of 329 individuals from Nubia and Central Sudan that date from the Late Pleistocene to the mid-Holocene are studied. Using 3D imaging techniques, we investigated outer and inner metric aspects of upper central incisors, and first and second upper molars. RESULTS: Late Paleolithic and Mesolithic foragers display homogeneous crown dimensions, dental tissue proportions, and enamel thickness distribution. This contrasts with Neolithic trends for significant differences from earlier samples on inner and outer aspects. Finally, within the Neolithic sample differences are found between Nubian and Central Sudanese sites. DISCUSSION: Substantial dental variation appears to have occurred around 6000 bce in the Nile Valley, coinciding with the emergence of food-producing societies in the region. Archeological and biological records suggest little differences in dietary habits and dental health during this transition. Furthermore, the substantial variations identified here would have happened in an extremely short time, a few centuries at most. This does not support in situ diet-related adaptation. Rather, we suggest these data are consistent with some level of population discontinuity between the Mesolithic and Neolithic samples considered here. Complex settlement processes could also explain the differences between Nubia and Central Sudan, and with previous results based on nonmetric traits.

Using agro-ecological zones to improve the representation of a multi-environment trial of soybean varieties.

This research introduces a novel framework for enhancing soybean cultivation in North America by categorizing growing environments into distinct ecological and maturity-based zones. Using an integrated analysis of long-term climatic data and records of soybean varietal trials, this research generates a zonal environmental characterization which captures major components of the growing environment which affect the range of adaptation of soybean varieties. These findings have immediate applications for optimizing multi-environment soybean trials. This characterization allows breeders to assess the environmental representation of a multi-environmental trial of soybean varieties, and to strategize the distribution of testing and the placement of test sites accordingly. This application is demonstrated with a historical scenario of a soybean multi-environment trial, using two resource allocation models: one targeted towards improving the general adaptation of soybean varieties, which focuses on widely cultivated areas, and one targeted towards specific adaptation, which captures diverse environmental conditions. Ultimately, the study aims to improve the efficiency and impact of soybean breeding programs, leading to the development of cultivars resilient to variable and changing climates.

Total metabolic tumor volume on 18F-FDG PET/CT is a game-changer for patients with metastatic lung cancer treated with immunotherapy.

PURPOSE: Because of atypical response imaging patterns in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs), new biomarkers are needed for a better monitoring of treatment efficacy. The aim of this prospective study was to evaluate the prognostic value of volume-derived positron-emission tomography (PET) parameters on baseline and follow-up 18F-fluoro-deoxy-glucose PET (18F-FDG-PET) scans and compare it with the conventional PET Response Criteria in Solid Tumors (PERCIST). METHODS: Patients with metastatic NSCLC were included in two different single-center prospective trials. 18F-FDG-PET studies were performed before the start of immunotherapy (PETbaseline), after 6-8 weeks (PETinterim1) and after 12-16 weeks (PETinterim2) of treatment, using PERCIST criteria for tumor response assessment. Different metabolic parameters were evaluated: absolute values of maximum standardized uptake value (SUVmax) of the most intense lesion, total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), but also their percentage changes between PET studies (ΔSUVmax, ΔTMTV and ΔTLG). The median follow-up of patients was 31 (7.3-31.8) months. Prognostic values and optimal thresholds of PET parameters were estimated by ROC (Receiver Operating Characteristic) curve analysis of 12-month overall survival (12M-OS) and 6-month progression-free survival (6M-PFS). Tumor progression needed to be confirmed by a multidisciplinary tumor board, considering atypical response patterns on imaging. RESULTS: 110 patients were prospectively included. On PETbaseline, TMTV was predictive of 12M-OS [AUC (Area Under Curve) =0.64; 95% CI: 0.61 to 0.66] whereas SUVmax and TLG were not. On PETinterim1 and PETinterim2, all metabolic parameters were predictive for 12M-OS and 6M-PFS, the residual TMTV on PETinterim1 (TMTV1) being the strongest prognostic biomarker (AUC=0.83 and 0.82; 95% CI: 0.74 to 0.91, for 12M-OS and 6M-PFS, respectively). Using the optimal threshold by ROC curve to classify patients into three TMTV1 subgroups (0 cm3; 0-57 cm3; >57 cm3), TMTV1 prognostic stratification was independent of PERCIST criteria on both PFS and OS, and significantly outperformed them. Subgroup analysis demonstrated that TMTV1 remained a strong prognostic biomarker of 12M-OS for non-responding patients (p=0.0003) according to PERCIST criteria. In the specific group of patients with PERCIST progression on PETinterim1, low residual tumor volume (<57 cm3) was still associated with a very favorable patients' outcome (6M-PFS=73%; 24M-OS=55%). CONCLUSION: The absolute value of residual metabolic tumor volume, assessed 6-8 weeks after the start of ICPI, is an optimal and independent prognostic measure, exceeding and complementing conventional PERCIST criteria. Oncologists should consider it in patients with first tumor progression according to PERCIST criteria, as it helps identify patients who benefit from continued treatment. TRIAL REGISTRATION NUMBER: 2018-A02116-49; NCT03584334.

Curriculum content for Environmental Sustainability in Dentistry.

OBJECTIVES: (i) To identify suitable strategies and opportunities to embed Environmental Sustainability (ES) within an existing Oral Health Professional (OHP) curriculum through a series of focus groups with students and academic staff and (ii) To create high-level evidence-based and subject-specific ES content through an approach grounded in evidence and collaboration with key stakeholders in OHP education. METHODS: Focus groups were used to explore academic staff and student views on appropriate teaching and assessment methods for ES. Content statements were developed from an extensive literature search, mapped to curriculum subjects, and validated through consultation with students, discipline-experts and education-experts. RESULTS: Five themes were identified from the focus groups: ES transcends all disciplines of dentistry and oral healthcare; baseline knowledge transmission with relevant practical application; viewing and modifying existing teaching and assessment events through a different lens; normalising the topic of ES to support attitude and behaviour change and safeguarding against misinformation and disinformation. Forty-four content statements were developed and mapped to nineteen curriculum subjects. CONCLUSIONS: This study identifies for the first time a comprehensive strategy for the inclusion and delivery of ES (method and content) in the curriculum. A novel method to define and map curriculum content has been explored and validated using a range of complementary methodologies. A comprehensive and robust list of evidence-based and subject-specific educational content statements have been defined in the field of Environmental Sustainability in dentistry and oral healthcare. CLINICAL SIGNIFICANCE: Oral healthcare has a significant environmental impact, the key to all mitigation strategies is educating the profession at all levels.

'It's like being in a tunnel': Understanding the patient journey from tooth loss to life with removable dentures.

INTRODUCTION: The aim of this study was to conceptualise the key stages of the patient journey in the provision of a new denture and examine the factors leading to successful patient-related outcomes. METHODS: Two partially dentate patient samples were included: (i) Denture wearers - patients who had a denture fitted within the previous five years and (ii) New dentures - patients receiving treatment for a new or replacement denture. The methods involved direct targeted participant observations of the denture fitting process, debriefing interviews and a follow-up focus group exploring the patient journey. Data were analysed through the use of phenomenology and grounded theory. RESULTS: Interviews were completed with twenty participants of the denture-wearing sample (11 males and nine females, age range 22 to 86 years). Thirteen participants were included in the treatment journey sample in two primary care settings (six males and seven females, age range 55 to 101 years). Tooth loss and recovery was described as being in an 'emotional tunnel' resulting from 'bodyphonic processes' associated with tooth loss. 'Bodyphonia' subsequently became the context for 'taking control' and 'managing disclosure' when living with a removable denture. Different courses through this process can be readily observed, moderated by different variables (i.e., previous experience, working knowledge, a good fit, the treatment alliance, negotiated compromises and bounded responsibility). CONCLUSIONS: An'integrating framework' that seeks to describe the patient journey from the experience of tooth loss to recovery with a denture is proposed. This framework could be used to aid development of a clinical pathway to guide treatment options. CLINICAL SIGNIFICANCE: This paper conceptualises the patient journey. It stresses the importance of understanding the stages patients go through and highlights that for the dental team, the try-in stage is perhaps the best stage to give information about the denture and plans for continued care.

Environmental sustainability: the attitudes and experiences of UK students in the oral health care profession.

Objective This study aims to provide insight into the attitudes and perspectives of undergraduate dental students from UK dental schools regarding environmental sustainability in dentistry (ESD) and the manner and extent in which ESD is included in the current undergraduate oral health care curricula.Methods This study is a multi-centre, nationally representive study involving a cross-sectional online survey of undergraduate Bachelor of Dental Surgery and dental hygiene and therapy students in UK-based dental schools. Data analysis was conducted through descriptive statistics and thematic analysis.Results In total, 263 students from 13 UK schools completed the survey, resulting in a national school response rate of 68.4%. Key findings are: 97.3% of students believe that the dental profession should be more actively engaged in environmental sustainability but students currently have very little exposure to ESD at an undergraduate level; and 76.8% of students expressed that they are concerned about the impact that oral health care provision has on the environment, but only 23% of students have independently researched ESD.Conclusions Students identify that oral health care professionals should become more engaged in efforts to mitigate the negative impacts from our activities on the environment, principally via education at all levels. The data from this study provide insight into the current level of awareness and concerns for the environmental impacts of oral health care provision, and are a powerful driver for the inclusion of ESD into the undergraduate curriculum in UK based dental schools.

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd.

Prognostic Value of a New Right Ventricular-to-Pulmonary Artery Coupling Parameter Using Right Ventricular Longitudinal Shortening Fraction in Patients Undergoing Transcatheter Aortic Valve Replacement: A Prospective Echocardiography Study.

Introduction: Right-ventricular-to-pulmonary artery (RV-PA) coupling, measured as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP), has emerged as a predictor factor in patients undergoing transcatheter aortic valvular replacement (TAVR). Right ventricular longitudinal shortening fraction (RV-LSF) outperformed TAPSE as a prognostic parameter in several diseases. We aimed to compare the prognostic ability of two RV-PA coupling parameters (TAPSE/PASP and the RV-LSF/PASP ratio) in identifying MACE occurrences. Method: A prospective and single-center study involving 197 patients who underwent TAVR was conducted. MACE (heart failure, myocardial infarction, stroke, and death within six months) constituted the primary outcome. ROC curve analysis determined cutoff values for RV-PA ratios. Multivariable Cox regression analysis explored the association between RV-PA ratios and MACE. Results: Forty-six patients (23%) experienced the primary outcome. No significant difference in ROC curve analysis was found (RV-LSF/PASP with AUC = 0.67, 95%CI = [0.58-0.77] vs. TAPSE/PASP with AUC = 0.62, 95%CI = [0.49-0.69]; p = 0.16). RV-LSF/PASP < 0.30%.mmHg-1 was independently associated with the primary outcome. The 6-month cumulative risk of MACE was 59% (95%CI = [38-74]) for patients with RV-LSF/PASP < 0.30%.mmHg-1 and 17% (95%CI = [12-23]) for those with RV-LSF/PASP ≥ 0.30%.mmHg-1; (p < 0.0001). Conclusions: In a contemporary cohort of patients undergoing TAVR, RV-PA uncoupling defined by an RV-LSF/PASP < 0.30%.mmHg-1 was associated with MACE at 6 months.

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

INTRODUCTION: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. METHODS: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses. RESULTS: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of - 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. CONCLUSIONS: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. TRIAL REGISTRATION NUMBER: REPAIR NCT02310672.