Serious adverse events associated with new vaccines targeting SARS-CoV-2 are of high interest to the public and to public health as a worldwide mass immunization campaign has been initiated to contain the ongoing COVID-19 pandemic. We describe a series of 4 individuals with signs of a myocarditis/pericarditis according to cardiac MRI results in temporal association with currently in the European Union authorized SARS-CoV-2 vaccines. We found mild abnormal MRI results independent of the type of SARS-CoV-2 vaccine. There is a need of continuing monitoring outcomes of myocarditis cases after COVID-19 vaccination as recently published cases suggest an uncomplicated short-term course whereas the long-term implications are not yet known but taking the available evidence into account the benefits of using COVID-19 vaccines still clearly outweigh the risks. Before the COVID-19 pandemic, there have only been a few reports of myocarditis and pericarditis as an adverse event following immunization with the exception of cases following live-attenuated smallpox vaccine .Serious adverse events associated with new vaccines targeting SARS-CoV-2 are of high interest to the public and to public health as a worldwide mass immunization campaign has been initiated to contain the ongoing COVID-19 pandemic.SARS-CoV-2 vaccines currently authorized for use in the European Union by the European Pharmacy Agency include the messenger RNA (mRNA) vaccine Comirnaty (Pfizer-BioNTech), Spikevax (Moderna) and the vector-based vaccines Vaxzevria (AstraZeneca), and Vaccine Janssen (Johnson and Johnson) .We describe a series of 4 individuals with signs of a myocarditis/pericarditis according to cardiac MRI results in temporal association with SARS-CoV-2 vaccination to investigate any differences regarding the phenotype.For this report we retrospectively reviewed cardiac MRI exams performed at our institution between 07/01/2021-09/06/2021 for MRI findings of cardiac inflammation such as myocarditis or pericarditis associated with SARS-CoV-2 Vaccination. We reviewed the medical records regarding the timing of COVID-19 or SARS-CoV-2 vaccination and the vaccine used. All available demographic, clinical or laboratory information were documented .The study complies with the declaration of Helsinki. Approval was obtained from the ethics committee of Charite – Unversitätsmedizin Berlin. All examinations have been clinically indicated.Cardiac MRI was performed at 1.5T/3T  and evaluated using a standardized diagnostic protocol as described previously . The proPatient 1, a healthy 21-year-old male, received his second vaccination dose of Spikevax (Moderna). The following day the patient complained about chest pain and discomfort, shortness of breath, limited physical capacity and malaise. At presentation to the hospital the electrocardiogram showed no pathological findings. The serum levels for C-reactive protein and NT-proBNP were normal. High-sensitive Troponin T was elevated up to 526 ng/l . A coronary angiography was performed with exclusion of a coronary artery disease. CT pulmonary angiography excluded a pulmonary embolism. Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease.Cardiac MRI at 3 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction and normal values for the global longitudinal strain. T2 weighted images indicated a regional edema anterolateral/inferolateral  with corresponding elevated quantitative myocardial T2 mapping parameters up to 70 ms  . CorrespPatient 2, a healthy 42-year-old male, received the second vaccination dose of Comirnaty (Pfizer-BioNTech). Two days later, the patient presented to the emergency room of a referring hospital with chest pain and discomfort, shortness of breath and a decreased physical capacity.The electrocardiogram on admission showed no pathological findings. The serum levels for C-reactive protein  and cardiac necrosis marker were elevated with a highsensitive Troponin-I level of 4,868 pg/ml  and creatinin kinase of 581 U/l . The levels for D-Dimer and BNP were normal. A coronary angiography was performed with exclusion of a coronary artery disease. CT pulmonary angiography excluded a pulmonary embolism. Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease.Cardiac MRI at 3 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction but reduced values for the global longitudinal strain with −17.8% . T2 weighted images indicated a regional edema inferior/inferolateral  with corresponding elevated quantitative myocardial T2 mapping parameters up to 53 ms  and corresponding subepicardial LGE in this region . The gloPatient number 3 was an 18-year-old healthy and athletic young man. The patient reported that shortly after a vaccination with Janssen (Johnson and Johnson), he initially experienced an episode of fever and limb pain. The initial symptoms subsided significantly after 3 days. However, a marked limitation of physical capacity and a feeling of chestpain and discomfort at rest and under physical stress remained. After the complaints persisted even for 2 months after vaccination, an outpatient presentation was made for further diagnostics. The electrocardiogram showed no pathological findings. Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease. Cardiac MRI at 1.5 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction and normal values for global longitudinal strain. The images showed a mild pericardial effusion in the area of the free RV wall and the basal posterior LV wall up to a maximum of 4 mm with evidence of inflammatory changes of the pericardium in the T2 weighted images and the LGE images in the area of the lateral LV wall. The global T2 relaxation time  and T1 relaxation time  were normal. Assuming a discrete pericarditis of the LV-lateral area, a native MRI follow-up after 3 months was recommended.Patient number 4, a healthy 18-year-old male received the first dose of Vaxzevria (AstraZeneca) at the end of June 2021. The patient reported new episodes of chestpain and discomfort and exercise limitation ~10 days after the vaccination. Initially, no medical presentation was made in the expectation that the symptoms would disappear. After a clear increase of the symptoms in the course of time, the patient presented to the emergency department of a referring hospital. The electrocardiogram on admission showed ST segment elevation in the inferior leads . A coronary angiography was performed with exclusion of a coronary artery disease. The serum levels for C-reactive Protein  and highsensitive Troponin-I  were normal. Creatinin kinase was increased with a serum level of 255 U/l . Transthoracic echocardiography showed normal myocardial function without wall motion abnormalities or relevant valvular heart disease.Cardiac MRI at 1.5 Tesla showed a normal left and right ventricular size with normal left and right ventricular ejection fraction and normal values for global longitudinal strain. The examination showed a mild to moderate pericardial effusion up to 11 mm in the mid-posterior wall of the LV. There was no evidence of acute cardiac inflammation in the T2 weighted and LGE images. The global T2 relaxation time  and T1 relaxation time  were normal. In the absence of signs of acute cardiac inflammation in the T2 weighted images and the LGE images, the pericardial effusion was considered as a possible residual of an expired pericarditis/myocarditis.Myocarditis is an inflammation of the heart muscle in the absence of ischemia . If it iFor vaccine associated myocarditis the underlying mechanisms are not fully understood either. Molecular mimicry between the spike protein of SARS-CoV-2 and self-antigens, trigger of preexisting dysregulated immune pathways, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have recently been proposed .Vaccine associated myocarditis is still overall rare and more common in males and the young population . The AdvThe reasons for male predominance is unknown, but theories relate to sex hormone differences in immune response and myocarditis and underdiagnosis of cardiac disease in women .Severity and clinical presentation of myocarditis or pericarditis vary among patients. Symptoms might include dyspnea, chest pain or palpitations, although especially in younger children other symptoms might be present . The cliAs also seen in our patients the clinical course of SARS-Cov2 vaccination associated myocarditis is typically mild and self-limited . Most caRegarding the guidelines for a mild and uncomplicated myocarditis/pericarditis a myocardial biopsy or viral serology was not performed in our patients. According to the guidelines the management depends on supportive therapy with targeted cardiac and anti-inflammatory medications and specific interventions if necessary , 11. ExeWe found mild abnormal MRI results independent of the type of SARS-CoV-2 vaccine. We hypothesize, that abnormal findings might be present independent of vaccine and potentially might also be present when patients are flu-vaccinated. Future research work should also focus on this aspect. A more pragmatic approach might be to look first for cardiac abnormalities in cases of cardiac symptoms after vaccination, such as elevated lab values as troponin and NTproBNP or abnormalities at echocardiography as previously described from our group post COVID-19 .In conclusion clinicians should be aware of vaccine-induced myocarditis as a possible adverse event after SARS-CoV-2-vaccination.There is a need of continuing monitoring outcomes of myocarditis cases after COVID-19 vaccination as recently published cases suggest an uncomplicated short-term course whereas the long-term implications are not yet known.Taking into account the available evidence including the risks of myocarditis and pericarditis, it can be determined that the benefits of using COVID-19 vaccines still clearly outweigh the risks. There is a need for a continued educational campaign for the public regarding the risk of COVID-19 and the benefits and risks of a SARS-CoV-2 vaccination.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Charite Unversitätsmedizin Berlin. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.The first draft of the manuscript was written by CJ and all authors commented on previous versions of the manuscript. All authors contributed to the study conception and design, read, and approved the final manuscript.SK received funding from the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research).SK as a researcher is supported by a grant from Philips Healthcare. CS is an employee of Philips Healthcare. The following authors report financial activities outside the submitted work: BP reports having received consultancy and lecture honoraria from Bayer Daiichi Sankyo, MSD, Novartis, Sanofi-Aventis, Stealth Peptides and Vifor Pharma; and editor honoraria from the Journal of the American College of Cardiology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Quantification of natural knee kinematics is essential for the assessment of joint function in the diagnosis of pathologies. Combined measurements of tibiofemoral and patellofemoral joint kinematics are necessary because knee pathologies, such as progression of osteoarthritis and patellar instability, are a frequent concern in both articulations. Combined measurement of tibiofemoral and patellofemoral kinematics also enables calculation of important quantities, specifically patellar tendon angle, which partly determines the loading vector at the tibiofemoral joint and patellar tendon moment arm. The goals of this research were to measure the differences in tibiofemoral and patellofemoral kinematics, patellar tendon angle (PTA), and patellar tendon moment arm (PTMA) that occur during non-weight-bearing and weight-bearing activities in older adults. Methods: High-speed stereo radiography was used to measure the kinematics of the tibiofemoral and patellofemoral joints in subjects as they performed seated, non-weight-bearing knee extension and two weight-bearing activities: lunge and chair rise. PTA and PTMA were extracted from the subject’s patellofemoral and tibiofemoral kinematics. Kinematics and the root mean square difference (RMSD) between non-weight-bearing and weight-bearing activities were compared across subjects and activities. Results: Internal rotation increased with weight-bearing (mean RMSD from knee extension was 4.2 ± 2.4° for lunge and 3.6 ± 1.8° for chair rise), and anterior translation was also greater (mean RMSD from knee extension was 2.2 ± 1.2 mm for lunge and 2.3 ± 1.4 mm for chair rise). Patellar tilt and medial–lateral translation changed from non-weight-bearing to weight-bearing. Changes of the patellar tendon from non-weight-bearing to weight-bearing were significant only for PTMA. Conclusions: While weight-bearing elicited changes in knee kinematics, in most degrees of freedoms, these differences were exceeded by intersubject differences. These results provide comparative kinematics for the evaluation of knee pathology and treatment in older adults. In vitro studies have documented how alteration in tibiofemoral joint translation and rotation can change patellofemoral joint function  quantify differences in tibiofemoral and patellofemoral kinematics, and patellar tendon angle and moment arm that occur from non-weight-bearing to weight-bearing in older adults; 2) determine if changes in tibiofemoral kinematics correspond with changes in patellofemoral kinematics; and 3) examine whether these differences in kinematics were variable between individuals.2, height = 166.8 ± 10.9 cm) provided informed consent and participated in the University of Denver Institutional Review Board-approved study.Seventeen healthy individuals with no history of injuries or surgeries to the lower limbs  was used to measure the kinematics of the tibiofemoral and patellofemoral joints in each subject’s dominant knee . HSSR caParticipants performed three activities: 1) knee extension in which the individuals were seated and slowly extended their knee from high flexion to full extension (seated knee extension); 2) weight-bearing deep knee bend (lunge); 3) and standing up from a chair without arm support (chair rise) . One subThree-dimensional models of the distal femur, proximal tibia, and patella bones were reconstructed from the CT data using ScanIP (Simpleware Inc.). Positions of the three-dimensional bone models were matched to the two-dimensional stereo radiography images to quantify the translational and rotational pose of the tibia and patella relative to the femur .th-order low-pass Butterworth filter with a cutoff frequency of 2 Hz for all three activities. The contact points of the femur on the tibial plateau were estimated with tibiofemoral low-point kinematics , valgus rotation (TVV), anterior translation (TAP), patellar flexion (PFE), tilt (PTilt), and medial translation (PML). In addition, the patellar tendon angle (PTA) was taken as the line between the inferior pole of the patella, the tibial tuberosity, and the long axis of the tibia. Patellar tendon moment arm (PTMA) was calculated as the perpendicular distance from the patellar tendon to the instantaneous axis of rotation of the tibiofemoral joint. The patella tendon was defined as a straight line from the patella apex to the tibial tuberosity, and the instantaneous axis of rotation was calculated using the equations described by On average, tibial rotation (TIE) was more internal during weight-bearing . AverageMost of the subjects remained near neutral alignment or varus TVV,  throughoTibial anterior translation TAP,  during tLow-point kinematics indicated a more medial pivot  for ten of the subjects for all three activities  and the lowest PTAs at maximum knee flexion  was highest at full extension  and lowest at high knee flexion angles  for all three activities, with notable intersubject differences in the amount of rotation . AverageLike prior studies, general trends in tibia motion relative to the femur were similar for all subjects across activities. Tibial kinematics during seated knee extension agreed with R2 = 0.96 for knee extension). Moreover, weight-bearing had the smallest effect on patellar flexion with the lowest scaled RMSD of all the kinematics measured ; however, those who utilized greater external/internal tibial rotation during their movements did not show greater patellar tilt or translation. In other words, inducing high amounts of tibial rotation may influence patellar tracking in vitro (While several studies have presented the tibiofemoral or patellofemoral kinematics separately, few studies have focused on investigating the kinematic relationship between joint motions . In agre flexion . Some inin vitro , but thiin vitro , yet theOur results for PTA were consistent with the magnitude and trend of previous studies that measured PTA during knee extension and deep knee flexion . In agreOur results for PTMA were supported by values reported in previous studies. In Comparison of our results to a prior work in younger healthy subjects revealed some qualitative similarities and differences. For example, TIE was greater in our study than that reported by There were several notable limitations of this study. The results were based on the measurement of one trial for each activity and subject. Repeated measurements may have given better results by enabling assessment of intra-subject variability; however, this was deemed unjustifiable for the additional X-ray exposure. In addition, compared to traditional motion capture, the number of subjects might be considered relatively small; however, the subject numbers were comparable to other studies of knee kinematics using similar imaging technology . The numThis study investigated the natural kinematics of the tibia and patella relative to the femur in healthy, older adults using a high-speed stereo radiography system. Measurements were made during a non-weight-bearing activity and two weight-bearing activities for a cohort of older adults. While weight-bearing elicited changes in knee kinematics, intersubject differences exceeded the differences observed due to weight-bearing in most DOFs. Similarly, patellar tendon angle and moment arm were consistent for the three activities but varied substantially among subjects. These results provide comparative kinematics for the evaluation of knee pathology and treatment in older adults and emphasize the need for considering subject-specific kinematics.


Non-invasive detection of blood-based markers is a critical clinical need. Plasma has become the main sample type for clinical proteomics research because it is easy to obtain and contains measurable protein biomarkers that can reveal disease-related physiological and pathological changes. Many efforts have been made to improve the depth of its identification, while there is an increasing need to improve the throughput and reproducibility of plasma proteomics analysis in order to adapt to the clinical large-scale sample analysis.We have developed and optimized a robust plasma analysis workflow that combines an automated sample preparation platform with a micro-flow LC–MS-based detection method. The stability and reproducibility of the workflow were systematically evaluated and the workflow was applied to a proof-of-concept plasma proteome study of 30 colon cancer patients from three age groups.This workflow can analyze dozens of samples simultaneously with high reproducibility. Without protein depletion and prefractionation, more than 300 protein groups can be identified in a single analysis with micro-flow LC–MS system on a Orbitrap Exploris 240 mass spectrometer, including quantification of 35 FDA approved disease markers. The quantitative precision of the entire workflow was acceptable with median CV of 9%. The preliminary proteomic analysis of colon cancer plasma from different age groups could be well separated with identification of potential colon cancer-related biomarkers.This workflow is suitable for the analysis of large-scale clinical plasma samples with its simple and time-saving operation, and the results demonstrate the feasibility of discovering significantly changed plasma proteins and distinguishing different patient groups.The online version contains supplementary material available at 10.1186/s12014-022-09390-w. Plasma is the primary sample for clinical proteomics studies . AlthougMass spectrometry (MS) has become the mainstay for high-throughput proteome profiling in various biological systems. Due to the complex protein composition and the high dynamic range of proteins in plasma , 8, it iIn this study, we present a robust and reproducible high-throughput sample preparation workflow for micro-flow LC–MS/MS-based plasma proteome analysis. Considering the detection requirements of clinical plasma samples, we carried out in-solution digestion of plasma proteins without additional protein depletion and prefractionation. The automatic pipetting platform integrated all the in-solution sample preparation steps and could be customized according to the various sample size. Specifically, this automated workflow can handle dozens of samples at the same time in one cycle or complete the automation of large-scale samples through multiple cycles. In addition, the combination of micro-flow LC–MS/MS can achieve plasma proteome analysis with significantly improved throughput and stability. Lastly, the developed workflow was subsequently applied in a proof-of-concept plasma proteome study of colon cancer patients with different ages.Plasma samples from 30 patients with stage III/IV colon cancer, and no other primary cancer diagnosis, including fifteen males and fifteen females  were selected for this study from the Department of Oncology, Shenzhen People’s Hospital. Plasma samples were collected at the time of plasma biochemical examination. The clinical information of the colon cancer plasma samples has been listed  formic acid (FA) and analyzed by using a reported micro-flow LC–MS/MS method . This miThe raw data were processed using Sequest HT  integratPatient plasma specimens are one of the most commonly used and easily accessible resources for clinical pathological investigation. Complicated sample preparation procedures and nano-flow LC–MS/MS-based proteomic analysis have been the mainstream methods for in-depth exploration of plasma proteomics. Conventional in-solution digestion is the most classical method can be used for protein digestion of various sample types. With the throughput requirements for clinical samples and biomarker discovery, the aim of this study is to develop and optimize the in-solution protein digestion protocol on an automated liquid handling system, achieving efficient preparation of plasma samples. The workflow of automated sample pretreatment combined with micro-flow LC–MS/MS system can be applied to the high-throughput analysis of clinical samples. The advantages of this strategy are reflected in two aspects. Firstly, compared with traditional manual analysis of only one set of samples per experiment, the liquid handling platform can process dozens of samples simultaneously in an automated manner, saving time and labor costs. Secondly, micro-flow LC–MS/MS system can significantly reduce the analysis time and improve the stability compared with nano-flow LC–MS/MS method .In this study, we made full use of the remaining plasma samples after biochemical examination of cancer and performed all preparation steps in a 96-well plate of the AMTK-LH1808 liquid handling workstation. To evaluate the workflow, 12 of the 30 AMTK blocks in the system were selected, including functional modules such as the orbital shaker and the heating block. An overview of the deck setup is shown in Fig. A total of two reactions occurred in the pretreatment process of plasma samples, namely reduction-alkylation reaction and protein digestion. The reaction conditions here are the main factors affecting automated sample preparation performance. Therefore, we investigated critical reaction conditions, including reaction time, temperature, and the combination of proteases. As shown in Fig. Evaluation of reproducibility and quantification performance of three replications in an automated operation is shown in Fig. To test the performance of our home-optimized automated workflow, it was compared with the automated uHTPPP workflow by analyzing the same plasma sample in four replicated wells. According to the official data provided by ThermoFisher in 2020, less than 200 proteins were identified . As illustrated in Fig. To further assess the reproducibility of the automated workflow for large-scale clinical sample preparation, we examined both the well-to-well and day-to-day reproducibility. The pipette head of AMTK LH-1808 used in this study has a maximum of 32 channels, hence, four of them were randomly selected for day-to-day repeatability evaluation -approved biomarkers  in our qAfter optimizing the automated plasma proteome profiling workflow, we applied it to the colon cancer plasma proteomic analysis as a proof-of-concept study. A total of 30 colon cancer patient samples at stage III or IV were used for this analysis. According to the age distribution of patients in the sample database, they were divided into three different age groups, including 30–49 years old group, 50–69 years old group, and over 70 years old group, with 10 samples in each group. After processed with our automated plasma proteomics workflow, all 30 samples were analyzed by the micro-flow LC–MS method. On average, 287 protein groups and 2 184 peptides per sample were identified  and variable importance in projection (VIP) scores were computed to detect inherent trends within data of all the proteins using their LFQ intensities. As shown in Fig. Herein, we developed an automated sample preparation and robust analysis platform for proteomic profiling of large-scale clinical plasma samples. Plasma proteins were treated by in solution digestion without protein immunodepletion and prefractionation. Considering the inherent pipetting error of the automated device for minute volumes, we started with 5 μL of plasma samples, which is a small amount for clinical testing, while our manual operation only used a starting amount of 1 μL . DependiFrom the perspective of data acquisition, the application of micro-flow liquid chromatography in this study improved the analytical throughput and robustness of the plasma samples. Nevertheless, compared with the throughput of the automated pretreatment platform, the throughput of LC–MS analysis still needs to be improved. Systematic studies have shown that the same 1 mm i.d. × 150 mm column could be used to analyze > 7 500 samples including specimens such as human cell lines, tissues, and body fluids and still with excellent reproducibility and protein quantification performance . The resThe automatic workflow was further applied to a proof-of-concept plasma proteome study of colon cancer in different age groups. Interestingly, a series of proteins were identified to distinguish different colon cancer age groups, with the most significantly changed proteins found between the two groups with the largest age gap. Over the past several years, multiple studies about aging of the plasma proteome have been conducted. Among the differentially expressed proteins in the three age groups, there are proteins involved in healthy aging, such as IGFALS , and proIn this study, we develop an automated and robust plasma proteomics workflow that can be used for large-scale clinical plasma proteomic analysis. The workflow combines efficient automated sample preparation techniques with micro-flow LC–MS-based methods. Compared with the manual workflow, this approach can analyze dozens of samples simultaneously with higher throughput and reproducibility. Without protein depletion and prefractionation, more than 300 protein groups can be identified in a single analysis, including the quantification of 35 FDA-approved markers from plasma. This workflow is particularly suitable for the detection and analysis of large-scale clinical plasma samples due to its simple and time-saving operation. The results of proof-of-concept study confirmed the feasibility of the workflow to discover potential biomarkers from large clinical plasma sample cohorts.Additional file 1: Supplementary figures of the automated plasma proteome profiling procedure's performance and proteomics analysis of colon cancer patients.Additional file 2: Clinical information of the colon cancer patients.Additional file 3: Significantly changed proteins found in patients.


Ultrafast plasma dynamics play a pivotal role in the relativistic high harmonic generation, a phenomenon that can give rise to intense light fields of attosecond duration. Controlling such plasma dynamics holds key to optimize the relevant sub-cycle processes in the high-intensity regime. Here, we demonstrate that the optimal coherent combination of two intense ultrashort pulses centered at two-colors (fundamental frequency,  A common theme in all these techniques is the optimal control of ultrafast electron dynamics for efficient and tunable HHG, currently being utilized in the attosecond beamlines existing in academic laboratories as well as large-scale research facilities11. One such control is to use multi-color pulses to shape the laser field that is driving the interaction. In the relativistic domain, such control is achieved by utilizing an appropriately synthesized light field12 and through a proper choice of interaction media13.Intense sub-femtosecond pulses of X-ray or extreme ultra-violet (XUV) radiation are of primary interest, in several areas of fundamental and applied research including plasma physics, material science, chemical-biology, etc., driving the quest for the new generation of bright light sources spanning the aforementioned spectral range. A coherent attosecond waveform, the shortest of such fields, is produced primarily via the high harmonic generation (HHG) process7. Such a source has demonstrated its scalability with incident laser intensity14 and showed its potential in terms of efficiency15, spectral extent17, beam properties20, divergence control22, pulse energy24, attosecond pulse duration26 and pulse separation28. In addition, a successful combination of the damage-less nature of the medium, relativistic optics,22 and efficient coherent frequency up-conversion together hold promise to offer the only potential approach for achieving super high intensities30 needed for probing vacuum quantum electrodynamics with currently available high power lasers34. Thus, the importance of boosting the quality of surface plasma based sources8 is of central importance.When a high-power light field is tightly focused on an overdense plasma surface, the intensity reaches a value such that electron motion becomes relativistic over sub-cycle timescale, launching ultrafast charge separation dynamics that is responsible for the subsequent emission of coherent XUV radiation35, utilization of polarization gating37 carrier envelope phase control in few-cycle pulses38 have been proposed and explored. In two-color driven surface plasma, some initial one-dimensional simulations and models40 hinted at the possibility of improved high harmonic efficiency. Recently, two experiments demonstrated the potential of two-color driven sub-cycle control of plasma mirror in the moderately relativistic case41.Relativistic high harmonics from plasma mirrors offer a promising path for generating bright attosecond light pulses. However, a major challenge is to tailor the process to generate isolated attosecond pulses, well adapted to pursue timed-resolved investigations. Different techniques for generating isolated attosecond pulses from solid density plasma have been proposed and theoretically explored. Each one of them has its relative advantages and is applicable under different pulse parameter regimes. Techniques based on the controlled introduction of the spatio-temporal coupling45 or alternatively through the phase control of each frequency component in frequency space48. Another scheme that has been used quite frequently to generate the bicolor field from the fundamental near the interaction point, while allowing quasi-independent control over the two. In this case, the functional building blocks of the optical setup consist of frequency doubling, independent polarization control, and timing control that generates two-color fields in the colinear mode of operation49. Our computational results demonstrate that by mixing a sufficient amount of second harmonic  relativistic particle-in-cell simulations, mimicking realistic experimental conditions, and investigate two-color optimal coherent control of ultrafast relativistic dynamics of a solid density surface plasma and the subsequent generation of high order harmonics. Such a multicolor drive field is currently accessible. Experimentally, multiple options have been demonstrated and utilized to generate co-linear two-color ultrashort pulses. Waveform shaping on sub-cycle time scales is achieved through the usage of waveform synthesizers51. Two key parameters that influence the interaction regime13 are the dimensionless peak laser vector potential I is the incident laser intensity and 51 and the references therein).The wide range of accessible laser-matter parameter space and a diversity of allowed experimental geometries permit several mechanisms to concomitantly participate in the high harmonic generation process52. However, under a different set of interaction conditions, a more favourable bunching of the electron can take place, undergoing collective acceleration in synchrotron-like trajectories. The relativistic electron bunch and the ensuing ultrafast nanometer-scale dynamics lead to the generation of synchrotron-like coherent radiation called coherent synchrotron emission (CSE)56. The emitted high harmonics in CSE have distinct spectral characteristics57 and temporal features58 compared to ROM harmonics, and both the processes have been identified in experiments59.When a high contrast, relativistically intense . This push-phase usually takes place during the initial half of the optical cycle. In the latter half of the optical cycle, a restoring force is developed due to charge separation. The electrons are pulled back into the vacuum by the combined effect of the optical field and the field generated by the charge separation and generate a relativistic energy electron bunch (pull phase)63. An 800 nm, p-polarized Gaussian pulse .In order to probe the process in the relevant intensity and pulse duration regime, we undertake a series of virtual experiments by conducting two-dimensional (2D) relativistic Particle-in-Cell (PIC) simulations using the code PICCANTEps level pulse temporal contrast of more than 67 and/or by improving the available temporal contrast by utilizing the plasma mirror device68. The plasma density gradient is controlled by employing a separate pre-pulse for generating a controlled pre-plasma on the target13. By varying the delay between the pre-pulse and the high contrast main pulse, the high harmonic generation interaction is optimized28.In a laboratory experiment, the pulse spatial contrast of the focal spot would determine the quality of the transverse plasma profile in the interaction plane. The pulse temporal contrast on the other hand affects the initial longitudinal plasma density profile (its shape and steepness) and thus determines the target conditions at which the main interaction takes place. In order to enable an optimal high harmonic generation process, one needs to ensure a controlled interaction with a predefined preplasma scale length. There are two components to it. Clean interaction is experimentally achieved by employing a main pulse that has a high temporal contrast . At the peak intensities utilized for the current investigation, a typical Ze is given by, 69, where c, 70. For the solid target used in our case, 71 and hence we have used collisionless, fully relativistic PIC for the investigation. The simulation box of size In addition, the PIC simulations performed in this study do not take into account the influence of collisions. The regime of interaction for relativistic high harmonic generation involves ultrashort pulses at relativistic intensity addressing within the pulse duration effects. The typical electron energies involved in the process are such that the cross-sections for collisions are significantly reduced, making such an approximation a reasonably good one. As an illustration, the typical timescale at which electrons with kinetic energy 72. Therefore, a scan on the density scale-length (L) is performed in order to investigate the optimum high harmonic generation conditions. Figure The high harmonic intensity emitted during the relativistic laser-plasma interaction is optimal for appropriate steepness of the plasma vacuum boundarymentclass2pt{minimmentclass2pt{minim61, the harmonic intensity follows a different trend72. High harmonic generation is efficient for the sharp density gradient for which mirror-like plasma vacuum boundary is formed and undergoes complex oscillatory motion with relativistic velocity also known as the relativistic oscillatory mirror (ROM) model52. Figure 51. The scaling law in the high harmonic spectrum shown in Fig.  Figure mentclass2pt{minimmentclass2pt{minimmentclass2pt{minimmentclass2pt{minimmentclass2pt{minimmentclass2pt{minimmentclass2pt{minimx–y plane, and the propagation coordinate is given by FFT and IFFT refer to Fast Fourier Transform and Inverse Fast Fourier Transform respectively and In our coordinate system, the propagation of the reflected and incident electromagnetic fields lie in the mentclass2pt{minimmentclass2pt{minim74 and bulk semiconductor crystal75.The push-pull dynamics on the plasma-vacuum boundary can be tuned to a great extent by engineering the driving field. Subsequently, a considerable control over high harmonic generation can be achieved. Mixing an appropriate amount of second harmonic , the PM undergoes denting22 which leads to the sharpening of the PM density gradient due to laser radiation pressure. Such a process introduces changes in the instantaneous plasma density gradient seen by the different cycles of the driver laser during the interaction with the PM. This affects the formation and the dynamics of the electron bunches and consequently impacts the as pulse train emission efficiency throughout the pulse duration. At high intensities where denting within the pulse duration is relevant22, this indeed leads to suppression of harmonic emission efficiency during the second half of the pulse, which has been confirmed previously in 3D PIC simulations35. All these factors play a role in deciding the optimal emission condition. The interaction simultaneously depends on multiple parameters in an interconnected fashion. This makes the optimization approach based on tuning one control parameter at a time much more difficult, and sometimes even impossible. But, recent studies indicate that there is significant scope to optimize the properties of the as pulses described here by adopting more advanced techniques based on machine learning87.We would note that the XUV as (FWHM) can be generated. The laser-plasma parameters presented and investigated in our work are accessible by the currently available state-of-the-art lasers and target designs. The results are valid for a few-cycle, carrier-envelope phase stabilized, high temporal contrast, high repetition rate relativistic intensity lasers89, and the predictions can be scaled up to the interaction driven by high-intensity low repetition rate Petawatt class lasers available worldwide90. In several investigations the efficacy of the high-intensity plasma medium in controlling the recombination of laser beams91, tight focusing of both the laser93 and generated high harmonics22 and diffraction both static94 as well as dynamic diffraction26 of the generated harmonic pulses have already been experimentally demonstrated. Temporal light field shaping in combination with such existing plasma optics technologies has the potential to provide a viable route to achieve very high fields in the XUV or X-rays, opening up the possibility to study non-linear XUV processes in atomic and molecular physics95 or even to pursue extreme high field physics circumventing the limitations of the laser technologies29.In this work, we have shown that by tailoring the temporal shape of the interacting laser field, it is possible to generate isolated attosecond pulses all optically. The results show that a fourfold enhancement in the high harmonic flux can be achieved by mixing an appropriate amount of the second harmonic with the fundamental frequency driving pulse and precisely controlling the delay between the two fields. An optimal two-color driving field favourably modifies the spatio-temporal dynamics of the relativistic surface electrons, enabling one to control the attosecond burst generation in the time domain. Under such optimal conditions, an isolated attosecond burst of duration 200


Dynamic Intraligamentary Stabilization (DIS) is a technique for the repair of acute anterior cruciate ligament (ACL) injuries. The purpose of this study was to investigate the potential challenges of ACL reconstruction (ACLR) following failure of DIS.A retrospective analysis of patients with failure of primary ACL repair performed with DIS was undertaken. Failure was defined as abnormal knee laxity (positive Lachman and/or pivot shift) and/or severely restricted range of motion. Medical and surgical records were reviewed and preoperative standard anteroposterior and lateral X-rays were assessed.Between July 2015 and May 2022, 10 patients  with failure of DIS were referred to and surgically treated at a single centre. In four patients, single-stage ACLR was performed following the removal of the tibial monoblock. In six patients, arthrofibrosis and excessive tibial tunnel enlargement following the removal of the monoblock prevented single-stage ACLR. These patients underwent arthroscopic arthrolysis and tibial tunnel bone grafting as a first-stage revision procedure.In the present case series, single-stage ACLR was performed in only four (40%) of ten patients following failure of ACL repair with DIS. Arthrofibrosis and excessive tibial tunnel enlargement following the removal of the monoblock prevented single-stage ACLR in six (60%) patients. It is important for clinicians to inform patients that, in the event of failure of ACL repair with DIS, they may run a high risk of undergoing two-stage ACLR.Level IV, Case Series. An anterior cruciate ligament (ACL) tear is a common injury, which can lead to knee instability, interfering with sports and activities of daily living. ACL injuries can be treated both conservatively and surgically. In the event of surgical treatment, anatomical ACL reconstruction (ACLR) is accepted as the gold standard , 2. HoweThe patients included in this case series are part of our ACL clinical pathway. They gave their written informed consent to grant us permission to use their medical data gathered during their treatment. The project has received the approval of the National Ethics Committee for Research . Data acquisition and storage were notified to the National Data Protection Committee.Patients with failure of primary ACL repair with DIS performed elsewhere and referred to Centre Hospitalier de Luxembourg (Luxembourg) were identified. Failure was defined as abnormal knee laxity (positive Lachman and/or pivot shift) and/or severely restricted range of motion. All the revision procedures were performed by the same senior surgeon (RS). Medical and surgical records were reviewed and preoperative standard anteroposterior and lateral X-rays were assessed. The radiological assessment was performed by an orthopaedic knee surgeon (RC). Femoral tunnel position was assessed according to the Bernard and Hertel grid method . The cenBetween July 2015 and May 2022, 10 patients  referred to our institution for failure of primary ACL repair with DIS underwent surgery. In four patients, a single-stage ACLR was performed following the removal of the tibial monoblock. In six patients, due to arthrofibrosis and excessive tibial tunnel enlargement following the removal of the monoblock, arthroscopic arthrolysis and tunnel bone grafting were performed as a first-stage revision procedure. Patient characteristics and preoperative radiographic measurements are reported in Table A 32-year-old male twisted his knee while playing rugby about six months prior to presentation. Four years before, he underwent ACL repair with DIS. At the clinical examination, he had full range of motion (ROM) and positive Lachman and pivot-shift tests. The patient wished to return to his previous sport (rugby) and ACLR was therefore recommended. Preoperative anteroposterior and lateral X-rays showed the correct position of the femoral and tibial tunnels Fig. . He undeA 27-year-old male presented with persistent knee pain and activity limitation about 10 months after he underwent ACL repair with DIS. He had a five-degree extension deficit, a negative Lachman test but a positive pivot-shift test. Due to activity limitations and a wish to return to football, ACLR was recommended. Arthroscopy revealed femoral tunnel malposition (anterior placement). Arthroscopic arthrolysis was performed and the tibial monoblock was removed. The patient underwent single-stage anatomical ACLR with a quadriceps tendon-bone autograft and lateral meniscus repair.A 23-year-old male presented with effusion, pain and instability following a knee injury that occurred a few days before while playing football. He underwent ACL repair with DIS 1.5 years before presentation. At the clinical examination, he had positive Lachman and pivot-shift tests. The tibial monoblock was removed and the patient underwent single-stage bone-patellar-tendon-bone autograft ACLR and repair of a medial meniscus ramp lesion.A 47-year-old female who injured her ACL and underwent ACL repair with DIS one year before presentation. She complained of knee pain and instability. At the clinical examination, she had a severe (30 degrees) extension deficit and a positive Lachman test. The patient underwent arthroscopic arthrolysis due to generalised synovitis and arthrofibrosis Fig.  a-b and A 33-year-old female who underwent ACL repair with DIS six months before and presented with knee pain and functional impairment. She had severely restricted ROM (10–60 degrees) and swelling. A synovial fluid examination showed no sign of infection. The patient underwent arthroscopic arthrolysis due to pronounced arthrofibrosis and removal of the tibial monoblock. The large tibial bone defect (12 mm diameter) was bone grafted with a femoral head allograft. The patient had an ROM of 0–140 degrees at the end of the procedure. She complained of persistent instability at the follow-up appointments  and an ACLR was recommended. However, the patient moved abroad and continued her treatment elsewhere.A 20-year-old female presented with knee pain and significant functional impairment. She underwent ACL repair with DIS seven months before presentation. She had knee effusion, significant muscle atrophy and restricted ROM (10–100 degrees). Preoperative X-rays showed a significant malposition of the femoral tunnel. Moreover, the endobutton had not flipped over the femoral cortex Fig. . The patA 29-year-old female presented with knee pain and instability. She underwent ACL repair with DIS 2.5 years before presentation. She had an ROM of 0–90 degrees and a positive Lachman test. During arthroscopic examination, scar tissue formation in the intercondylar notch was found and debrided. Following the removal of the tibial monoblock, the patient underwent single-stage quadriceps tendon-bone autograft ACLR. A concomitant lateral meniscus root repair and medial meniscus ramp lesion repair were performed.An 18-year-old female presented with knee pain and swelling. She underwent ACL repair with DIS about four months before presentation and had an ROM of 15–80 degrees. Arthroscopy revealed a rupture of the ACL and generalised arthrofibrosis. The femoral tunnel was located in a non-anatomic, anterior position. The removal of the tibial monoblock left a large (12 mm diameter) bone defect Fig. , which wA 27-year-old female who underwent ACL repair with DIS prior to presentation. She had knee pain, a positive Lachman test and an ROM of 0–50 degrees. At arthroscopy, the ACL was partially torn and generalised arthrofibrosis was present. Extensive arthrolysis was performed. The removal of the tibial monoblock left a bone defect of 10–11 mm, which was bone grafted with a femoral head allograft. The patient was followed up for about four years. At the latest follow-up, she complained of subjective instability and had positive Lachman and pivot-shift tests. An ACLR was recommended, but the patient refused treatment due to her inability to pause her work as a cleaner.A 52-year-old female presented with pain in her knee such that normal walking was significantly limited. She underwent ACL repair with DIS about four months prior to presentation. Her ROM was 30–80 degrees. Arthroscopic arthrolysis due to generalised arthrofibrosis was performed. Arthroscopy also revealed a cyclops lesion, which was debrided together with the ACL remnant and the polyethylene wire. The removal of the tibial monoblock left a bone defect of 12 mm, which was bone grafted with a femoral head allograft. At the end of the procedure, the patient achieved an ROM of 0–110 degrees. She is under follow-up to evaluate a possible ACLR in a second stage.The most important finding in this case series was that single-stage ACLR was performed in only four (40%) of ten patients following failure of ACL repair with DIS. Arthrofibrosis and excessive tibial tunnel enlargement following the removal of the monoblock prevented single-stage ACLR in six (60%) patients. These patients underwent arthroscopic arthrolysis and tibial tunnel bone grafting as a first-stage revision procedure.DIS has been proposed as a technique for ACL repair to overcome the issue of cyclic loading of the repaired ligament during the healing phase . The devKnee arthrofibrosis is a known complication after ACL repair with DIS , 14, 21 The large tibial bone defect following the removal of the monoblock was the other factor which prevented single-stage ACLR in the present case series. The bulky monoblock used for DIS might be a major downside of this ACL repair technique. According to the developers , one of This study is important as it is, to the authors’ knowledge, the first report describing the surgical challenges following failure of ACL repair with DIS. Patients should be informed that there is a high risk of two-stage ACLR in the event of failure of ACL repair with DIS. This is because of the arthrofibrosis and/or the large tibial bone defect resulting from the removal of the monoblock.The main limitation of this study is the small number of patients. ACL repair with DIS is a technique that is rarely used in our geographical area. All the patients included in this series underwent ACL repair with DIS elsewhere and were referred to our institution because of postoperative problems or new trauma. Some information about the primary surgery  was not available. However, the aim of this study was not to describe the results or complications of ACL repair with DIS but instead to evaluate the surgical challenges in the event of revision of a failed DIS. Finally, this case series represents a single-centre and single-surgeon experience. It might be argued that the decision not to perform a single-stage ACLR was dependent on the operating surgeon and was then potentially biased. However, this decision was based on well-known principles of ACL surgery. Full knee extension should be achieved before ACLR , 26 and In the present case series, single-stage ACLR was performed in only four (40%) of ten patients following failure of ACL repair with DIS. Arthrofibrosis and excessive tibial tunnel enlargement following the removal of the monoblock prevented single-stage ACLR in six (60%) patients. It is important for clinicians to inform patients that, in the event of failure of ACL repair with DIS, they may run a high risk of undergoing two-stage ACLR.


Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADD/MTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective β-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADD/MTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinson’s Disease, Alzheimer’s Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADD/MTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype. HADHA (OMIM 600890) and HADHB (OMIM 143450). This enzyme complex catalyzes three reactions. The long-chain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) are carried by the α-subunit, while the long-chain 3-ketoacyl-CoA thiolase (LCKAT) is localized on the β-subunit [HADHA are responsible for LCHAD deficiency (LCHADD), whereas variants in HADHA and HADHB cause MTP deficiency (MTPD). Both diseases are autosomal recessive disorders of the mitochondrial long-chain fatty acid oxidation (lc-FAODs) affecting the degradation of chain fatty acids with a chain length > C12 [https://www.screening-dgns.de/Pdf/Screeningreports/DGNS-Screeningreport-d_2019.pdf; accessed on 15 May 2022) [The mitochondrial trifunctional protein (MTP) of the β-oxidation pathway is a α2β2 heterotetramer multienzyme complex encoded by two different genes, DHB OMIM 43450. ThDHA OMIM 00890 andDespite early diagnosis and therapy initiation, LCHADD and MTPD present with retinopathy and neurodegenerative symptoms originally attributed to the accumulation of toxic acylcarnitines, oxidative stress and energy deficiency. These symptoms specific for LCHADD and MTPD are progressive and cannot be avoided. Studies in the fibroblasts of patients with lc-FAODs have demonstrated that the accumulating fatty acids due to defective β-oxidation are likely involved in remodeling processes leading to an alteration of the profile and content of complex lipids ,8. Here, we aim at outlining the importance of these complex molecules in the pathophysiology of lc-FAODs. We summarize the evidence that exists in support of the hypothesis that profile disturbances of mitochondrial cardiolipins and sphingolipids are likely involved in LCHADD/MTPD disease development. Based on these observations, we propose a novel mechanism that considers dysregulated complex lipids as a contributing cause in the progressive neurodegenerative symptoms of LCHADD/MTPD. Very recently the crystal structure of the human MTP has been elucidated . Due to The aberrant metabolism of sphingolipids characterized, i.e., by the accumulation of specific species with the subsequent alteration of ceramide/sphingomyelin ratio, glucosylceramides, ceramides and glactolsylceramides  results In addition to MS and amyotrophic lateral sclerosis (ALS) , the rolAlthough this information does not completely clarify the molecular mechanism, it clearly indicates that a multifactorial system contributes to the clinical feature in these diseases. In contrast to other fatty acid oxidation disorders, LCHADD/MTPD are characterized by the high accumulation of hydroxylated acylcarnitines . PreviouBased on these observations, here we propose a comprehensive pathomechanism for the progressive neurodegeneration in LCHADD/MTPD that includes the experimental evidence reported in the past years . First, In the light of the existing literature, it is clear that the dysregulation of complex lipids is a common element in the onset of several neurodegenerative diseases. In this context, the very recent reports on the altered composition of cardiolipins, sphyngomyelin and ceramides described in the fibroblasts of LCHADD patients led us to formulate the hypothesis of a more complex multifactorial pathogenesis behind the progressive neurodegenerative symptoms in this disease also involving the complex lipids. However, it is unclear whether the described alterations are a consequence of oxidative stress, remodeling or to the accumulation of fatty acids rather than an unforeseen independent effect. However, they may explain why despite therapy and metabolic maintenance, the symptoms remain progressive. We would also highlight the fact that these data have been retrieved from fibroblasts which of course never allow a full extrapolation to patients. Whether the same alteration of complex lipids and modulation by medium-chain fatty acids may also occur in vivo is currently under investigation.


The need for masking protocols in care centers for older adults exacerbated communication challenges in an already difficult environment. The purpose of this study was to alleviate the burden of communicating while wearing masks by providing a virtual staff training that introduced a headset amplifier and communication tips. The training was delivered via Zoom to small groups of staff at three Programs for All-inclusive Care for the Elderly (PACE®) organizations. The training included education about the impact of age-related hearing loss, instructions for using a headset amplifier, and communication tips. Staff were encouraged to use the amplifier with as many participants as possible to ease communication while wearing masks—rather than targeting participants based on hearing status. A pre/post quasi-experimental approach was undertaken. Fifty-one staff members completed the training and immediate pre/post questionnaires to measure knowledge gain. Follow-up questionnaires (including open-ended responses) were collected at 2- (n = 29), 4- (n = 23), and 6-months (n = 23) post-training. In addition, we completed one focus group (n = 5) and one in-depth interview regarding the feasibility of participation in the research project and brainstorming to increase use of the amplifiers. By integrating quantitative and qualitative findings, we highlight communication improvements when using the amplifiers and tips for integrating amplifiers into group care programs. The findings from this study will contribute to the development of a large-scale intervention to address hearing loss and support communication for older adults in group care settings.


Monolayers of transition-metal dichalcogenides with direct band gap located at the binary  The two-dimensional confinement of charge carriers in TMDC monolayers leads to a reduced dielectric screening of the Coulomb interaction and a formation of excitons with binding energies of hundreds of meV2. Due to a strong spin-orbit coupling in the TMDC monolayers and a resulting valley-contrasting spin splitting of the energy gap at the 3. Thus, the TMDCs exhibit unique magneto-optical and opto-electronic properties which are very promising for applications in spin- and valleytronics5.Two-dimensional (2D) materials have attracted considerable scientific attention in the last decade. In particular, transition-metal dichalcogenide (TMDC) monolayers, such as MoS8; however, their identification in optical spectra was beyond the reach of simple structures exfoliated directly on standard SiO9. Recent progress in elaborating high-quality van der Waals (vdW) heterostructures based on hBN-encapsulated TMDC monolayers allows for observing the subtle optical properties of the exciton complexes thus offering the exploration of many-body effects including electron–electron and electron–phonon interactions17. For W-based vdW structures, electron–electron interactions manifest themselves in a trion photoluminescence (PL) line splitting into an inter-valley triplet and intra-valley singlet whose energies are separated by about 6 meV18. Alternatively, the electron–electron coupling may yield the observation of the biexciton fine structure19. Instead, electron–phonon interactions give rise to a coupling between the ground and excited states of the neutral exciton realized by an exchange of phonons in a Raman scattering process20.In addition to neutral excitons, a manifold of exciton complexes may be formed with binding energies of tens of meV22. The optical UPC is a fundamental light–matter interaction, an anti-Stokes-like process, in which an absorbed photon receives energy from the environment and is re-emitted at an energy higher than the excitation energy. Different mechanisms are known for describing UPC in different material systems; however, the mechanisms of exciton UPC in particularly 2D quantum materials are not well understood23. In that context, an open question is related to the exciton emission upconverted from three- or four particle states which are addressed in the transparency window of the TMDC monolayer. Additionally, hitherto, only in WS14.Moreover, photonic upconversion (UPC) is a highly relevant phenomenon of light-matter interaction which not only is studied in fundamental sciences like physics and chemistry, but also finds application in fluorescence UPC in optical fibersIn the current manuscript, we demonstrate the UPC of the exciton emission, for the first time, in hBN-encapsulated WS24. Since the exciton energy Figure mentclass2pt{minim24 allows us to assume that the electron concentration in s25 attributes the lowest electron density to the sample s7. Also, defects randomly distributed in the monolayer may act as donors or acceptors leading to a significant p- or n-doping26.As depicted in Fig. It is worthwhile to emphasize that vdW heterostructures assembled from an hBN-encapsulated WSx-axis.The regular and upconverted PL of the hBN/WSentclass1pt{minimaentclass1pt{minimaThe UPC PL is excited resonantly by scanning the laser energy from the low-energy flank of the Tentclass1pt{minimaentclass1pt{minimaentclass1pt{minimaFor the exciton emission upconverted from the trion states, we propose the following spin-conserving scattering processes, where we consider a 17. In this resonant phonon scattering process the spin as well as the valley momentum are conserved. At the final stage, one resident electron remains at the spin-up subband of the The UPC of the exciton emission based on addressing the intervalley triplet trion T17 that the contribution of different phonon modes to UPC processes in TMDCs strongly depends on the temperature, dielectric environment and carrier density. The UPC rate of the homopolar mode A28. The theoretical analysis has also shown17 that UPC rates due to EInterestingly, it has been recently discussed by Ayari et al.29, the electrons and holes are scattered so that an electron–hole pair is located both at the 30. This anisotropic flip-stop-like exchange interaction is caused by spatially shifted probability densities of the electron and hole at the K31, represents the XXConsidering the neutral biexciton as real intermediate state for the upconverted X emission, we propose the initial excitation of two virtual excitons at the The temperature-dependent UPC PLE shall provide insight into an increasing phonon population as well as a thermally enhanced electron scattering. In Fig. T, whereby the TFrom the fitting of the different exciton PL lines by a combination of Lorentzian curves, we evaluate the integrated intensity of the biexciton and trion PL. Figure 14, where the UPC PL of the exciton becomes intensified at 120 K and even exceeds the regular PL which practically remains constant with increasing temperature. The thermally induced PL enhancement in the vdW heterostructure studied may be caused by a more efficient non-radiative relaxation of the carriers to the band minima, a thermally induced brightening of dark states and a dissociation of carriers from defects contributing to the excitonic emission. The temperature-dependent growth observed in the exciton UPC efficiency is governed by an increasing phonon population leading to more probable phonon-mediated scattering of the electrons14. Moreover, at high temperatures the electron–electron scattering within the UPC from the singlet trion is more likely to take place. This thermally more efficient scattering channel explains the enhanced contribution of The intensities of the regular and upconverted exciton PL in hBN-encapsulated WS32. However, it is worth noting that the circular polarization degree of trions varies in different monolayers, since it results from the interplay between different effects, such as scattering processes (radiative and non-radiative types), photo-doping, and free carrier redistribution among the two K-valleys32. High positive values of the circular polarization degree of the triplet trion are associated with an efficient spin-valley pumping of the resident electrons in a WS32.Finally, we elucidate the circular polarization properties of the regular and upconverted PL as well as Raman scattering lines performing quasi-resonant and circularly polarized PL and UPC PL experiments. Figure 33.In the PL spectra we also distinguish Raman scattering features in the energy range of 2.044–2.062 eV. They are presented in Fig. 34. This discrepancy is likely caused by a possible scattering of bright excitons into momentum-dark states due to the interaction with K-point phonons or electrons. It is also worthwhile to mention that the preservation of the exciton valley polarization, for T11; see also Fig. Figure We present temperature-dependent and polarization-resolved PL of the bright neutral exciton upconverted from singlet and triplet negative trions and the neutral biexciton, for a hBN-encapsulated WSThe WS35. The WSxyz stage. The application of a long-working distance objective enables us to locate and deterministically transfer selected flakes to the substrate by carefully bringing the stamp in contact with the substrate. After each transfer step, the samples were heated to We prepared hBN-encapsulated WSThe samples were mounted on the cold finger of a vibration-isolated closed-circle cryostat which allowed for temperature variations between 7 and 300 K. The PL was excited by the second harmonic  of a continuous-wave single-mode Nd:YAG laser. The UPC PLE was excited by a continuous-wave dye laser equipped with DCM whose emission was tuned in the range from 602 (2.06 eV) to 650 (1.91 eV). The laser beam was focused on the sample under normal incidence using a long-working distance microscope objective with 50


The strong rate and temperature dependence of rubbers and their composites motivates research into understanding their mechanical response under a wide range of conditions. However, experimental characterisation of the rate-temperature dependence of soft rubbers is challenging. In this methods paper, an improved methodology is proposed for conducting Dynamic Mechanical Analysis (DMA) experiments on rubbers. The higher quality data produced can be used in time-temperature superposition (TTS) applications to derive a more accurate definition of the rubber's rate-temperature dependence. Overall, the improvements obtained can be summarised as follows:  Specifications table*Method details See attached PDF file accompanying this document.N/A


It is still uncertain whether patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) who require long-term oral anticoagulation (OAC) should also receive antiplatelet treatment (APT). This meta-analysis aims to compare the efficacy and safety of OAC alone with OAC plus APT in individuals with AF and stable CAD. The current meta-analysis was conducted as per the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE). We performed electronic searches using PubMed, EMBASE, and Cochrane Library. The efficacy outcomes assessed in this meta-analysis included cardiovascular death, myocardial infarction, stroke (ischemic and hemorrhagic), and all-cause mortality. The safety outcome included major bleeding events. A total of five studies were included in the current meta-analysis enrolling 9199 patients with stable CAD and AF. Out of these five studies, three were observational and two were randomized controlled trials (RCTs). Our study showed no significant difference between two groups in the incidence of cardiovascular mortality , myocardial infarction , all-cause mortality  and stroke . However, lower incidence of major bleeding events in patients who received OAC alone as compared to patients who received a combination of OAC and anti-platelet  were found. The current meta-analysis showed that OAC monotherapy is associated with a lower incidence of major bleeding events in patients with stable CAD and AF. It is also not associated with an increased risk of all-cause mortality, cardiovascular death, stroke, and myocardial infarction. Atrial fibrillation (AF) is a disorder of heart rhythm that can cause irregular and rapid heartbeat . IndividIndividuals with CAD and AF usually receive a combination of OAC and APT. As per the guidelines of the European Society of Cardiology (ESC) and American College of Cardiology-American Heart Association (ACC-AHA), for AF patients with recent stent implantation or/and acute coronary syndrome (ACS), combined therapy of OAC and APT is ideal for 12 months but people with stable CAD and AF, the evidence is limited . In persThere has not been much research done on the optimal antithrombotic therapy for persons with AF and stable CAD. To reduce the risk of bleeding in this population, the 2016 European AF guideline and some professional consensus advise taking oral anticoagulation alone without any antiplatelet medication -11. ThesMethodsThe current meta-analysis was conducted as per the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE).Search StrategyWe performed electronic searches using PubMed, EMBASE, and Cochrane Library for searching relevant articles using the following keywords: “stable coronary artery disease”, “atrial fibrillation”, “oral anticoagulant”, “anti-platelets”, “anti-thrombotic” and “cardiovascular outcomes” without putting restrictions on year and language of publication. A reference list of all included studies was also searched to identify any relevant article.Study Selection and Quality AssessmentTwo authors reviewed the titles or abstracts of studies independently to identify the eligibility based on the inclusion and exclusion criteria. Randomized control trials (RCTs) and observational studies were eligible for inclusion if they compared OAC monotherapy with a combination of OAC and SAPT in patients with a medical history of AF and stable CAD. AF included permanent, long-standing persistent, persistent, and paroxysmal. Stable CAD is defined as coronary artery stenosis (≥ 50%) in one or more than one main coronary artery but did not require revascularization. In these patients, revascularization should be done at least six months before. We included studies that reported one of the three cardiovascular-related outcomes assessed in the current study . We included studies that reported risk estimates for the investigated outcomes based on time‐to‐event data (hazard ratio {HR}). We excluded studies that assessed antithrombotic therapy in patients with AF and CAD after the percutaneous intervention.Assessment of study quality was done by the two authors independently using Newcastle-Ottawa Quality Assessment Scale for observational studies and the Cochrane bias risk assessment tool for RCTs. An agreement between the two authors was mandatory for the final studies classification. The disagreement between the two authors was resolved via consensusOutcome MeasuresThe efficacy outcomes assessed in this meta-analysis included cardiovascular death, myocardial infarction, stroke (ischemic and hemorrhagic), and all-cause mortality. The safety outcome included major bleeding events.Data ExtractionData from relevant articles were extracted using pre-designed data extraction sheets. Two reviewers independently extracted data from relevant articles. Following data were extracted from articles: a) first author b) year of publication c) study design d) groups e) sample size f) follow-up period g) participant characteristics f) outcomes. The disagreement between the two authors was resolved via consensus. One author entered the data into the Review Manager version 5.4.1 .Statistical AnalysisReview Manager version 5.4.1 was used to perform statistical analysis. Baseline characteristics of the pooled study population were given as mean and standard deviation for continuous variables and frequency and percentages for categorical variables. Because of the observational nature of most of the included studies in the current meta-analysis, the random effect model (inverse‐variance weighting) was used. Since the random-effect model considers the expected between-study heterogeneity when combining the results of separate studies, the random-effect model meta-analysis provides more cautious estimates than the fixed-effect model meta-analysis. A meta-analysis of hazard ratio (HR) was done and the results were presented with a 95% confidence interval (CI). Forest plots were generated for each of the outcomes assessed in this meta-analysis. Heterogeneity between studies was assessed using the Cochran Q test. To determine the degree of between‐study heterogeneity Higgins I-square statistics were calculated. P-values less than 0.05 were considered statistically significant.ResultsFigure The study characteristics of all included studies are shown in Table Overall, the quality of the included studies was high as shown in Table Our study showed no significant difference between the two groups in the incidence of cardiovascular mortality  as shown in Figure Our analysis showed no significant difference in regards to the incidence of stroke between the two study groups  as shown in Figure Subgroup AnalysisTable DiscussionThis meta-analysis aims to compare OAC monotherapy with a combination of OAC and SAPT in patients with atrial fibrillation and stable CAD. The findings of our meta-analysis showed that no significant difference was there in regards to cardiovascular mortality, stroke all-cause mortality, and myocardial infarction. However, pooled analysis of four observational studies and two RCTs showed that the incidence of major bleeding was significantly lower in patients who received OAC alone as compared to patients who received a combination of OAC and SAPT. These findings were unaffected by the study methodology.Of the included studies in the current meta-analysis, there were RCTs conducted to compare the efficacy and safety of OAC monotherapy and combination therapy of OAC and SAPT in patients with stable CAD and AF. A study conducted by Matsumura-Nakano et al. found no significant difference in any of the outcomes assessed in the current meta-analysis . This RCThe EPIC-CAD trial is currently in progress, which is an investigator-initiated, multicenter, open-label randomized trial comparing the safety and efficacy of anticoagulant monotherapy with the combination of anticoagulant and antiplatelet drugs in patients with AF and stable CAD . HoweverEven though guidelines usually recommended OAC monotherapy for patients with AF and stable CAD, the literature supporting the use of OAC monotherapy has been limited . All of Clinicians need to assess not just the risk of stroke, but also the bleeding and coronary events risk before making decisions for patients with AF and stable CAD. The best antithrombotic therapy should be chosen using a risk-factor-based methodology, according to the 2013 ACC guideline for AF . The majThe current meta-analysis has certain limitations. Firstly, the limitations of the studies we included, such as the observational character of several of the studies, greatly limit our findings. Secondly, our meta-analysis did not account for the use of variable cut-off for scores like HAS-BLED and CHADS2 square, used by the included studies. Thirdly, we were not able to analyze whether there is a certain group in which OAC plus SAPT treatment may be effective as we did not have access to patient-level data.The current meta-analysis showed that OAC monotherapy is associated with a lower incidence of major bleeding events in patients with stable CAD and AF. It is also not associated with an increased risk of all-cause mortality, cardiovascular death, stroke, and myocardial infarction. The beneficial impacts of OAC monotherapy were consistent across different types of study designs. In the end, large-scale randomized trials are required on high-risk populations comparing different OAC monotherapies to validate the findings of the current meta-analysis.


However, from a practical standpoint, direct utilization of sunlight is often unfeasible due to its intrinsic intermittency and fluctuating intensity  a photosensitizer, which is responsible for light absorption and charge separation, and (ii) catalytic units, capable of storing photogenerated electrons and holes to facilitate the conversion of substrates into products al-based . Moleculrategies .2 reduction and H2 evolution.Different reaction schemes can be designed depending on the chemical feedstock or fuel to be produced by the reductive half-reaction. All these processes require electrons which should ideally be provided from a parallel oxidative process in an electronically coupled anodic compartment . In thisAlemán and Mas-Ballesté have reviewed the application of Covalent Organic Frameworks (COFs) and Covalent Triazine Frameworks (CTFs) in photocatalytic oxidation processes comprising oxidation of organic substrates such as alcohols, sulfides, and amines, as well as water oxidation to dioxygen when coupled with suitable metal oxides as co-catalysts. The effects of porosity and crystallinity on the final photocatalytic activity have been critically evaluated, highlighting the potential and future challenges for the design and practical application of these interesting organic-based reticular materials.To shed light on the new developments in the field of hybrid materials for the oxidation half-reaction, Gong et al. who constructed a novel photoanode material for the water oxidation reaction by replacing conventional mesoporous TiO2 with anatase-wrapped arrays of single-crystal TiO2 rutile nanorods (ARNRs). Functionalization with polymeric carbon nitride as the sensitizing unit and CoO(OH)x as the catalyst turned out to be effective in promoting visible-light-driven oxygen evolution. The promising performance of ARNRs as large surface area electron-collector in hybrid photoanodes based on polymeric light-harvesting materials is expected to stimulate further efforts in the field of photoelectrochemistry for solar fuels.Although the choice of the light-harvesting components and catalytic units are usually of fundamental importance for water oxidation in hybrid photoanodes, semiconductor support also plays a key role. This challenge has been addressed by 2 reduction currently represents one of the most important conversions, as it combines the possibilities of generating a fuel  with the control over the CO2 level in the atmosphere. A major challenge in CO2 reduction is steering the selectivity towards carbon-based products while suppressing the competitive H2 evolution reaction. Obermeier et al. have reported the synthesis of novel molecular catalysts based on Earth-abundant 3d transition metals  with pentadentate nitrogen and sulfur-chelating ligands and their application under light-driven conditions with copper and iridium complexes as light-harvesting photosensitizers and triethylamine as the sacrificial electron donor. By varying the choice of metal and ligand of the catalyst as well as the photosensitizer the authors have identified conditions to control the product selectivity towards either CO, H2, or a mixture of both. These results thus point out how modification of molecular catalysts through chemical synthesis represents a valuable tool to fine-tune the selectivity of (photo)catalytic small molecule activation.On the reductive side of AP, CO2 as a feedstock for organic synthesis, Franceschi et al. have provided a thermodynamic analysis guided by DFT computations to predict the reactivity of carbanions with CO2 based on the acidity of the CH/C− couple, which is relevant for reactions such as photo- or electro-driven carboxylations. Interestingly, the predicted reactivity trend has been substantiated with electrochemical studies involving, among others, flavone and chalcone as model compounds, thereby proving the versatility of the presented method to target novel reactivity patterns aimed at the fixation of CO2 into organic scaffolds.Addressing the role of directly using CO2 reduction Cerpentier et al. report on the synthesis of two supramolecular dyads that combine a ruthenium polypyridine photosensitizer with either a rhenium catalyst for light-driven CO2 reduction or a platinum catalyst for H2 production. Bearing suitable anchoring groups on the ruthenium polypyridine unit enabled immobilization onto mesoporous NiO electrodes and thereby the construction of photocathodes for CO2 or proton reduction, respectively. Differences in reactivity suggest differences in mechanism between operation in homogeneous solution and on NiO. Time-resolved infrared spectroscopy and spectroelectrochemistry methods finally provide important insights for the construction of active photocathodes.In the context of hybrid electrodes for proton or COOverall, the set of papers collected represents cutting-edge scientific reports in a very important research field, which are expected to stimulate scientific discussions and novel ideas to target the critical, global challenge of developing new, practical, and cost-efficient renewable energy technologies.


When updated clinical trial data becomes available reassessing the cost-effectiveness of technologies may modify estimates and influence decision-making. We investigated the impact of updated trial outcomes on the cost-effectiveness of percutaneous mitral repair (PR) for secondary mitral regurgitation. We updated our previous three-state time-varying Markov model to assess the cost-effectiveness of PR + guideline directed medical treatment (GDMT) versus GDMT alone. Key clinical inputs  and heart failure hospitalisations (HFH)) were obtained using the 3-year trial findings from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy) RCT. We calculated incremental cost-effectiveness ratios (ICER) and report how these differ between analyses based on early (2-year) and updated (3-year) evidence. Updated trial data showed an increase in mortality in the intervention arm between two and three years follow-up that was not seen in the control arm. Deterministic and multivariate cost-effectiveness modelling yielded incremental cost effectiveness ratios ICERs of €38,123 and €31,227 /QALY. Compared to our 2-year based estimate  these results imply an approximate 1.5-fold increase in ICER. The availability of updated survival analyses from the COAPT pivotal trial suggests previous estimates based on 2-year trial findings were over optimistic for the intervention. Reconststgenreg  and the g [stpm2  packagesg [stpm2  and 2021g [stpm2 .The implied in-trial poorer survival in the PR + GDMT arm after two years could be attributable to a temporary anomaly, although this seems unlikely in view of the quality and size of COAT and the fact that half of participants were still at risk after 2 years follow up. We therefore looked for “real world” studies with substantial follow up beyond two years to see how these compared with the COAPT KM for the PR + GDMT arm followed for three years. We found two studies, Velu et al. 2017  and AdamThese studies suggest that the post-2 year survival downturn seen in the PR + GDMT arm of COAPT is not an exclusive feature of COAPT. We therefore compared observed three year COAPT survival with survival models developed in COAPT-based CE analyses to ascertain how previous CE studies’ modelling of survival might conform to or depart from the three-year in-trial findings. The various CE analyses have used several distinct and different approaches to model survival  to the intervention arm flexible model. The resulting models and extrapolations for each arm Figs  and 4 haWith 2.5% annual discounting (in line with a French perspective) this economic model generated ICERs of € 38,123 / QALY and € 25,416 / LYG, substantially greater than our previous analyses based on 2-year results from COAPT of € 21,918 / QALY and €14,434 / LYG. Estimates of cost effectiveness are seen to be strongly impacted by using updated data from COAPT. The current model delivers 3.6 LY and 2.7 LY in intervention and control arms respectively, providing an increment of 0.94 LY benefit.Lifetime life-year-gain (LYG) is an important element common to all the CE analyses, places our results in context and allows a direct comparison between different economic models avoiding complication from different jurisdiction costs and quality of life measures. Because differing quality of life (utility) estimates have been employed in individual studies QALY benefit across studies may not directly relate to LY benefit, nevertheless despite considerable variation there is approximate correspondence between different benefit measures .We undertook scenario analyses to determine the effect on our LY benefit estimates of substituting our survival models with those from Baron, Shore or NICE-guideline . The resThe confidence intervals around survival models were wide ; this toSeveral statistical methods are available to extrapolate beyond the observed in-trial mortality data. These methods make use of different functional forms that, as is clear from previous CE analyses of PR , can resIt seems axiomatic that cost-effectiveness (CE) estimates are best served by making use of the most mature trial data available. Our analyses is the first to contribute this new perspective for PR in that we take account of the downturn in survival seen in the MitraClip arm of COAPT after two years, for proper comparison earlier CE studies require update. Should the downturn transpire to be anomalous in light of longer term results from COAPT (four year results from COAPT are awaited), or are very particular to only the COAPT population then our perspective can be replaced by further updated CE estimatation based on later COAPT trial findings. The available “real world” studies –20 with The two-year results fom COAPT  have beeIt could be argued that the GDMT arm might exhibit a downturn in survival similar to that seen for the MitraClip arm after two years follow up if cross-over to MitraClip after two years had not been permitted for GDMT recipients. At two years, 144 patients remained at risk but only 53 subsequently crossed over. KM plots for the GDMT arm based on two and three-year follow up were very similar over the first two years with the further year follow up continuing the similar trajectory  rather than the patient data from the COAPT trial; however due to the high quality of the plots available from Mack et al.,  and the Our work has clear implications: in this study the availability of updated survival analyses of the main trial is likely to have relevance to decision-making and/or pricing discussion as part of health-technology assessment (HTA). Indeed, should a health technology have a less or a more favourable ICER with more mature survival data, one would expect that any corresponding patient access scheme might be revised accordingly. There is however no implication of our work at physician level since our results cannot be used for the purpose of patient selection.More broadly, technology appraisals are frequently undertaken when mid/long-term follow-up trial data may be lacking. This was recently emphasized by Tai et al.  based onAnother contribution of our work is that the elements of model structure we employed are simple and adaptable, and have the potential to be readily populated with data pertaining to devices for additional cardio-vascular conditions.Analyses of the cost-effectiveness of the MitraClip device should be updated in the light of the latest available data. Our results indicate that the difference in observed survival of MitraClip recipients between two-year results and three-year results from COAPT will appreciably influence cost-effectiveness estimates.S1 FileRed plot = PR + GDMT, black plot = GDMT.(PDF)Click here for additional data file.S2 FileTable of demographic characteristics of real world studies and of COAPT. Figure with COAPT at three years (green) versus real world studies .(PDF)Click here for additional data file.S3 FileTable with previous studies.(PDF)Click here for additional data file.S4 FileFigure with Standard parametric models (red lines) were fit to in-trial survival for the GDMT arm of COAP (black line with 95% CI).(PDF)Click here for additional data file.S5 FileFigure showing Standard parametric models that were fit independently to in-trial survival  arms of COAPT an-d extrapolated to 20 years.(PDF)Click here for additional data file.S6 FileFig A: Flexible parametric model (red line) and 95% CI (blue line) 3-yr follow up; Fig B: Modelled extrapolation beyond 3-yr follow up COAPT (green line) compared to five year real world study of Velu et al.(PDF)Click here for additional data file.S7 FileFigure with the Comparison of two year (black) and three year (red) Kaplan Meier analyses.(PDF)Click here for additional data file.


Young people moving from adolescent secure inpatient units to adult care in the UK present with multiple and complex needs and are more likely to experience poor transition outcomes related to enduring dependency on mental health services. However, there is lack of knowledge about the feasibility of transitional care models improving transition outcomes.The MOVING FORWARD study aims to implement a new transition intervention model for young people transitioning from adolescent secure services to adult-oriented settings and test the feasibility of a future cluster trial measuring its effectiveness.The design of the study is a three-arm feasibility, cluster randomised controlled trial comparing the MOVING FORWARD intervention against standard transition preparation in six adolescent secure services.Young people between 17-19 years, their parents/carers and key workers will be allocated in two conditions and will receive four transition preparation workshops across six months. Data will be collected at three time points: (T0) baseline, (T1) 6-12 months post-intervention, and (T2)18-24 months post-baseline.Thirteen young people and 17 staff members have contributed to the intervention design through online Advisory Groups. Common identified themes included appropriateness of module content and support during delayed transitions. An intra-class correlation coefficient will be calculated to inform the power of sample size. With a sample size of 50, we will be able to estimate a drop-out rate of 80%.This research will provide practitioners and policy makers with an evidence-based framework about barriers and facilitators to the proposed intervention and will enable services to reflect on quality of transitional care delivery.No significant relationships.


It is well established that non-coding RNA (ncRNAs) may affect normal gene expression and disease progression, and become a new class of targets for drug discovery . DiffereTraditional methods for ncRNA prediction are not only time-consuming but also random and blind . With thThe following articles in this Research Topic address the problem of prediction of ncRNA based on computational methods.5-Methylcytosine RNA Methyltransferases-Related Long Non-coding RNA to Develop and Validate Biochemical Recurrence Signature in Prostate Cancer” Wang et al. the authors identified and characterized a series of m5C-related long non-coding RNAs (lncRNAs) in prostate cancer (PCa). Univariate Cox regression analysis and least absolute shrinkage and selector operation (LASSO) regression analysis were implemented to construct a m5C-related lncRNA prognostic signature. The study revealed that the m5C-related lncRNA signatures could precisely predict biochemical recurrence in patients with PCa by the score of the proposed model of m5c-lnc.In the article entitled “Ranolazine Inhibits Pyroptosis via Regulation of miR-135b in the Treatment of Diabetic Cardiac Fibrosis” Ren et al. the authors elucidated the mechanism of action of ranolazine against diabetic cardiac fibrosis and to investigate the role of miR-135b in this process. They reported for the first time that hyperglycemia decreases miR-135b expression in cardiac fibroblasts, and ranolazine treatment of diabetic cardiac fibrosis is mediated by the miR-135b/caspase-1/TGF-β1 pathway. The study provided a solid theoretical basis for understanding the pathogenesis of diabetic cardiac fibrosis and the clinical use of ranolazine in the treatment of diabetic cardiomyopathy.In the article entitled “Inferring microRNA regulation: A proteome perspective” Ofer and Linial presented a different paradigm for predicting miRNA-regulated genes based on the encoded proteins by using a supervised machine-learning approach. The model highlighted the value of information embedded in the functional proteome in revealing the complexity of regulation by microRNA (miRNAs). The article concluded that protein function is informative across species in predicting post-transcriptional miRNA regulation in living cells. In the future work, a similar AI-based approach will be useful for creating a generalized model for post transcriptional regulation in living cells by ncRNAs .The article entitled “Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile” Shen et al. performed unsupervised clustering using TCGA-retrieved prognostic miRNAs expression profiles. By assessing principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and consensus heatmaps, two clear cell renal cell carcinoma (ccRCC) subtypes were identified. The work described the molecular heterogeneity among ccRCC cancers and provided potential targets used as effective biomarkers for ccRCC diagnosis and prognosis.The article entitled “These articles highlighted the important role of ncRNAs in the regulation of gene expression by interactions between ncRNAs and other biological molecules. Computational methods can predict potential outcomes based on multi-source data from experiments. These articles cover the latest advancements in ncRNA research. In particular, ncRNAs include miRNAs, lncRNAs, circRNAs (circular RNAs), snRNAs , and small interfering RNA (siRNA). Among these, miRNAs and lncRNAs have been the most frequently studied, and the articles in this Research Topic place a special emphasis on miRNAs and lncRNAs. In the future, attention should be given to other ncRNAs and not be limited to miRNAs and lncRNAs.