The aim of this study was to assess the short-term responsiveness of measurement instruments aiming at quantifying the acute psycho-physiological response to load in high-level adolescent soccer players.Data were collected from 16 high-level male youth soccer players from the Under 15 age group. Players were assessed on two occasions during the week: after 2 days of load accumulation (“high load”) and after at least 48 h of rest. Measurements consisted of the Short Recovery and Stress Scale (SRSS), a countermovement jump (CMJ) and a sub-maximal run to assess exercise heart-rate (HRex) and heart-rate recovery (HRR60s). Training load was quantified using total distance and high-speed running distance to express external and sRPE training load to express internal load. It was expected that good instruments can distinguish reliably between high load and rest.p = 0.04 to p = 0.83. Moderate changes were observed for HRex , while small changes were evident for HRR60s . Only small to moderate repeated-measures correlations were found between the accumulation of load and acute responses across all measurement instruments. The strongest relationships were observed between HRex and total distance .Odd ratios (0.74–1.73) of rating one unit higher or lower were very low for athlete-reported ratings of stress and recovery of the SRSS. Standardized mean high load vs. rest differences for CMJ parameters were trivial to small (−0.31 to 0.34). The degree of evidence against the null hypothesis that changes are interchangeable ranged from Results suggest that most of the investigated measurement instruments to assess acute psycho-physiological responses in adolescent soccer players have limited short-term responsiveness. This questions their potential usefulness to detect meaningful changes and manage subsequent training load and program adequate recovery. Athlete monitoring frameworks are widely implemented and considered as important aspects of the training process to maximize sports performance and health, and in turn minimize injury risk, in professional senior and youth soccer environments. The training process is the systematic repetition of physical training comprising external, i.e., the prescribed quantity and intensity of the training plan, and internal load, i.e., psycho-physiological stress experienced by an athlete during the training session and subsequent associated responses  change countermovement jump variables, psychological variables , and heat rate variables derived from a 4-min sub-maximal shuttle run. This information potentially provides practitioners working with youth soccer players additional insight regarding the usefulness of commonly used measurement instruments to assess acute responses to load.Data were collected from 16 male youth soccer players  . A schematic overview is illustrated in Participant's standing height, body mass and chronological age were measured during the first week of the study. Standing height  and body mass  were measured according to standardized ISAK measurement techniques  for children/adolescents , eccentric rate of force development , eccentric impulse , concentric impulse , average eccentric velocity , average concentric velocity , force at zero velocity , duration of eccentric phase , duration of concentric phase , countermovement depth  . Left-side and right-side vertical forces were summed to single force-time curves for analysis. Data were collected and stored using the proprietary application  on a tablet  connected e et al. . The fol cm) see . Coeffic−1. After the 4-min continuous shuttle run, players were required to remain in a stationary standing position avoiding any movement. Heart rate was recorded continuously at 1 Hz  and raw data were subsequently downloaded from manufacturers' proprietary software . Mean heart rate during the final 30 s  of the 4-min continuous shuttle run was computed . Reliability of the selected parameters were assessed in a recent short-term between-days reliability study conducted in youth soccer players  recovery period was performed outdoor at the start of the training session on an artificial turf. Recent research indicated that the assessment of heart rate during sub-maximal runs fluctuates in relation to short-term accumulation of load making this measurement instrument a viable option to monitor cardio-respiratory responses to load , high-speed running distance . Internal training load was determined by multiplying the session-rating of perceived exertion (sRPE) by the session duration in minutes to derive sRPE training load . During each training session athletes wore a GPS device  sampling at 10 Hz. The device was worn on a custom chest belt and athletes were assigned the same device throughout the study period. The following external load variables were selected: total distance , and submaximal running heart rate variables  over the training week . Correlated random effects were fit by specifying a random intercept for athlete ID and a random slope for time  to account for the individual player difference over the training week. Autocorrelation was specified via the exponential variance-covariance matrix and weights were specified via a constant variance function structure to allow for heterogenous within-subject variances by time .Data are presented either as mean with standard deviations (SD) or 90% confidence intervals (90% CI). Items of the SRSS were treated as ordinal variables and analyzed rmcorr package . In addition, repeated-measures correlations (rm-r) between changes in the measurement instruments and indicators of external and internal load were computed [Descriptive data (mean ± SD) for total distance, high-speed running distance and sRPE training load across the data collection period were 10,461 ± 2,644 m, 821 ± 420 m and 921 ± 274 AU. Daily and accumulated training loads are summarized in p = 0.20 to p = 0.98. Trivial to small standardized changes were evident across the parameters of the CMJ. The degree of evidence against the null hypothesis that changes are interchangeable ranged from p = 0.04 to p = 0.83, indicating large confidence intervals and in turn a wide range of plausible true effects. A moderate  decrease in HRex and small  increase in HRR60s was observed across the two testing assessments.Descriptive statistics, results of the linear mixed models and standardized mean differences are summarized in Repeated-measures correlations between changes in the measurement instruments and indicators of external and internal load revealed small to moderate associations . The strThe aim of the current investigation was to determine short-term responsiveness of measurement instruments aiming to quantify the acute psycho-physiological response to load in high-level adolescent soccer players. The results of the study demonstrated that (1) magnitudes of changes were trivial to small for athlete-reported ratings of stress and recovery (<1 AU) and CMJ parameters (0–13%) and smaller than the typically observed day-to-day variability , (2) a moderate change with a narrow range for plausible true effects as inferred by the confidence limits, exceeding the typically observed day-to-day variability, was observed for HRex, while a small change was evident for HRR60s, which was however smaller than the typically observed day-to-day variability, and (3) small to moderate relationships were evident between the accumulation of load and acute responses. Collectively, these findings highlight the poor responsiveness of most investigated parameters questioning their potential utility to monitor psycho-physiological responses to load that are beyond the typically observed day-to-day variability in adolescent soccer players. As such, using these measurement instruments to make conclusions on an athlete's psycho-physiological status and in turn to adjust subsequent training loads cannot be recommended.The current study is one of the first to investigate the relationship between training load indicators and acute psycho-physiological responses in adolescent soccer players. Findings of this study support previous studies that identified a limited responsiveness of measurement instruments that aim to quantify the acute psycho-physiological response to load in adolescent athletes  was substantially greater than the reported day-to-day variations previously reported within similar populations , day-to-day variability for HRR60s  exceeded by far the observed change in our study (2.1%) (Rabbani et al., Limitations of the current study also need to be acknowledged. Although our training load indicators matched the commonly used ones (Nosek et al., This study provides practitioners with a better understanding of the relationships between indicators of training load and common measurement instruments to quantify acute responses to load in adolescent soccer players. Our findings suggest that the limited responsiveness of athlete-reported questionnaires and CMJ parameters means that these measurement instruments are unlikely to provide insight into the acute psycho-physiological responses to load. As such, practitioners utilizing athlete-reported questionnaires and CMJ parameters to quantify acute psycho-physiological responses to load should do so with caution while exploring other measurement instruments to provide more nuanced insights into the constructs of fatigue and recovery. In contrast, HRex during a submaximal run reflects acute responses of the cardiorespiratory system to load and might therefore be used by practitioners to manage training load or program adequate recovery. However, changes in HRex need to be interpreted within the context of the training program as acute negative and chronic positive cardiorespiratory changes follow the same pattern.Taken together, our results suggest that most of the investigated measurement instruments to assess acute psycho-physiological responses have limited short-term responsiveness to training load. As such, these measures provide limited information for practitioners when evaluating the psycho-physiological response of adolescent soccer players to training load. Future studies should investigate the chronic responsiveness of measurement instruments for adolescents of varying maturity status in order to better understand the usefulness of such parameters to manage subsequent training load and recovery more effectively.Due to club policy data cannot be shared. However, we created a detailed outline of the statistical process see  providinThe studies involving human participants were reviewed and approved by Ethics Committee of the Saarland University, Germany. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.LR, BD, PE, SS, and TM contributed to the design and conceptualization of the study, to the analysis and interpretation of the results, and to the writing of the manuscript. All authors made substantial contributions to the manuscript and critically revised and reviewed the manuscript and approved the submitted version. All authors contributed to the article and approved the submitted version.The 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.


Rationale: Metastatic melanoma is the most aggressive and dangerous form of skin cancer. The introduction of immunotherapy with Immune checkpoint Inhibitors (ICI) and of targeted therapy with BRAF and MEK inhibitors for BRAF mutated melanoma, has greatly improved the clinical outcome of these patients. Nevertheless, response to therapy remains highly variable and the development of drug resistance continues to be a daunting challenge. Within this context there is a need to develop diagnostic tools capable of predicting response or resistance to therapy in order to select the best therapeutic approach. Over the years, accumulating evidence brought to light the role of microRNAs (miRNAs) as disease biomarkers.Methods: In particular, the detection of miRNAs in whole blood or specific blood components such as serum or plasma, allows these molecules to be good candidates for diagnosis, prognosis and for monitoring response to anticancer therapy. In this paper, we evaluated circulating basal levels of 6 previously identified miRNAs in serum samples of 70 BRAF-mutant melanoma patients before starting targeted therapy.Results: Results show that the circulating levels of the oncosuppressor miR-579-3p and of the oncomiR miR-4488 are able to predict progression free survival (PFS) but not overall survival (OS). Most importantly, we observed that the best predictor of disease outcome is represented by the ratio of circulating miR-4488 vs. miR-579-3p (miRatio). Finally, the combination of the Lactate dehydrogenase (LDH) blood levels with the two circulating miRNAs alone or together did not produce any improvement in predicting PFS indicating that miR-579-3p and miR-4488 are independent predictors of PFS as compared to LDH.Conclusions: All together these data underscored the relevance of circulating miRNAs as suitable tools to predict therapy response in melanoma and maybe further developed as companion diagnostics in the clinic. The treatment of metastatic melanoma has seen considerable progress in recent years thanks to the advent of targeted therapy and of immunotherapy with immuno-checkpoint inhibitors (ICI) Tissue biopsy is the current "golden standard" for cancer diagnosis and evaluation. However, the surgical removal of tumor tissue is considered rather an invasive procedure and is associated with several limitations It is important to address two issues regarding circulating miRNAs i.e. normalization and quantification. The first problem derives from evidence showing that there are no circulating miRNAs that can act as reference genes. The canonical small nuclear RNAs used as reference genes in cellular/tissue samples, such as RNU48 and RNU6, are not suitable for normalizing extracellular miRNAs due to RNase-mediated degradation In recent years, our laboratory has intensively studied the role of miRNAs in melanoma progression and resistance to BRAF/MEK inhibitors In this retrospective study, we analyzed serum samples from 70 BRAF-mutant melanoma patients coming from two cancer centers namely the National Cancer Institute IRCCS "G. Pascale Foundation" in Naples and the IRCCS Regina Elena National Cancer Institute in Rome (IRE). The general characteristics of the 70 BRAF-mutated melanoma patients are summarized in Table p < 0.05) between the two groups. In particular, melanoma patients undergoing fast PD were characterized by higher circulating levels of miR-4488 as compared to patients experiencing DC. miR-579-3p levels showed the opposite trend. The other miRNAs evaluated were not able to significantly distinguish patients with PD from. DC patients. Based on these results, we decided to focus further studies on these two miRNAs. We further subdivided the 70 melanoma patients into the following four groups according to the RECIST criteria: i.e. CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease and evaluated the distribution of miR-4488 and miR-579-3p  p Figure C. In detp Figure D.Hence, we can conclude from these data that the circulating levels of the oncosuppressor miR-579-3p and of the oncomiR miR-4488 are able to identify BRAF-mutated melanoma patients who benefit or not from target therapy with BRAF and MEK inhibitors.One useful approach used to evaluate the expression levels of miRNA in biological fluids is determining their expression ratio especially when anti-correlated candidates are being examined  .The predictive potential of the combination of miR-4488 upregulation and miR-579-3p downregulation was further assessed by constructing receiver operating characteristic (ROC) curves. The parameters of sensitivity, specificity and accuracy were evaluated together in order to assess the Area Under Curve (AUC) and to evaluate the performance of each classifier in a single measure. In particular, miR-579-3p yielded an AUC value of 0.682 . Results from the Kaplan-Meier analysis clearly showed that high expression levels of miR-579-3p before starting therapy are a predictive factor of better PFS in metastatic melanoma patients , i.e. the absolute expression levels of miR-579-3p and miR-4488 as well as their ratio. The goal was to determine whether these parameters may also serve to predict response to targeted therapy. This is of interest because in clinical practice this would be more advantageous as compared to normalization vs. a set of given miRNAs and the results will be easier to interpret. Again, ROC analysis was applied to identify a specific cut-off in order to generate Kaplan-Meier curves to test the potential value of these miRNAs. As shown in Figure Finally, these results were also plotted as bar graphs where melanoma patients were separated by CT cut-off values derived from ROC curves in the two groups of high or low expressors of miR-579-3p or miR-4488, respectively. The resulting graphs, show that the group of patients with CT cut-off values below the median, i.e. the one composed of high miR-579-3p expressors is enriched for longer PFS as compared to the group of patients with CT cut-off values above median A. The retable S3In the last part of this study, we carried out a univariate and multivariate analysis to assess the predictive value of miRNA levels alone or in combination with the measure of lactate dehydrogenase (LDH) levels in blood. It is well known that the baseline LDH value represents one of the main prognostic factors associated with overall survival of patients with advanced melanoma Metastatic BRAF-mutated melanoma patients  were enrolled in this retrospective study. All of them were treated with inhibitors of the MAPK pathway, i.e. vemurafenib or dabrafenib (as BRAF inhibitors) alone or in combination with cobimetinib or trametinib, respectively (as MEK inhibitors) between April 2013 and February 2019. Serum samples (1ml) from all patients before starting MAPK therapy were collected and preserved at the the National Cancer Institute IRCCS “G. Pascale Foundation”, Naples, Italy and the IRCCS Regina Elena National Cancer Institute, Rome, Italy, tumor biobanks.The use of human samples was approved by Istituto Pascale's Ethical Committee with the protocol DSC/1504 on June 11, 2014 and DSC/2893 on April 11, 2015 and the IRCCS Regina Elena National Cancer Institute in Rome (IFO) Ethical Committee with the protocol 8393 of 23.07.2017. All patients signed an informed consent. Patients eligible for inclusion in this study were candidates for therapy with BRAF inhibitors and MEK inhibitors. All melanoma patients were ≥ 18 years old and were able to understand and willingly sign the informed consent form which had been submitted to their attention.The diagnosis was confirmed as locally advanced stage melanoma histology or metastatic  staging Circulating miRNAs were extracted from the serum of 70 melanoma patients before the beginning of therapy through using the miRNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. Since the concentration of total RNA was undetectable either when using the Nanodrop system or the Qubit assay, we arbitrarily decided to reverse transcribe four microliters of RNA for each sample as performed in our previous published work http://www.ciidirsinaloa.com.mx/RefFinder-master/) ratio miR-4488: miR-579-3p). Finally, univariate and bivariate cox regression models were applied to obtain hazard risks (HR) with their relative 95% Confidence Intervals (95%CI) and all the results were plotted into forest plots Data of circulating miRNAs were normalized using both the Global Mean normalization and the web-tool RefFinder . Targeted therapy is frequently accompanied by the rapid development of drug resistance which results in a highly aggressive disease often associated with cross-resistance to ICI. Hence, an easily measurable biomarker capable of predicting failure to targeted therapy in-advance which may aid clinicians in making the best therapeutic decision.MicroRNAs have been proposed as promising biomarkers in oncology for early diagnosis, prognosis and therapeutic response prediction including melanoma. In particular, specific miRNAs are able to differentiate melanoma patients from healthy subjects or distinguish between metastatic and non-metastatic melanoma patients. Numerous miRNAs were found dysregulated in tumor samples or in the bloodstream of patients with melanoma. Previous studies have identified a useful panel of cf-miRNAs  to detect the presence of metastasis in patients with melanoma ab initio of those patients who can benefit or not from MAPKi therapy. It is worthy to note that the 6 miRNAs are divided into three oncomiRs  and three oncosuppressors  found to be deregulated in plasma samples derived from 25 resistant BRAF-mutated melanoma patients in our previous published study In line with this body of evidence, our research group carried out a retrospective analysis of 70 serum samples derived from BRAF-mutated melanoma patients treated with MAPKi therapy. In particular, we evaluated the expression levels of 6 cf-miRNAs as predictors of response to therapy before starting treatments. The goal of this study was to identify a possible "mini-signature" among these 6 miRNAs, able to discriminate Establishing the best first-line therapy can be crucial point in obtaining a greater patient survival. In conclusion, starting from these intriguing findings, two important steps need to be addressed in the near future which entail: 1) strengthening our discovery by enrolling a larger cohort of BRAF-mutated melanoma patients; 2) expanding the same type of study also to melanoma patients who are undergoing immunotherapy in order to identify miRNAs capable of predicting the response to immune checkpoint inhibitors.Supplementary figures and tables 1-3.Click here for additional data file.Supplementary table 4: DB pazienti target therapy Pascale patients 1.Click here for additional data file.Supplementary table 5: DB Target therapy  Pascale patients 2.Click here for additional data file.Supplementary table 6: DB Target therapy TubeList Prog Melanomi IFO.Click here for additional data file.


A majority in the photoacoustic (PA) community unconditionally accepts that pulse PA signals show much higher signal-to-noise ratios (SNRs) than continuously excited PA signals. However, we indicate this existing notion would not be valid for very low optical-fluence light-emiting diodes (LEDs)/laser diodes (LDs)-based PA systems.We demonstrate in theory and simulation that when the optical fluence of PA-excitation waveforms is much lower than the American National Standards Institute (ANSI) maximum permission exposure (MPE), matched filtered PA signals from chirp waveforms show higher SNRs than those of pulse train waveforms.We theoretically derive the PA SNR expression considering the pulse fluence reduction factor based on the ANSI MPE. We investigate and analyze SNR ratios of the pulse train and chirp-waveform matched filtered PA signals with conceptual understanding. We also perform brute-force simulations to extract PA SNRs for the verification of the result.The brute-force simulations show that the matched filtering with chirp waveforms could achieve better SNRs than pulse train waveforms for very low-fluence PA systems. As the fluence is smaller, the SNR of the matched filtered PA signals is more dominant than that of pulse trains in a wider PA data acquisition time range. In addition, estimated SNR ratios adopting actual parameters of LED/LD-based pulse train PA systems in previous literature support the finding of this paper.The result can extend the possibility of applying various continuous waveform techniques already studied in the conventional radar technology to PA systems of limited optical power, which would diversify and expedite the research and development of LED/LD-based, compact, and cost-effective PA systems. For decades, various imaging modalities adapting this PA effect have been developed in the field of biomedical optics due to several distinctive advantages over purely optical imaging,,,,,,,–The optical sources for the generation of PA waves are categorized into pulse and continuous waveforms.,,–,,in-vivo using the customized LED driver that operated LEDs in the pulse-mode at 40-KHz repetition rate of 200-ns pulse width. Stylogiannis et al.High-power tunable pulse lasers for PA spectroscopic imaging, such as optical parametric oscillator and dye lasers, are expensive and bulky. These drawbacks limit the suitability of pulse PA sources for constructing cost-effective, compact, and multi-wavelength PA imaging systems. In addition, high-power tunable pulse lasers typically have pulse repetition rates smaller than several tens of Hz, which implies the inadequacy of performing real-time PA measurements, such as monitoring rapidly changing biomedical properties.,––In the previous studies comparing SNRs of PA signals by pulse and continuous optical waveforms, it was assumed that the fluence of those incident beams reached the ANSI MPE and the pulse width was less than several nanoseconds.In this paper, we investigate the SNRs of PA signals induced by a single pulse, pulse train, and continuous chirp waveforms when the fluence of these optical beams is much lower than the ANSI MPE, as commonly happens in LED/LD-based PA imaging systems. If there is no absolute benefit on pulse PA signals in terms of an SNR, it is not necessary to stick to pulse-mode PA measurements with LEDs/LDs considering extra customized pulse current drivers. First, we derive the PA SNR expression in the frequency domain to analytically compare the SNRs for pulse and continuous waveforms. Next, by applying the reasonable assumptions to the frequency domain SNR expression, we derive the SNR ratio between PA signals from single pulse and matched filtering with a chirp waveform. Starting from this theoretically derived SNR ratio form, we investigate and analyze SNR ratios for pulse train and chirp-waveform matched filtered PA signals considering the same bandwidth and duration. Especially, we examine how the SNR ratios are characterized with the parameters of practically constructed LED/LD pulse-mode PA systems reported in the previous literature. Finally, we present the conclusion with discussion, which might significantly influence the research trend of constructing compact, cost-effective PA spectroscopic imaging systems.2,,,–The overall process of deriving the PA SNR expression in the frequency domain follows the description in the previous literature.max means a maximum value of the PA signal. Note that Eq. (4) is for the SNR squared because we derived Eq. (4) from the maximum PA power divided by the PA noise variance. The statistical descriptors, such as mean and variance, should be originally determined by averaging over the ensemble realizations for the maximum PA value. In almost all PA SNR studies, however, the ensemble realizations are unrealistic. The alternative method to calculate those statistical descriptors is to assume the noisy PA data as an ergodic random process,,In reality, a measured PA signal is typically contaminated with a significant amount of noise, such as ultrasound thermal noise. If we denote the noise spectrum by ,,,Assuming the PA noise is a stationary random process that is additive to noise-free PA signals, 3,The SNR of Eq. (6) is valid for arbitrary waveform and filtering spectra, The maximum fluence of incident optical waveforms to the human skin is limited by the ANSI MPE, which is ,,For the chirp waveform, the filter spectrum, ,,,As the example examining the SNR ratio of Eq. (10) affected by the term, If the pulse width, 44.1We suppose a pulse train waveform, where there are –The maximum pulse number in Eq. (14) for the derivation of Eq. (15) implies the repetition rate of pulse train waveforms could be impractically high. To circumvent this impractical assumption, the fixed repetition rate of a pulse train, 4.2Since the same optical component  radiates either pulse train or chirp waveforms, the irradiance of a chirp waveform must be determined based on the condition of the single pulse energy of a pulse train. From this concept, it is reasonable to consider that the maximum chirp waveform irradiance is equivalent to the pulse power divided by the pulse width, Since the chirp waveform irradiance is limited as Eq. (18) and the pulse train SNR is decreased as ,It is possible to extend the pulse train duration to average more pulse PA signals to increase the SNR. The chirp waveform duration longer than ,If the maximum pulse repetition rate in a LED/LD-based pulse PA system is noted as Assuming 4.3,,,,5Bulky pulse lasers can generate high-power pulse trains that are composed of a few tens of nanoseconds pulses with the 19), and  that are,,–,,The duration of chirp waveforms for PA radar is generally in the range of fulfilling the thermal confinement (a few tens of milliseconds), not the stress confinement (a few tens of nanoseconds) for a typical biomedical tissue.It is frequent that the pulse fluence of LED/LD-based pulse train PA systems is reduced more than a few thousandths of the ANSI MPE. The result in this paper indicates it would be advantageous in terms of an SNR to operate such very low optical-power PA systems with the matched filtering process with chirp waveforms rather than pulse trains. Investigating SNR ratios from brute-force simulation adopting parameters of the actual LED/LD-based PA systems supports the finding of this paper. In addition, continuously operating LED/LDs circumvents the extra work of fabricating pulse current drivers and the risk of reducing the lifetime of those optical components. We hope the result in this paper extends the research of applying various continuous waveforms already studied in the conventional radar technology to PA systems of limited optical power. This would diversify and expedite the research and development of LED/LD-based, compact, and cost-effective PA systems in the field of biomedical optics.


Pedicle screw insertion is considered a complex surgery among Orthopaedics surgeons. Exclusively to prevent postoperative complications associated with pedicle screw insertion, various types of image intensity registration-based navigation systems have been developed. These systems are computation-intensive, have a small capture range and have local maxima issues. On the other hand, deep learning-based techniques lack registration generalizability and have data dependency. To overcome these limitations, a patient-specific hybrid 3D-2D registration principled framework was designed to map a pedicle screw trajectory between intraoperative X-ray image and preoperative CT image. An anatomical landmark-based 3D-2D Iterative Control Point (ICP) registration was performed to register a pedicular marker pose between the X-ray images and axial preoperative CT images. The registration framework was clinically validated by generating projection images possessing an optimal match with intraoperative X-ray images at the corresponding control point registration. The effectiveness of the registered trajectory was evaluated in terms of displacement and directional errors after reprojecting its position on 2D radiographic planes. The mean Euclidean distances for the Head and Tail end of the reprojected trajectory from the actual trajectory in the AP and lateral planes were shown to be 0.6–0.8 mm and 0.5–1.6 mm, respectively. Similarly, the corresponding mean directional errors were found to be  Currently, Pedicle Screw Insertion (PSI) is a common type of surgery performed to fix fractures, decompression or deformities of vertebrae. In PSI surgery, once the entry point (facet joint and transverse process junction) for screw insertion is identified, using a high-speed burr, posterior cortical breaching is performed. This is followed by insertion of gearshift probe to a depth of 20 mm to 25 mm, pointing the tip in a lateral to medial direction, and then insertion is continued to the desired depth . During PSI is associated with a wide variety of postoperative complications due to vertebra’s complex structure and its proximity to neighboring tissue regions. In the PSI procedure, varieties of postoperative complications exist—these include injuries to the nerve root, spinal cord or vascular systems such as azygos vein, intercostal artery, inferior vena cava in the thoracic region, and mainly the aorta and common iliac vessel in the lumbar spinal region . In addiA better screw trajectory plan relative to patient-specific vertebral morphology leads to a gratifying PSI surgery. The screw insertion plan includes assessment of vertebral morphology and pedicular dimension analysis such as its diameter, length and angle. Additionally, entry point, pedicular center point, and the target region inside the vertebral body are identified. The ideal screw trajectory is planned along the cylindrical axis of the pedicle . HoweverAccording to the study conducted for quality practice, freehand-based PSI surgeries strongly recommend experienced surgeons over novice ones . In addiThe previously described conventional PSI procedure is completely based on manual feedback. In this procedure, the target region cannot be directly visualized and fiducial marker or tracker-based navigation tools are also not widely practiced. Hence, the quality of the surgery that surgeons experience is truly instinctive. In addition, because of the limited vision provided by the intraoperative radiographs, surgeons could perceive the positioning of the screws incorrectly. Furthermore, the practice has too much exposure to the X-ray radiations due to the necessity of acquiring a series of images intending to confirm the navigation of the surgical tool all through the posterior entry point to the anterior most targeted point. Hence, to estimate 3D screw pose in the intraoperative environment utilizing minimal intraoperative X-ray images, a 3D-2D image registration-principled semi-automated navigation tool is designed. The proposed framework addresses the challenges encountered during PSI surgery by naturally fitting in line with the existing PSI procedures usually practiced in many local hospitals.The image registration-based navigation systems had been designed to function as a navigation tool in the operation theater ,20. The The literature survey includes intensity-based 3D-2D registration principled PSI navigation tools designed for the clinical applications and their pros and cons. In addition, an alternative to intensity-based 3D-2D registration technique, i.e., Iterative Control Point 3D-2D registration—a sub-type of feature-based registration and its significance and limitations in a clinical application perspective are discussed. In addition, we have discussed the latest navigation technologies that would be ubiquitously utilized in Orthopaedics surgeries in the coming future.The 3D component model of the pedicle screw was designed, and its position from multiple radiographs was registered onto 3D CT to function as a navigation tool in PSS . Three iUneri and team designed a tool to overlay scanned and parameterized model of probe tool and pedicle screw onto pCT through known component-based registration . In thiseast 100 . In anoteast 100 , a near To simulate the spinal fixation procedure, a two-stage deformable registration framework was designed to register device models of K-wire and spinal fixation rods on CT image . The X-rAn intraoperative image guidance system based on 3D-2D registration was designed to provide visualization of pedicle screw navigation in the CT image . The RegA Convolutional Neural Network (CNN)-based deep learning framework was designed for automatic PS segmentation and pose estimation . InitialOn the other hand, to measure 3D Acetabular cup orientation after the Total Hip Replacement (THR) surgery, a 3D-2D registration-based tool was designed. The tool utilizes a single 2D postoperative AP radiograph to get registered with 3D preoperative CT image . The regIn another work, to assist pelvic screw placement and patient-specific screw trajectory planning, and to provide surgical guidance and quality assurance—a trackerless registration of deformable K-wire device was presented . The autAs an alternative to intensity-based 3D-2D registration, a point set-based 3D-2D registration—a sub type of feature-based registration was proposed. This point set registration includes an Iterative Control Point (ICP) registration type wherein the target points are registered with source point sets. These registration techniques are popular for their simplicity and low computational complexities . The ICPTo support in neurointerventions a framework was designed by McLaughlin et al.  wherein To overcome the issues of deep learning-based registrations such as the data dependency and poor generalization ability, and to avoid high computational complexity associated with intensity-based 3D-2D registration, a hybrid registration framework possessing ICP-DRR-based registration modules is proposed. The proposed framework incorporates landmark-based registration to naturally fit in line with the existing surgical practice wherein surgeons intuitively map target points between the interimaging datasets. The framework bypasses the requirement of consecutive DRR image generation during the optimization stage of conventional intensity-based 3D-2D registration, hence making the system applicable in faster intraoperative applications without necessitating any GPU  or parallel computation platforms.Without acquiring intraoperative radiographic images HoloLens—a Head Mounted Display (HMD) based visual augmented reality-based navigation systems were developed to improve the accuracy and reproducibility in orthopaedic surgeries ,38,39. TAlternatively, to practice pedicle screw insertion, various robot-assisted surgery systems have been developed ,41. MostThe registration framework is divided into two stages, i.e., anatomical landmark registration followed by trajectory registration. The stage I, as depicted in The stage I process includes preprocessing of pCT, trajectory planning in pCT, C-arm camera modeling, DRR generation, and cost function optimization utilizing certain anatomical landmarks from 3D and 2D planes.The pCT and X-ray images are acquired at resolution as mentioned in the To generate the DRR images of pCT in various directions, the movement of the C-arm camera is modeled utilizing the extrinsic and intrinsic matrix of the C-arm imaging device. The extrinsic parameter includes translational (The landmarks from the 3D plane to the 2D plane can be projected as follows. Consider a source point Sourceto object vectorSource to center point of projection vectorD is the projection point of object vector on the center axis t” as defined in Equation (If Equation .(3)t=SPProjection of object point “Source to object projection point distance vector on center axisMagnification factorProjection coordinates on the detector planeM) and finally the magnified length between the projected point and the The algorithm can be summarized in three simple steps. Initially, object point to center axis distance is measured  of anatomical tissues are cumulated along the virtual X-ray in the AP and lateral directions, as depicted in Equation , l is thel index .(9)μ over “Equation . On optiEquation .(10)mPDThe designed framework employs Covariance Matrix Adaptation Evolution Strategy  based optimization considers sample mean and variance from the current and previous generations. When samples get mutated across generations, the evolution path reveals correlation information. This concept of the evolution path updates the covariance matrix in a significant way by exploiting the correlation between the consecutive steps. Suppose if successively selected mutations are parallel correlated, the evolution path will be longer, signifying that search direction is the same, and consequently step size is increased for faster convergence. Otherwise, when they are anti-correlated, short step sizes are considered. This process is known as cumulative step size adaptation ,48.The mean and variance of transformation parameters are selected from the knowledge of the difference between the initial projected image and the real X-ray image. The larger variation in sample distribution may converge the objective function to local maxima driving the localization to inappropriate transformation. Hence, mean and variance are chosen such that the generated DRR image would include major anatomy as appearing in the real X-ray image. The total number of evaluations and population size are set to 2000 and 50, respectively. The rest of the parameters are defined as per the work Hansen et al. . In the The stage II includes trajectory axial mapping on pCT at the registered vertebral pose. After the pilot hole creation, a radio-opaque pedicular marker is placed inside the pilot hole, and on optimal landmark registration, the pose of this marker is axially mapped on pCT in the world coordinate system utilizing the designed C-arm camera model. The head and tail ends of the radio-opaque pedicular marker of length 3 cm are back-projected onto pCT, and intersection points of virtual X-rays are computed to identify the entry point and target point. The accuracy of trajectory mapping depends on the accuracy of anatomical landmark registration. On imprecise pose estimation, the positions of the landmarks can be varied about their previous markings or different landmark combination sets can be selected. Because of registration errors, mainly due to imprecise landmark identification and localization, and imprecise anatomical landmark mapping between the AP and lateral X-ray images, the trajectories in AP and lateral directions did not get intersected. In such a scenario, the midpoint of the shortest distance between the trajectories is identified as the corresponding localization point. The trajectory evaluation is performed on the intraoperative radiographic planes, and the registration accuracy is evaluated based on three surgeons’ feedback.To evaluate the precision of 3D-2D registration, various regularizations were followed. These standardizations define the evaluation protocol, evaluation criteria and definition of ground truth registration, etc. . The mar of 2 mm . In some of 2 mm  and Uner of 2 mm , the reg of 2 mm . The sta of 2 mm .After the trajectory mapping in the 3D plane, the registered trajectory is back-projected on the 2D plane to measure its pose relative to the marker pose. In our framework evaluation, seven different metrics are considered. This includes errors in localizing the trajectory entry and target positions, trajectory angles in two planes, and the difference in trajectory lengths. The Euclidean distance and geometrical angle error measurements are performed separately in the AP and lateral planes. To strengthen the previously defined assessments and for reliability, all the metrics are evaluated by the surgeons. Furthermore, after the stag-I registration, the screw positions from AP and lateral X-ray images are overlaid on corresponding DRR images. This information strengthens surgeons’ interpretation of screw position in 3D plane relative to the vertebral anatomy as displayed in 2D image. This test supports detecting the possibilities of any breaches that can be sensed utilizing AP and/or lateral C-arm images in the intraoperative environment without postoperative CT images .On optimum registration, the mPDE measurement stagnated at optimum value and registered the landmarks with better accuracy. After the anatomical landmark registration, the DRR image projected the same anatomical region as that of a real X-ray image possessing an optimal match in terms of structure, pose and shape. On backprojection, the marker’s head and tail ends of trajectories did not get intersected due to imprecise one-to-one landmark alignment in the AP and lateral directions. The distance between the unconnected trajectories for different vertebrae is shown in In addition to 2D directional angle errors, head and tail end displacements between the actual and the registered trajectories were measured by overlaying trajectory points on intraoperative radiographs. The marker length difference was measured between the estimated trajectory length and the marker’s ground truth length value. On global optimal registration, these metrics should result in a zero value, signifying that the entire vertebra is registered optimally without any misalignment between the AP and lateral planes. Registration errors together with the screw head end blocking a portion of the marker in the AP direction resulted in a nonzero trajectory length difference.Due to vertebral deformation between the intraoperative and preoperative environments, individual vertebra was subjected for deformable registration. Hence, though images possessing multiple vertebral levels were acquired once, different but closer registration parameters were estimated for individual vertebra. Under the postural spine deformations, such deformable registration practice are found to be locally rigid but globally deformable.The framework bypasses the requirement of several image preprocessing techniques, such as filtering, image enhancement, feature extraction and segmentation processes, that are usually practiced in 3D-2D image registrations to minimize the intensity differences or for better feature mapping between the projected and real X-ray images. In addition, the ICP-DRR based anatomical landmark registration bypasses the requirement of computation intensive projection image generation during the optimization stage, hence supporting the framework’s applicability in the faster intraoperative applications assisting with clinically acceptable registration accuracy. Such landmark-based registration framework is suitable especially in surgical procedures wherein surgeons navigate surgical tools through referring to their intuitive 3D-2D landmark mapping knowledge.The registration accuracy depends on corresponding 3D-2D anatomical landmark identification and the accuracy with which 3D-2D pose is estimated. The accurate landmark identification was challenging due to low-contrast intraoperative X-ray images and vertebral level missing EOV. Hence, during the landmark registration, it was imperative to minimize the error in mapping 3D-2D landmarks. When the vertebra level misses EOV, landmark registration improves after the right identification of corresponding control points subjected to different out-of-plane transformations. More often, vertebral centroids, pedicle centers and inferior ends of the spinous process were employed for landmark registration in the AP plane. Alternatively, when vertebral body endplates’ anterior and posterior edges were displayed, the corresponding landmarks control points were selected to register the landmarks subjected to out-of-plane rotations. A combination of many such landmarks with optimal 3D-2D mapping knowledge can be utilized to estimate individual vertebral poses in optimally matching projection images with the intraoperative radiographs acquired in various planes. Due to the defective shape of the L4 vertebral level, there were challenges associated with the fractured vertebra while registering in the lateral plane. The imprecise vertebral body corner points identification due to its fragmented body region resulted in moderate magnification factor registration.Whenever vertebral endplates and pedicles miss the EOV projection in a real X-ray image, and when the head end of the screw blocks a portion of marker length in the AP direction; the trajectories in the AP and lateral directions majorly deviated from getting intersected. A study can be performed on these aspects by acquiring multiple oblique images.The working principle of the designed framework naturally fits in line with the existing PSI surgeries that are currently practiced in local hospitals. The designed ICP-DRR based hybrid registration framework accurately mapped the pedicle screw trajectory between intraoperative X-ray images and preoperative CT images. The trajectory registration was completely dependent on anatomical landmark registration. On unclear visibility of anatomy, a combination set of multiple landmarks was identified for the optimal vertebral pose estimation. The estimation of marker length and 2D directional vectors can be further optimized by additionally referring to the oblique images. The generated DRR images after anatomical landmark registration clinically validated the estimated ICP registration parameters. The control point-based registration through bypassing the projection image generation process of intensity-based registration has made the registration process suitable for faster intraoperative applications. The patient specific registration framework such as ours is free from data requirement and generalizability issues associated with deep learning based 3D-2D registration frameworks. Automated landmark identification in both 3D and 2D planes along with parallel computation-based registration can further accelerate the registration process.


Teaching Point: Synthetic CT images can improve evaluation of bony lesions on MRI and show potential for fracture evaluation, but validation is needed. A 20-year-old woman was referred to the emergency department after a fall from a height of 4 meters. She had severe pelvic pain and could not bear weight on the left leg. X-rays showed no fracture.Since she suffered from neurological complaints, a pelvic MRI scan was performed. Sacral bone marrow edema was seen on T1- and fat-suppressed T2-weighted MR images  and 1B. The sCT images were reconstructed from the 3D T1MGE images with commercially available software , using a deep learning method based on CNN U-net architecture. This method exploits local spatial contextual information in the multiecho data to reconstruct the latent bone structures, which was learned using paired MRI and CT data. The resulting sCT image expresses radiodensity contrast in Hounsfield units.The clear depiction of the fractures on the sCT images is largely due to the detailed delineation of the cortical bone. The excellent cortical delineation of synthetic CT has been first demonstrated in the imaging of the sacroiliac joints: sCT had higher diagnostic performance in the detection of bony lesions (such as erosions) compared with routine T1-weighted MRI [Currently, data for fracture detection using sCT imaging is based solely on observational case studies and validation for use of the technique in trauma patients is still mandatory. Nevertheless, this case demonstrates the potential of sCT imaging as a harmless, radiation-free alternative to classic CT imaging to (re)evaluate fractures or other lesions of the cortical bone. The absence of ionizing radiation, its high similarity of the sCT images with classic CT and the one-stop-shop visualization of soft tissues and bones alike make sCT imaging very appealing as a potential future technique for clinical practice.


Cardiac rehabilitation for heart failure continues to be greatly underused worldwide despite being a Class I recommendation in international clinical guidelines and uptake is low in women and patients with mental health comorbidities.Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) programme was implemented in four UK National Health Service early adopter sites ‘’ betweenCompared to the REACH-HF multicentre trial, patients treated at the Beacon Site were more likely to be female (33.8% vs 22.9%), older (75.6 vs 70.1), had a more severe classification of heart failure (26.5% vs 17.7%), had poorer baseline health-related quality of life (MLHFQ score 36.1 vs 31.4), were more depressed (HADS score 6.4 vs 4.1) and anxious (HADS score 7.2 vs 4.7), and had lower exercise capacity (ISWT distance 190 m vs 274.7 m). There appeared to be a substantial heterogeneity in the implementation process across the four Beacon Sites as evidenced by the variation in levels of patient recruitment, operationalisation of the REACH-HF intervention and patient outcomes. Overall lower improvements in patient-reported outcomes at the Beacon Sites compared to the trial may reflect differences in the population studied (having higher morbidity at baseline) as well as the marked challenges in intervention delivery during the COVID-19 pandemic.The results of this study illustrate the challenges in consistently implementing an intervention  into real-world practice, especially in the midst of a global pandemic. Further research is needed to establish the real-world effectiveness of the REACH-HF intervention in different populations.The online version contains supplementary material available at 10.1186/s12872-022-02707-5. Understanding of real-world implementation and impact on patient-reported outcomes of an evidence-based intervention for heart failure.Rehabilitation EnAblement in CHronic Heart Failure may be a viable cardiac rehabilitation alternative for older patients and patients with mental health comorbidities and lead to an increase in the uptake of cardiac rehabilitation in these currently underserved populations.More effort is needed to offer the programme to a wider range of patients. This can be achieved by improving referral pathways and/or making the programme more accessible/appealing to different patients.The study is unique in utilising routine data to evaluate the real-world implementation of trial evidenced intervention; the findings can inform future studies employing similar methodologies.This study is part of a larger implementation project , the maiCardiac rehabilitation for heart failure continues to be greatly underused worldwide despite being a Class I recommendation in international clinical guidelines. Less than 20% of eligible patients in Europe receive this intervention  and feweThe Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) programme is a clinically effective and cost-effective, home-based, healthcare professional-facilitated cardiac rehabilitation programme for patients with heart failure . The 12-Moving research findings into routine clinical practice is a well-documented challenge , 15. OncThis study aimed to answer the following research questions: (1) What are the variations in the implementation process across the four Beacon Sites and how do such variations impact on patients’ outcomes?, (2) Are patients receiving the REACH-HF intervention at the Beacon Sites comparable to those recruited into the trial and more representative of the general population of heart failure?’ and (3) Are changes in outcomes of interest derived from routine data collected at the Beacon Sites for patients receiving the REACH-HF intervention comparable with the changes observed in the REACH-HF trial?.The current effectiveness-implementation study used a multi-centre prospective cohort design to evaluate the implementation process and compare trial evidence with routinely collected pre-treatment and post-treatment healthcare data during the real-world implementation of the intervention at four Beacon Sites.The Beacon Sites selection process is described in detail in the published protocol  and summThree cohorts of patients with heart failure were compared in the study: patients who received REACH-HF at the Beacon Sites, patients who received REACH-HF within the multicentre randomised controlled trial and the general population with heart failure – all heart failure patients (except those receiving REACH-HF at the Beacon Sites) in the National Audit of Cardiac Rehabilitation (NACR) database who received cardiac rehabilitation during the Beacon Site period (between June 2019 and June 2020).Audit data (see Results Tables) from the NACR database were used to understand the implementation process by considering how the intervention was delivered and the socio-demographic characteristics and medical data of patients treated in the Beacon Sites. The audit data were also used to compare patient characteristic and real-world changes in outcomes of patients receiving the REACH-HF programme to the prior clinical trial findings . A detaiA download of the NACR data was conducted by the NACR data scientist (AH) in February 2021. We focused on the four-month trial follow-up timepoint, as it was the best match for the time period between pre-treatment and post-treatment assessments at the Beacon Sites (mean 125.2 days). Due to data governance requirements, analyses using individual patient-level data were conducted by NACR staff.g) [Descriptive statistics were used to report the characteristics of the study sites and the patient sample. To explore whether the MLHFQ within-group change in the NACR data was different from the within-group change in the trial, a three-group  comparison (ANCOVA) was conducted with adjustment for MLHFQ baseline score, age and sex. To understand the within-group differences at the Beacon Sites and the trial, we used a standardised mean difference approach and calculated effect sizes for primary and secondary outcome measures adjusted for the sample size (Hedges’ g) , 21.Implementation activity at the Beacon Sites is summarised in Table On average, patients received 7.5 (SD 3.9) clinical sessions  over 125.3 days (SD 47.4). There was a large variation in the number of sessions attended with a minimum of one and a maximum of 24 sessions. A similar variation was observed with treatment duration, 70 days was the minimum and 299 days the maximum.The comparison of key participant characteristics across the three cohorts can be found in Table Referral sources for patients treated at the Beacon Sites can be found in Table Table The pre-treatment and post-treatment effect sizes calculated at the Beacon Sites Table  did not We observed the following pattern of variation in the magnitude of effect sizes at the individual Beacon Sites – a deterioration in all outcome measures at Site 1, no change in the MLHFQ and a small positive change in the mental health measures at Site 2, a small positive change in all available outcome measures at Site 3 and a small, a medium and a large effect size at Site 4 for the MLHFQ, and the HADS depression and anxiety domains, respectively. Table 9 in Additional file The primary and secondary analysis confirmed that the results found in the REACH-HF trial intervention group were not replicated in the Beacon Site population. However, it was difficult to conclude definitively that the real-world implementation resulted in lower effectiveness, as there were substantial differences between the trial and the Beacon Sites in terms of the patient population and the level of implementation (treatment dose/duration). We also encountered a small sample size and missing data, which introduced selection bias into the study, further complicated by a lack of a non-treatment control group. The discrepancies in the implementation process and population characteristics observed in the study are consistent with other studies looking at the implementation of interventions that have been found to be effective in trials. At the Firstly, the COVID-19 pandemic led to substantial variations in the delivery of the programme across the Beacon Sites. Our findings suggest that when delivered as part of routine practice, the programme was spread out over a longer time period ; there was also a large variation in the number of treatment sessions received. This might suggest reduced treatment fidelity, leading to lower effectiveness. The inability to deliver the treatment as it was intended  might have resulted in a diminished quality of care compared to the trial. For example, having to substitute face-to-face home visits for phone sessions might have impacted the nurse’s ability to deliver the person-centred interactions that are at the core of the intervention .Secondly, compared to the trial population, patients treated at the Beacon Sites were older, more depressed and anxious, had lower exercise capacity, and experienced more debilitating symptoms of heart failure. The 4.7-point difference in mean MLHFQ between cohorts is close to the minimal clinically important difference of five points , which sHistorically, the uptake of cardiac rehabilitation in older patients with heart failure and in patients with mental health issues has been particularly low , 26. As Using routinely collected audit data was a low-cost and a low research-burden option that allowed us to conduct a rapid review of the implementation process and to compare REACH-HF trial outcomes with real-world implementation outcomes. The study is of high clinical relevance, as the initial results suggest that the REACH-HF programme may be a viable cardiac rehabilitation alternative for older patients and patients with mental health comorbidities, both often underrepresented in traditional centre-based programmes . However, steps need to be taken to make the programme more accessible to a wide range of patients. The study also provides good insight into conducting implementation research in challenging contexts and during unprecedented  times.The main limitations of the study were the substantial variations in implementation of the treatment, high levels of missing data, a limited sample size that may have introduced selection bias , and a lack of a comparable patient group .More research, as is currently being conducted in the SCOT REACH-HF project, which is examining the real-world roll out of REACH-HF across six health boards in Scotland , is needAdditionally, as the amount of NACR routinely collected data from cardiac rehabilitation teams offering the REACH-HF intervention UK-wide increases, more rigorous analysis of implementation effectiveness can be applied  and outcomes). However, steps should be taken to reduce the amount of missing follow-up data, particularly for key outcome measures such as health-related quality of life.Our data suggest that changes in patient-related outcomes seen in the REACH-HF randomised trial were not replicated in the real-world setting of this study. They also suggest that offering home-based cardiac rehabilitation may facilitate uptake amongst older patients and those with mental health comorbidities. However, our results need to be interpreted carefully given substantial differences in the populations treated and the context of the COVID-19 pandemic, which may have affected the intensity of treatment delivery.Additional file 1: Setting up the Beacon Sites.Additional file 2: Detailed description of primary and secondary outcome measures.Additional file 3: Table 6. REACH-HF activity at individual Beacon Sites between June 2019 and June 2020.Additional file 4: Table 7a. Socio-demographic characteristics of patients enrolled onto the REACH-HF programme at individual Beacon Sites between June 2019 and June 2020 (including missing data) AND Table 7b. Comparison of patients receiving the REACH-HF intervention at the Beacon Sites between June 2019 and June 2020, those recruited into the REACH-HF trial and the general heart failure population recorded in the NACR database between June 2019 and June 2020 (excluding Beacon Sites patients).Additional file 5: Table 8. Referral sources for patients enrolled on the REACH-HF programme at individual Beacon Sites between June 2019 and June 2020.Additional file 6: Table 9. Effect sizes for primary and secondary outcome measures at individual Beacon Sites for patients receiving REACH-HF programme between June 2019 and June 2020.


N = 3,583) using the 2015–2016 Myanmar Demographic and Health Survey.Hepatitis B virus birth dose (HepB-BD) vaccination is recommended to reduce mother to infant transmission. We evaluated the HepB-BD status of women who gave birth between 2011 and 2016 , but only 43% received recommended ANC services, and 60% gave birth at home. The overall HepB-BD coverage rate was 26%. Vaccination coverage was higher in urban areas and was inequitably concentrated among children of more educated and wealthier women. HepB-BD coverage was also positively associated with receipt of ANC at non-governmental facilities, and delivery at a facility, skilled provider at birth and Cesarean delivery. After adjusting for sociodemographic and health system factors, receipt of the HepB-BD was positively associated with weekly media exposure, receipt of recommended ANC, and Cesarean delivery, and inversely associated with home delivery.Both socioeconomic and health systems factors influenced suboptimal and inequitable vaccination coverage. Improved access to quality ANC and delivery services may increase HepB-BD coverage although targeted approaches to reach home births are likely required to achieve national goals.The online version contains supplementary material available at 10.1186/s12913-022-07902-w. An estimated 257 million people worldwide live with chronic Hepatitis B virus (HBV) infection, predominantly in Asia . UntreatIn Southeast Asia the overall prevalence of HBV among children below the age of 5 has been reported at 1.1% , and theOur study aimed to investigate national coverage and inequity of the HepB-BD and to examine the relationship between maternal and health system factors and HepB-BD vaccination. Our a priori hypothesis was that accounting for utilization of antenatal and delivery care services would attenuate many of the expected associations between socio-demographic factors and HepB-BD coverage.We used the first Myanmar Demographic and Health Survey (DHS) , a crosspost-hoc sensitivity analysis we limited the definition of vaccination to the children who had the vaccine documented on their health card . The vaccination status of the most recent child was analyzed. For multiple gestation deliveries, the status of a single child was assessed, as all twins and triplets either had missing (< 1%) or concordant data.HepB-BD vaccination was defined as receipt of the HepB-BD within 24 h of delivery. Participants’ children were coded as vaccinated within 24 h based on documentation in the child’s health card or maternal report. Children were coded as not vaccinated if the health card did not document the HepB-BD vaccine or participants denied receipt or if participants didn’t know their child’s vaccination status. In a Our selection of potential predictors of HepB-BD vaccination and development of analytical models drew on the combination of two conceptual frameworks. Andersen’s model of medical care utilization emphasizes the complementary contributions of predisposing factors  and enabling factors  ; NuttingA simplified two-step pathway can be used to describe HepB-BD vaccination in Myanmar: first, the mother must deliver within a clinical care system where the vaccine is available; second, the health system must administer the vaccine within 24 h after birth. Socioeconomic inequities in access to ANC and delivery care have been documented in Myanmar ; inequitPotential predictors were selected based on their prior associations with receipt of the HepB-BD –24 or otSurvey responses of ‘don’t know’  and ‘unmeasured’ (birthweight), were combined with missing values and labeled as a separate category in the analysis accounting for 37% of predictor variables. The percent of missing data for each predictor was as follows: 2% of prepartum tetanus vaccination and mode of delivery, 5% of location of ANC, 6% of early ANC and number of ANC contacts, 24% of postnatal health check, 50% of low birthweight. In a sensitivity analysis we used multiple imputation with chained equations to create 50 datasets with imputed values for all variables, and no substantial differences in the estimated effect sizes were found when compared to the multivariable model without multiple imputation (data not shown).2 test. The health concentration index [p < 0.1), resulting in the removal of parity and the postnatal health check from the final model (Model 2). Colinearity was evaluated using weighted linear regression, and the Variance Inflation Factor (VIF) was < 3 for all predictors, signifying low concern for collinearity, while a link test and the Archer–Lemeshow Goodness-of-Fit test [p-values were two-sided and p < 0.05 was considered statistically significant. All analyses were performed with Stata 16.0 , using the conindex program to calculate concentration indices [Participant and health system characteristics were described with frequency distributions and differences between groups were evaluated with the Rao‐Scott χon index  was calcFit test  indicate indices .The present study was considered exempt by the UCSF Institutional Review Board. The survey protocol was reviewed and approved by the Ethics Review Committee on Medical Research including Human Subjects in the Department of Medical Research of the Myanmar Ministry of Health and Sports.Of the 12,885 women who completed the DHS Women’s Questionnaire, we excluded 9,399 who did not give birth between 2011 and 2016, and 96 who had missing data for HepB-BD status  received the HepB-BD vaccine, based on documentation in the child’s health card (5%) or maternal report (21%).C) provides a summary measure of health inequality that takes into account the entire distribution of vaccination coverage across values of ordinal (ranked) variables, and was positive and large for both years of maternal education  and household wealth index values . This indicates a skewed pattern of vaccination, with lower rates of vaccination among children born to women with fewer years of education, and those born into poor households.The Wagstaff-normalized concentration index , the national HepB-BD coverage was estimated to be 5%  . While tOur estimated coverage fell far short of Myanmar’s goal for 2020 (80% coverage) and the WHO goal of 90% by 2030 , 33. MyaWe observed large socioeconomic gradients in HepB-BD vaccination rates similar to those observed for other clinical and public health services in Myanmar, including childhood vaccination , 36, 37.post-hoc analyses we calculated concentration indices for all factors that retained statistically significant associations with vaccination in our final model except geographic zone , and found that they demonstrated large and inequitable distributions (C between 0.22 and 0.46) according to both household wealth and maternal education.In our full model (Model 2), we found that the associations of socioeconomic factors and HepB-BD vaccination were entirely accounted for by weekly media exposure and health system factors. At least three phenomena likely contributed to the larger than expected attenuation of socioeconomic inequities in HepB-BD coverage. First, the magnitude of the inequities in utilization of ANC and delivery care services were larger than anticipated. In Second, the correlations between HepB-BD vaccination and other ANC and delivery factors was stronger than anticipated. For example, all Cesarean surgeries were conducted by a skilled provider and they occurred almost exclusively (98%) in facilities with the highest rates of vaccination . The high correlation of the HepB-BD with other clinical services is consistent with our conceptual model and highlights how HepB-BD vaccines are unique among recommended immunizations in Myanmar in that they are administered almost exclusively by clinicians in healthcare settings. The greater separation between clinical services and vaccination by EPI teams likely partially accounts for the contrast between our results and those of a study in Myanmar of childhood vaccination, that found wealth-related inequalities in complete vaccine coverage persisted after controlling for ANC contacts .The third likely contributor to the large attenuation of inequities in HepB-BD vaccination coverage after adjustment for clinical factors is that the likelihood of receiving the vaccine is in fact similar for individuals who overcome barriers to accessing ANC and delivery services. This unexpected, though promising, finding suggests that additional barriers to the HepB-BD such as low health literacy, discrimination and out-of-pocket fees to purchase vaccines may not substantially impact the likelihood of receiving the HepB-BD for newborns delivered to women who can access healthcare services. Although our findings suggest that greatly enhanced access to ANC and delivery services – for births in facilities and in homes – likely would address inequities in HepB-BD coverage, improved access alone would not be sufficient to achieve coverage targets. Under our counterfactual scenario that assumed all pregnant women received the services associated with HepB-BD vaccination in our full model, the predicted probability of HepB-BD vaccination would have been only 0.49. Home birth (59% of deliveries in our sample) demonstrated the largest (inverse) association with HepB-BD vaccination (aOR 0.32). Achieving high coverage of the HepB-BD vaccine in Myanmar almost certainly will require concerted efforts to redistribute health services, to increase facility deliveries by overcoming barriers to facility delivery , 39, to Subsequent to fielding of the DHS in 2015–2016, public and private actors in Myanmar initiated changes that may have influenced HepB-BD vaccination coverage and modified its associations with the antenatal and delivery care factors presented here. In 2016 the Myanmar MOHS released a national strategic plan for HBV elimination that committed the MOHS to provide the HepB-BD free of charge for facility births and identified strategies for increasing coverage for deliveries that occur in homes or remote geographic locations , 42, 43.post-hoc sensitivity analysis  and recall bias may have influenced our estimation of coverage; in a Appendix  the crudOverall HepB-BD coverage was suboptimal in Myanmar. Large socioeconomic inequities in HepB-BD vaccination rates were observed, and these inequities were entirely explained by the inequitable distributions of ANC and delivery care factors. Achieving Myanmar’s goal of 80% HepB-BD vaccine coverage by 2030 will likely require targeted efforts to increase the availability of the HepB-BD for facility-based births, and to ensure the HepB-BD reaches children born at home.Additional file 1.


The migraine attack is classically divided into the prodromal, aura, headache and postdromal phase. Previous studies have highlighted non-headache symptoms associated with migraine occurring during the prodromal or postdromal phase. This study aimed to track the evolution of non-headache symptoms throughout all phases of the migraine attack. We also wished to delineate the phenotype of patients with more symptomatic migraine episodes and explore the association between non-painful symptoms and migraine disease activity and patients’ disability.Two-hundred and twenty-five migraine patients were enrolled and were asked to recall retrospectively whether non-headache symptoms occurred during the prodromal, headache and postdromal phase of their attacks. The occurrence of symptoms during the different migraine phases was tested using the Cochran’s Q tests, Cohen’s and Fleiss’ kappa. Differences between groups according to the presence of non-headache symptoms through the entire migraine attack and correlations between the frequency of non-headache symptoms experienced during all phases and patients’ disease activity and disability were also assessed.Ninety-nine percent of patients reported having at least one non-headache symptom in one phase of the migraine attack and 54% of patients had at least one non-headache symptom occurring during all phases of migraine. The occurrence of non-headache symptoms was different throughout the three phases of migraine, being higher during the headache phase than during the prodromal and postdromal phases. Symptoms with the highest co-occurrence throughout all migraine phases were neck stiffness, thirst and abdominal pain. Patients who experienced non-headache symptoms during all three phases of migraine were more frequently females, had a higher disability, were suffering from chronic migraine and had more frequently medication overuse headache.Migraine is a complex neurological disorder with a wide constellation of non-headache symptoms that can affect the burden of the disease. A better characterization of the evolution of non-headache symptoms through the different phases of migraine can enrich our knowledge on migraine pathophysiology and improve the management of the disease. Migraine affects around 1 billion people worldwide and is one of the leading causes of disability in people younger than 50 years . MigrainThe aim of this study was to characterize non-headache symptoms in a large sample of migraine patients and track the evolution of such symptomatology through the different phases of the migraine attack. We also sought to delineate the phenotype of patients experiencing non-headache symptoms during all phases of migraine and explore the association between non-painful symptoms and migraine disease activity and patients’ disability.We enrolled 225 patients with migraine who have attended the Headache Clinic at San Raffaele Hospital for their first clinic appointment from February 2019 to July 2021. Inclusion criteria were: age ≥ 18 years; a diagnosis of migraine based on the International Classification of Headache Disorder criteria (third edition) ; evidencThe study was approved by the local ethical committee and written informed consent was obtained from all participants.p <  0.05. Patients were divided into two subgroups according to the presence of non-headache symptoms through the entire migraine attack. Between-group differences in demographic and clinical characteristics were assessed using the independent t test or Mann-Whitney test for continuous variables and the Fisher exact test for categorical variables . Correlations between the frequency of non-headache symptoms experienced during all phases of migraine and patients’ disease activity and disability were assessed using the Spearman’s correlation test.Based on previous studies , 21, we The main demographic and clinical characteristics of migraine patients are summarized in Table Two hundred twenty-three (99%) patients reported having at least one non-headache symptom in one phase of their migraine attacks. One hundred and ninety five (87%) patients reported experiencing at least one non-headache symptom in two phases of their attacks and 122 (54%) patients had at least one non-headache symptom throughout all three phases of migraine. The mean number of non-headache symptoms occurring throughout the entire migraine attack was 1.24 (range: 0–10).p <  0.001), being higher during the headache phase than during the prodromal and postdromal phase. The occurrence of food craving did not significantly change over the migraine attack (Cochran’s Q test: p = 0.341) , while difficulty in concentration was most frequently reported during the headache phase  and fatigue  during the postdromal phase , MMD , intake of acute treatments , MIDAS , HIT-6  and NRS  scores were.The higher the number of non-headache symptoms experienced through all phases of migraine, the higher the MHD  was relatively small. Future studies using headache diaries to prospectively collect data regarding the occurrence of non-headache symptoms are needed. Moreover the occurrence of non-headache symptoms during the aura phase should be explored in the future.Overall, our results confirm the notion that migraine is not simply characterized by recurring pain episodes but is a far more complex neurological disorder with a wide constellation of non-headache symptoms that can play a role in increasing the burden of the disease. Although the identification of distinct migraine phases may ease the study of their underlying mechanisms, it should be kept in mind that most non-headache symptoms may occur throughout all phases. A better characterization of the evolution of non-headache symptoms through the different phases of migraine can improve our understanding of its pathophysiology. Non-headache symptoms should be investigated in routine clinical practice and the effect of acute and preventive treatments on such symptomatology should be further explored in future studies.


Brain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration.In this study, we used quantitative susceptibility mapping (QSM), an emerging MRI technique developed for quantifying tissue magnetic susceptibility, to examine brain iron accumulation in individuals with alcohol use disorder (AUD) and its relation to compulsive drinking.Based on our previous projects, QSM was performed as a secondary analysis with gradient echo sequence images, in 186 individuals with AUD and 274 healthy participants. Whole-brain susceptibility values were calculated with morphology-enabled dipole inversion and referenced to the cerebrospinal fluid. Then, the susceptibility maps were compared between AUD individuals and healthy participants. The relationship between drinking patterns and susceptibility was explored.Whole-brain analyses showed that the susceptibility in the dorsal striatum (putamen and caudate) among AUD individuals was higher than healthy participants and was positively related to the Obsessive Compulsive Drinking Scale (OCDS) scores and the amount of drinking in the past three months.Increased susceptibility suggests higher iron accumulation in the dorsal striatum in AUD. This surrogate for the brain iron level was linearly associated with the compulsive drinking pattern and the recent amount of drinking, which provides us a new clinical perspective in relation to brain iron accumulation, and also might indicate an association of AUD with neuroinflammation as a consequence of brain iron accumulation. The iron accumulation in the striatum is further relevant for functional imaging studies in AUD by potentially producing signal dropout and artefacts in fMRI images.The online version contains supplementary material available at 10.1007/s00213-022-06301-7. As a chronic relapsing disease, alcohol use disorder (AUD) represents one of the world’s most significant addiction problems and has a large impact on global public health. It is characterized by recurrent compulsive alcohol use despite significant alcohol-related behavioral, cognitive, physiological, and social problems. The Diagnostic and Statistical Manual of Mental Disorders fifth version (DSM-5) criteria of substance use disorder also emphasizes the compulsive quality as a central aspect of addiction  is an emerging MRI technique. It calculates the tissue frequency shift using phase information at different echo times from gradient echo images and then reconstructs the susceptibility maps  with a 12-channel head coil. A multislice 2D-GRE was used for the QSM analysis: TR = 358 ms; TE−3 to 106) with 10% random sub-sampling  to SPM12 TPM MNI template for statistical comparison. Whole-brain susceptibility values for each subject were included in a one-tailed t-test to find brain regions with differences in QSM intensity between the groups of AUD and healthy participants. Age and current smoke status were added as covariates of no interest. Although we had specific hypotheses for the basal ganglia, we conducted whole brain analyses to also exploratory look at other brain regions. A voxel-wise-threshold of P < 0.001 in combination with a cluster-extent threshold determined with random field theory in SPM12 was used for a corresponding cluster-level family-wise error (FWE) significance threshold of P < 0.05. We then generated a region of interest (ROI) using the significant voxels of the group comparison and averaged the susceptibility values in this ROI. A linear partial correlation controlling for age and smoke status was conducted between the mean susceptibility within the ROI and psychometric variables using SPSS . Correlation analyses were done to all participants, because in a group of healthy participants, there were also light to moderate drinkers, which could bring more information on linear relations between susceptibility and psychometrics. Psychometric data included the sum of ADS score, AUQ score, and the OCDS global score, according to the calculation rules from a previous study


A change in the coronary sinus (CS) activation pattern from an eccentric to a concentric pattern during the ablation of an orthodromic reciprocating tachycardia might falsely suggest the presence of a second  accessory pathway (AP) during tachycardia or the successful ablation of the left lateral AP under ventricular pacing despite persistent and unaffected AP conduction. Complete or partial intra-atrial block should be suspected when an abrupt change in the atrial activation sequence is noted during catheter ablation at the posterolateral and lateral aspects of the mitral annulus. The correct anatomical position of the CS catheter plays a vital role in the differential diagnosis of this situation. A premature ventricular beat timed when the His was refractory readily pre-excited the next atrial electrogram, confirming the presence of an accessory pathway (AP) . A change in the atrial activation pattern during narrow complex tachycardia was observed without a change in the tachycardia cycle length . What are the mechanisms of tachycardia and change in retrograde atrial activation patterns?A 33-year-old male patient with a history of attempted ablation for Wolff–Parkinson–White syndrome utilizing a left lateral pathway was brought to the electrophysiology laboratory because of his recurrent palpitations. A 12-lead electrocardiogram showed no baseline pre-excitation. On electrophysiological study, an anterograde investigation demonstrated a dual atrioventricular nodal physiology. Programmed atrial stimulation easily and reproducibly induced narrow QRS tachycardia 3 The presence of a second AP or an alternative arrhythmia mechanism should be kept in mind. First, the reversal of eccentric atrial excitation during orthodromic reciprocating tachycardia may falsely suggest the presence of a second  AP. On the other hand, when performing an ablation procedure with ventricular pacing, the operator could be misled to think that successful ablation has been performed due to the change from an eccentric atrial excitation pattern to a concentric pattern. This is despite persistent and unaffected AP conduction. However, if the CS catheter were advanced more anterolaterally , this would identify the persistence of the left lateral AP.7 Differential atrial entrainment from both CS distal  and proximal  sites revealed discordant results. The proximal CS is out of the circuit, but the distal CS is in the re-entry circuit. A possible mechanism of this phenomenon is the occurrence of an intra-atrial conduction block at the mitral isthmus level medial to the insertion of the AP.3 This is shown by the distal CS having a sharp, early A with the subsequent reversal from proximal to distal in the remaining electrograms . This is essentially a “signature” for this phenomenon. Luria et al. reported that intra-atrial conduction block may occur in 6.9% of left free-wall AP cases following radiofrequency (RF) delivery along the mitral isthmus, which anatomically is the narrower conductive tissue between the mitral annulus and the left inferior pulmonary vein.2 However, intra-atrial conduction block can occur even in a wide mitral isthmus, possibly because of areas of pre-existing functional block or scar.8 This phenomenon should be considered when evaluating patients who have undergone previous left lateral AP ablation of another concomitant AP or RF applications in inappropriate areas.3A change in the coronary sinus (CS) activation pattern from an eccentric to a concentric pattern during ablation of the left lateral AP has been previously described.


The World Health Organization has called for tailored, community-based interventions to address disparities in vaccination uptake affecting migrant and minoritised populations, however few exist. This study directly responds to global calls for community-centred and participatory approaches to engaging migrants in routine and COVID-19 vaccination.Black and African migrants are known to be at risk of under-immunisation and have lower COVID-19 vaccine uptake rates in high-income countries. This UK study will use community-based participatory approaches to engage Congolese migrants in co-developing a tailored intervention to increase vaccine uptake. A community-academic coalition will lead the study. Community members will be trained as peer researchers and financially compensated. The final output will be an intervention strategy tailored to and embedded within the Congolese migrant community.The coalition held 20 hours of planning meetings and peer researcher training in 2021 and co-developed a phased study involving 1) community days with poster walls and qualitative in-depth interviews with Congolese migrants, 2) interviews and workshops with local stakeholders, and 3) co-design workshops with Congolese migrants. Following outreach and pre-engagement, approximately 80 migrants attended the community days, with more than 50 interviews and 100% left positive feedback .Community-academic partnerships are resource-intensive but can be an effective means to build and maintain trust required to deliver a community-based research study. Academic partners should support community partners in understanding the research process to help manage expectations and provide financial compensation for their time and effort. This study offers an innovative engagement model and study design that can be adapted to other underserved populations.• Global policy-setting organisations have called urgently for participatory research that engages migrants in the co-production of tailored initiatives to address vaccination inequalities.• This study uses a novel, theory-driven, participatory approach to engage with and identify barriers to vaccination in Congolese migrants and co-design a tailored strategy to increase uptake.


AT can es (CVD) . For inses (CVD) . Similares (CVD) .The objective of this Research Topic was to receive studies that describe AT dysfunction in the metabolic syndrome and to delineate the role of AT-derived immunomodulatory factors in the development and progression of CVD. We also shed light on the role of “inside-to-outside” signaling (from the cardiovascular system to AT) in the cross-talk between the myocardium, the vasculature, and AT. Eight submissions were received .Shalaby et al. reviewed the detrimental role of ceramides in the pathogenesis of cardiometabolic disorders including CVD, type II diabetes and obesity. In this paper the authors discussed the mechanisms by which ceramides affect endothelial dysfunction  of abdominal aortic aneurisms (AAAs), help to sustain a deleterious inflammatory loop. They speculated that trained immunity, which is defined as a form of innate immune memory resulting in enhanced responsiveness to repeated triggers, can be induced and shaped in myeloid progenitor cells by specific innate stimuli and epigenetic and metabolic reprogramming events. This concept was supported by a bioinformatic analysis performed by the authors on AAA human samples and by data from the literature. PVAT also plays an important role in atherosclerosis. For instance, in obesity it promotes the initial step of endothelial dysfunction through mechanisms involving increased oxidative stress and proinflammatory cytokines production  and Neogenin 1 (Neo-1), an inflammatory regulator  with the pathogenesis of CVD. Proteins mainly involved in energy metabolism, inflammation and angiogenesis were highlighted as potential players in the cross-talk between VAT and CVD. Cabaro et al. investigated the paracrine effect of epicardial AT (EAT)-secreted IL-1β on post-operative atrial fibrillation (POAF). They found that patients with POAF had higher IL-1β levels in EAT conditioned medium when compared to the no-POAF group. Furthermore, human atrial fibroblasts exposed to IL-1β and IL-18 showed increased proliferation and migration as well as increased expression levels of proinflammatory and profibrotic genes.Four articles examined the mechanisms through which dysregulated AT can affect CVD development. oduction . The conoduction . Li et aegulator . OxLDL iLin et al. observed in a mouse model that the survival of fat grafts for soft-tissue reconstruction is affected by the spontaneous browning of WAT in situ. They showed that the local post-transplantation browning of WAT is accompanied by early angiogenesis and superior final graft retention. They proposed that avascularity and hypoxia during the early stage of fat transplantation promote the browning of white adipocytes leading to early revascularization. They also highlighted the beneficial clinical use of browning agents such as CL316243 . Interestingly, CXCL1 exerted a positive effect on the adhesion of endothelial cells suggesting a possible role for this adipokine in improving tissue vascularization.AT can be classified as white AT (WAT) or brown AT (BAT) depending on its metabolic, morphologic, and broader biological phenotype . BAT exeCL316243  in improTaken together, the articles published within this Research Topic highlighted the importance of deepening our knowledge of the cross-talk between AT and the cardiovascular system in order to assist the development of new and effective therapies for the leading cause of death, CVD.