The aim of the study was to assess associations between patients’ roles in decision-making, health literacy levels, and treatment outcomes of temporomandibular disorders (TMDs).Shared decision-making is defined as the process by which physicians and informed patients make a shared medical decision, taking into account the preferences and values of the patients. It is well known that shared decision-making practices improve both clinicians’ and patients’ satisfaction and lead to better treatment outcomesIn total, 131 participants were enrolled. Participants underwent interview and physical examination at baseline and six months after TMD management. TMD was diagnosed according to Diagnostic Criteria/TMD criteria. Myofascial trigger points were bilaterally evaluated in the two masticatory muscles including the temporalis and masseter muscles. The roles that participants preferred to play or had perceived during decision-making and their health literacy levels were assessed using Control Preferences Scale and Newest Vital Sign, respectively.Participants who perceived themselves as occupying active roles in decision-making showed higher health literacy levels than those with passive perceived roles. Participants with appropriate health literacy showed higher perceived participation levels in decision-making than did those with limited health literacy. The extent of subjective symptomatic improvement after six months of treatment showed significant associations with perceived role in decision-making, despite lack of significant relationships between perceived role in decision-making and the extent of improvement of objective parameters.Active participation of patients in decision-making improves the satisfaction but limited health literacy constitutes barriers to effective patient engagement during TMD management.The online version contains supplementary material available at 10.1186/s12903-022-02420-x. Temporomandibular disorder (TMD) is defined as a collection of conditions affecting the temporomandibular joint (TMJ), masticatory muscles, and surrounding structures, and it could manifest with high degree of complexity through a diverse and wide spectrum of etiology . The patShared decision-making is defined as the process by which physicians and informed patients make a shared medical decision, taking into account the preferences and values of the patients . It is wHealth literacy refers to a patient’s ability to gather, understand, and act on health information and make informed health decisions . The relThe influences of the patients’ participation in shared decision-making on treatment success and satisfaction, as well as the role of health literacy in patients’ participation and shared decision-making have been demonstrated in several conditions –14. HoweThis study is a cross-sectional study. A total of 131 Korean patients  who visited the TMJ·Orofacial Pain Clinic at a tertiary medical center in from July 2019 to July 2020 were enrolled. Patients with a history of head and neck trauma within 12 months of study entry; autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, fibromyalgia, and ankylosing spondylitis; craniofacial anomalies, including cleft lip and palpate; neurodegenerative disorders; history of temporomandibular joint surgery; routine intake of antipsychotic drugs; and communication incapability were excluded. Patients who were associated with worker’s compensation such as private or public insurance were also excluded from the study owing to secondary gain.All participants were interviewed and examined by a single TMD and orofacial pain specialist (JHK). The participants underwent an interview and a physical examination at baseline (T0) and six months after TMD management (T1). Assessments of both the roles that participants preferred to play, or had perceived themselves as playing during the decision-making process and the levels of health literacy of the participants were performed at T1.The research protocol was reviewed and found to be in compliance with the Helsinki Declaration and was approved by the Institutional Review Board of the Ajou University Hospital (AJIRB-MED-SUR-19-261). Informed consents were obtained from all participants.TMD was diagnosed according to the Diagnostic Criteria for/TMD (DC/TMD) criteria . ClinicaTo assess the confounding factors for TMD treatment, the Symptom Checklist-90-Revised (SCL-90-R)  was applThe Control Preferences Scale (CPS) was used to evaluate the roles that participants preferred to play or had perceived themselves as playing in actual decision-making during the six months of TMD management . The CPSThe Newest Vital Sign (NVS) was used to assess the participants’ levels of health literacy . The NVSThe participants who performed stabilization splint therapy and physical therapy for six months to manage the orofacial pain and parafunctional habits for six months were included in the study. The participants who showed limited range of jaw movement owing to disc displacement, sustained pain around masticatory muscles or preauricular area despite of 2 weeks of treatments including medication and habit control, and pathologic bony changes on TMJ condyles were prescribed stabilization splint therapy. All participants were instructed to wear their stabilization splints every night for at least seven hours per day during the treatment period. All participants were instructed to control for TMD-related contributing factors including excessive parafunctional habits, masticatory muscle tension, and conduct routine physical therapy such as 6 × 6 exercises  and moisPower analysis indicated that a total sample size of 131 participants in the F test with 3 groups and 2 times repetitions would provide a statistical power of 92.1% at a 0.05 significance level with an effect size of 0.25. Based on the Shapiro–Wilk normality test, the data were found to be normally distributed; therefore, parametric tests were applied.To compare the differences of demographic characteristics and parameters related with TMD of the participants including age, sex distribution, body mass index (BMI), education level, and classification of TMD based on DC/TMD criteria, duration of TMD, amount of pain free opening and maximum unassisted opening, number of active and latent TrPs in masticatory muscles, GCPS, and VAS among three groups, Acitve A, Collaborate-A, and Passive-A, one-way analysis of variance (ANOVA) and chi-square test were applied for continuous and categorical variables, respectively. Chi-square test was used to determine statistical differences of levels of preferred and perceived level of decision-making role and educational level accordance with the levels of health literacy. To estimate the responses of differences of the subjective and objective TMD treatment outcomes in accordance with the perceived role in decision-making, two-way repeated measure ANOVA was applied.P = 0.334), sex distribution (P = 0.159), duration of TMD (P = 0.395), distribution of DC/TMD diagnosis, amount of of pain free opening (P = 0.941) and maximum unassisted opening (P = 0.630), number of active (P = 0.060) and latent TrPs (P = 0.066) in the masseter and temporalis muscles, levels of GCPS (P = 0.180) and VAS (P = 0.092) among the groups in accordance with the levels of perceived roles in decision-making. Otherwise, significant differences of age (P = 0.002) and educational levels (P = 0.024) were detected among groups in accordance with the perceived roles in decision-making  decision-making role showed significant differences accordance with the levels of health literacy. On the other hand, the preferred role in decision-making did not show statistical significance accordance with the degree of health literacy (P = 0.053). The level of institutionalized education did not show direct relationships with degrees of health literacy (P = 0.151) (Table P = 0.023) (Table The distributions of perceived P = 0.00 decisioncy P = 0.51 (TableThe results from two-way repeated measure ANOVA demonstrated that there existed statistically significant relationships between time and groups in accordance with the patients’ perceived role in decision-making in VAS. On the other hand, the amount of pain free and maximum unassisted mouth opening and number of active and latent TrPs in the temporalis and masseter muscles did not show significant relationships. The distribution of GCPS showed significant differences among the groups but no differences were found among the groups in accordance with the extent of perceived decision-making Table . Hence, Considering the complex etiology and pathophysiology of the TMDs, educating the patients to promote their understanding of the properties of their conditions and helping them to make proper medical decisions are critical to the successful management of TMD. Shared decision-making procedures through which the physicians and informed patients make a shared medical decision regarding the values and preferences of the patients  can imprThe main finding of the present study was that the extent of subjective symptomatic improvement after six months of treatment presented significant difference in accordance with the level of perceived role in decision-making, despite a lack of significant differences regarding the extent of improvement of the objective signs including amount of pain free and maximum unassisted mouth opening and number of TrPs in masticatory muscles. The VAS and GCPS scores showed prominent improvement in participants with active and collaborative perceived roles in decision-making, while those with passive roles in decision-making showed symptomatic worsening. Previous studies showed similar results in which bidirectional shared decision-making could improve surgical outcomes as well as increase satisfaction in patients with strabismus or prostate cancer , 23. ThoThe aforementioned results showed an interesting point that even though the participants with limited health literacy played passive perceived roles in decision-making, they preferred active participation in their treatment. Previous studies already have reported that a limited understanding of medical knowledge, owing to a patient’s low level of health literacy, could act as a barrier for active participation in a treatment , 12, 13.To the best of the knowledge, the present study is the first attempt to reveal the impacts of shared decision-making in treatment outcomes and satisfaction of patients in TMD treatments. However, there are several limitations of the study. First of all, due to the characteristics of the TMD, few male participants were included, so limited information was provided. Second, all participants were recruited from a tertiary medical center, which might have resulted in the collection of distorted information about the shared decision-making and health literacy as compared information collected from ordinary individuals with TMDs. Thirdly, small sample sizes would inevitably lessen the validity of the results. Finally, even though the cultural background could critically influence on patients’ attitude and active participation during treatment, this study could not give meaningful information about that because only Koreans were included in the study. Therefore, future community-based studies with large sample sizes which include a sufficient number of male participants and participants with diverse ethnicity are needed. Moreover, attempts to develop appropriate forms of decision aid to help patients with low levels of health by allowing them to be more informed and more involved in shared decision-making should be tried.Hence, active participation in decision-making improves the satisfaction of TMD patients, whereas limited health literacy constitutes a barrier to effective patient engagement and shared-decision making in TMD management. Furthermore, further investigation of ways to inform patients with limited health literacy and encourage their active participation in shared decision-making in TMD management is warranted.Additional file 1: Table S1. The differences of psychological evaluation in accordance with level of perceived decision-making.


The purpose of this work is to explore delta-radiomics texture features for predicting response using setup images of pancreatic cancer patients treated with magnetic resonance image guided (MRI-guided) stereotactic ablative radiotherapy (SBRT).The total biological effective dose (BED) was calculated for 30 patients treated with MRI-guided SBRT that delivered physical doses of 30–60 Gy in three to five fractions. Texture features were then binned into groups based upon BED per fraction by dividing BED by the number of fractions. Delta-radiomics texture features were calculated after delivery of 20 Gy BED (BED20 features) and 40 Gy BED (BED40 features). A random forest (RF) model was constructed using BED20 and then BED40 features to predict binary outcome. During model training, the Gini Index, a measure of a variable’s importance for accurate prediction, was calculated for all features, and the two features that ranked the highest were selected for internal validation. The two features selected from each bin were used in a bootstrapped logistic regression model to predict response and performance quantified using the area under the receiver operating characteristic curve (AUC). This process was an internal validation analysis.After RF model training, the Gini Index was highest for gray-level co-occurrence matrix-based (GLCM) sum average, and neighborhood gray tone difference matrix-based (NGTDM) busyness for BED20 features and gray-level size zone matrix-based (GLSZM) large zones low gray-level emphasis and gray-level run length matrix-based (GLRLM) run percentage was selected from the BED40-based features. The mean AUC obtained using the two BED20 features was AUC = 0.845 with the 2.5 percentile and 97.5 percentile values ranging from 0.794 to 0.856. Internal validation of the BED40 delta-radiomics features resulted in a mean AUC = 0.567 with a 2.5 and 97.5 percentile range of 0.502–0.675.Early changes in treatment quantified with the BED20 delta-radiomics texture features in low field images acquired during MRI-guided SBRT demonstrated better performance in internal validation than features calculated later in treatment. Further analysis of delta-radiomics texture analysis in low field MRI is warranted. Radiomic analysis is the extraction of quantitative image descriptors from radiographic images. Radiomic texture features quantify image gray-level spatial relationships that are hypothesized to represent a tumor’s underlying microenvironment . Tumor hvia radiomic analysis may provide valuable personalized information that could lead to beneficial adaptation of the patient care path and improved outcome.Application of radiomic analysis in pancreatic cancer patients is of particular interest due to the poor treatment outcomes. The incidence of pancreatic cancer continues to increase with a low 5-year overall survival of approximately 9% and is predicted to be one of the top 5 contributors of cancer deaths among men and women in the United States in 2021 . SurgeryThe requirement and desire for better visualization of tumor target and organs at risk locations in patient populations like PDAC patients during therapy have driven the development of new image guidance technology. Magnetic resonance imaging (MRI)-guided radiotherapy units provide an ideal platform for treatment of pancreas SBRT patients because of the ability to acquire high-quality images. MR images have improved soft tissue contrast compared to traditional X-ray guidance modalities and allow for safe dose escalation and avoidance of critical organs in proximity to the target. The daily MRIs acquired prior to each treatment are a by-product of the patient care path but may contain valuable information about patient disease over the course of treatment. These daily images provide an opportunity for constructing models predictive of treatment response for PDAC patients using radiomic analysis. A previous work has indicated that the low field strength MR images provide an adequate base for texture analysis . FurtherUsing the average radiomic feature value throughout the treatment demonstrated possible prognostic utility, but consideration of the time that a prediction is made is important . A prediTo qualify, patients should have biopsy-confirmed PDAC, including locally advanced or borderline resectable disease. Additionally, each patient should have completed chemotherapy prior to MR-guided SBRT. Patients’ individual treatment schedules were used to group fractions with similar amounts of delivered dose together. The total biological effective dose (BED) was calculated for each patient using an alpha/beta ratio = 10 . PatientPatient treatment response was based upon post-surgery pathology or post-treatment imaging studies. Treatment response for patients who had undergone curative-intent resection following SBRT utilized tumor response grading with the College of American Pathologists (TRG-CAP). Response for patients with imaging studies was determined according to modified response evaluation criteria in solid tumors (mRECIST 1.1) , 28. A p3 voxel dimensions. Three variations of the clinical bSSFP sequence were included and can be seen in Daily images were acquired on the 0.35-T split-bore MRI-guided radiation treatment unit prior to each daily treatment . Images utilized for this work were acquired using the clinical pulse sequence. The sequence is a true fast imaging with balanced steady-state free procession pulse sequence (bSSFP). bSSFP is a popular choice for MR-guided RT systems because of the short acquisition time needed for volumetric image acquisitions, high signal contrast in soft tissue, insensitivity to motion, and minimal spatial integrity perturbation. The images contained a blend of T1- and T2-weighted visual characteristics . ClinicaAfter contouring, the GTVs were exported from MIM to be processed in MATLAB 2020b . Prior to radiomic texture feature calculation, the intensity range of each GTV was normalized by limiting the dynamic range using the methods of Collewet et al., the “± 3σ” method (S4) . The GTVvia the 3-D definitions using the 26-nearest neighbor voxels. GLCM-based features were calculated using a voxel displacement of one. The GLCM is populated by calculating the probability of gray-level intensities occurring together within a given region. While the GLCM records two voxel intensities, GLSZM and GLRLM record connected isotone zones and regions, respectively. Coordinates in the GLSZM correspond to the probability of a zone of a gray level of a size occurring with the region of interest. Similarly, the GLRLM encodes the probability of a gray level occurring in a connected run of a certain size. The NGTDM records the average difference between each gray level and the voxels surrounding it. Each radiomic texture feature sums over the probabilities within the class matrix. The result is a single descriptive number for each feature emphasizing different characteristics of gray-level intensity relationships within the image.All radiomic texture features were calculated Two sets of delta-radiomics texture features were calculated for each patient using the BED/fraction to group features calculated from different time points into similar delivered dose regions. The total BED was divided by the number of fractions and serves to represent features as a function of time and of dose. Delta-radiomics features were calculated by taking the difference in feature values between pre-radiation images (fraction 1 setup images) and then after a certain amount of dose was delivered. Specifically, for this patient cohort, the following dose bins of 20 and 40 Gy were used and named BED20 and BED40, respectively. BED20 features were calculated after the delivery of 20–30 Gy and BED40 features after 40 Gy.A supervised machine learning approach, random forest (RF), was used to explore the data and select potentially predictive features using a two-step process . RF is aA total of 30 patients were included for analysis. The RS group consisted of 11 patients with complete or partial responses. The patients with progressive and stable diseases were included in the NR group and totaled 19. The delta-radiomics texture features selected by each model as important for prediction during model training can be seen in The ROCs calculated during the logistic regression analysis and the RF model ROC estimates are displayed in via radiomic texture features induced by treatment is beginning to take hold with the increased reliance of imaging in radiation oncology. Jeon et al. calculated delta-radiomics texture features from T2-weighted diagnostic MR images acquired before and after preoperative chemoradiotherapy in locally advanced rectal cancer patients  in this work. The development and further validation of more specific response evaluation methods, such as PET response criteria in solid tumors (PERCIST) and/or metabolic imaging, might help increase certainty of classifying patients as RS and NR . The relThis work sought to explore the application and feasibility of delta-radiomics texture analysis in low field strength daily MR setup images. While it remains to be seen if the predictive power of the delta-radiomic texture features selected and the method of analysis utilized in this study will hold in a larger patient cohort, the application of delta-radiomics should be further pursued. The workflow developed in this study could be easily modified and applied to larger data sets as a step in building clinical models and applied to other clinical sites. Changes detected early in treatment could provide valuable information with time left for physicians to consider changes to the treatment regime, including further dose escalation or alternative immunotherapies. Further expansion of the patient library using more patients, external validation, and exploration of a multi-institutional dataset for building a model would appear to be justified.GNS24@miami.edu.The datasets presented in this article are not readily available because the raw image data will not be shared due to ongoing data collection. Requests to access the datasets should be directed to Garrett Simpson, The studies involving human participants were reviewed and approved by ViewRay Omnibus Patient Registry and Image Analysis Protocol, IRB#: 20160817, University of Miami IRB. The patients/participants provided their written informed consent to participate in this study.GNS performed texture analysis and statistical analysis, drafted manuscript, and prepared the figures/tables. WJ gathered patient response data, verified contouring, and made manuscript contributions. BS gathered patient response data, verified contouring, and made manuscript contributions. LP gathered patient response data, verified contouring, and made manuscript contributions. EM verified patient contouring and made manuscript contributions. DK was the statistician who contributed to machine learning work. JCF contributed to texture analysis, methods, figures, tables, and manuscript sections. ND contributed to texture analysis, methods, figures, tables, and manuscript sections. 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.


Zhou et al. provide a comprehensive review of how alternative splicing is involved in various pediatric liver diseases ranging from viral infections to tumors, highlighting specific genes and splicing mutations that contribute to the disease etiology. Elaborating on the cancer topic, Karakulak et al. review the molecular mechanisms that drive alternative splicing diversity in both healthy and tumor cells along with bioinformatic tools to assist the analysis of these changes. Karakulak and colleagues provide a long-overdue comparison of three recent studies that all performed pan-cancer analyses of isoform switches with predicted functional consequences -specific protein C (U1C) within the animal kingdom. The U1C protein is a splicing factor involved in 5’ splice-site recognition of pre-mRNA. Their analysis reveals high conservation of the gene, domain, and protein sequence and structure of U1C, which also helps to shed light on the functional impact of cancer mutations identified within the U1C gene.The origins of alternatively spliced exons are still under investigation. 5% of human exons are believed to have arisen via Alu exonization events. Koo et al. give an example on how alternative splicing can impact cell and tissue differentiation. Koo and collegues analyzed isoform expression in the peripheral hearing organ of the chicken. With a sophisticated experimental design, they measured and compared gene and isoform expression within three different positions of the cochlea. Their analysis revealed distinct expression and splicing profiles of the splicing factors PTBP3, ESRP1, and ESRP2 along the cochlea. The importance of assessing both gene and isoform expression was also highlighted in the study of He et al., who identified isoform switches during mouse oocyte maturation. Notably, the authors found that isoform expression changes could distinguish three oocyte developmental stages more accurately than gene expression data. Furthermore, for 512 genes, the authors found significant changes in the inclusion of 3′UTR regions during oocyte maturation. Such isoform changes are important not only in homeostasis. For instance, isoform switches in cancer genes drive oncogenesis or induce resistance to cancer therapies. An example of this is illustrated by Rieger et al., who identified an ASPP2 isoform that lacks the binding site to p53, thereby promoting chemotherapy resistance and tumorigenesis in colorectal carcinomas. Thus, the overexpression of the ASPP2κ isoform could become a prognostic biomarker for some colorectal cancer treatments.Paoli-Iseppi et al. provide a comprehensive review of long-read sequencing technologies, their enormous potential, and outstanding challenges. One of the significant advances highlighted by Paoli-Iseppi and colleagues is the considerable contribution of long-read technologies to the continuous improvement and completeness of the transcript annotation databases. We predict this trend will continue as long-read sequencing is increasingly applied in single-cell (In summary, these articles highlight that much more work on alternative splicing is needed to understand its biological importance. Crucial for this is the advancement of the technologies and methods to study alternative splicing. A new promising experimental approach is long-read sequencing, which sequences full-length mRNA molecules. Thus long-read sequencing does not require the complex and error-prone, but until recently, necessary assembly step . The appgle-cell . The incgle-cell , analysi


Pigmented paravenous retinochoroidal atrophy (PPRCA) is a rare fundus disease characterized by the presence of osteoblast-like pigment, atrophy of retinal pigment epithelium (RPE), and choroid deposition along the large retinal veins.A 55-year-old Chinese female presented with right eye distention and bilateral vision loss. Osteocyte-like pigmentation and retinal choroidal atrophy distributed along the large retinal veins were seen in the fundus of bilateral eyes. The atrophy in the left eye was more severe compared to the right eye. The patient also presented with bilateral acute angle-closure glaucoma (AACG) and posterior subcapsular cataract (PSC) accompanied with anterior segmental manifestations, similar to the complications of retinitis pigmentosa (RP). The patient underwent ultrasound biomicroscopy (UBM), Humphrey field analyser (HFA), optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein fundus angiography (FFA), electroretinogram (ERG), and electrooculography (EOG), all of which confirmed the aforementioned diagnose.PPRCA is a rare disease of unknown etiology. The patient in this case presented with complications similar to those of RP, and the two conditions may share a genetic basis. Further studies are needed to confirm this relationship.The online version contains supplementary material available at 10.1186/s12886-022-02355-5. PPRCA is characterized by osteoblast-like pigmentation along the large retinal veins accompanied with atrophy of the outer retina and choroid. This condition is prevalent in men, and it is symmetrical in bilateral eyes . The cauA 55-year-old Chinese woman was first seen at our hospital due to distention and vision loss in her right eye (oculus dexter (OD)) for one month. She was diagnosed with PPRCA twenty years ago and had no history of night blindness, ocular or systemic diseases or any other inflammatory and infection diseases. Best corrected visual acuity (BCVA) at the first visit was 0.2 in bilateral eyes, and the anterior segmental examination of the bilateral eyes revealed characteristic symptoms of AACG and PSC such as shallow anterior chamber and posterior subcapsular cataract. Intraocular pressure (IOP) in the OD was 37 mmHg and 18 mmHg in the left eye (oculus sinister (OS)). In bilateral eyes, HFA demonstrated that the visual field was extremely poor. Fig.  a to d RThis patient underwent trabeculectomy combined with cataract phacoemulsification aspiration followed by IOL implantation in the OD and Nd-YAG laser iridotomy in the OS. Intraoperative dilatation of the pupil in the OD revealed that the patient’s lens suspensory ligament was relaxed. Three months after surgery, the patient’s BCVA was 0.6 in the OD and 0.2 in the OS, IOP was 17 mmHg in the OD and 13 mmHg in the OS. A further OCT showed the area of intraretinal capsule-like hyporeflective signal in the macula had disappeared, but the other fundus symptoms did not improve significantly. Fig.  a to d TCRB1 gene locus in RP patients [PPRCA is a rare degenerative disease of the fundus of the eye with unknown etiology. It was originally discovered by Brown et al. during fundus examination of a male patient with mottled baldness . Typicalpatients . We haveThis patient showed severe PSC in bilateral eyes and laxity of the lens zonules and suspensory ligaments, which is similar to the symptoms of RP with PSC. We speculate that PPRCA triggered RPE and choroidal atrophy, and the degenerated retinal tissue produced cytokines which broke through the damaged blood-retinal barrier and to injure the lens. The ensued long-term inflammatory state triggered laxity of the suspensory ligament –10. ThisIn conclusion, we reported a rare case of PPRCA accompanied with AACG and PSC. We speculated that PPRCA might be an incomplete manifestation of RP. Given the poor understanding of PPRCA etiology, further genetic testing and more case studies are needed to investigate the relationship between PPRCA and RP.Additional file 1. Patient perspective.


Publisher Correction: BMC Public Health 22, 1827 (2022)https://doi.org/10.1186/s12889-022-14213-6In the original publication of this article : Box 1 wBox 1 Suggested approaches to include real-world data in evidence synthesis○ Database or registry used○ Hospital (and if possible specific department(s) data is from)○ Geographical area(s)Where the data is from:Time period of studyPopulation characteristics .Identify potential overlapping populations by extracting data on:Consider using a method of analysis which accounts for double-countingContact authors to clarify aspects of the studies that are unclearInclude all studies if double-counting cannot be fully determinedAnalyse studies at different time-pointsPreference of peer-reviewed studies○ Largest study ○ Most recent study○ Most complete dataRetain only one of any identified set of studies in which overlap is suspect by some rational criteria. For example, retain the:Options to minimise impact of double-counting of individuals/populations:Obtain individual patient dataAlways conduct sensitivity analysis to assess robustness of results.Authors could utilise an alternative study if the selected study does not have data for a particular outcome being analysedNOTE: The authors are not recommending these approaches rather highlighting possible options; further work is required to understand the implications of these methods.Provide rationale for studies included in the evidence synthesisDiscuss potential double-counting of data between studiesImplications of double-counting and method used to account for it regarding interpretation of results.Reporting on approaches taken:


Studies report discrepancies between CVP and JVP measurements. The mid-thoracic plane (MTP) at the anterior fourth intercostal space level indicates the zero-reference level (ZRL) for venous pressure measurement, and the midaxillary line (MAL) at fourth intercostal space is a point near the ZRL in the supine position. JVP is usually measured from the sternal angle (SA) with further addition of 5 cm (JVP-SA + 5) and CVP in the supine position from MAL (CVP-MAL). However, no report has compared CVP measured from MTP (CVP-MTP) with CVP-MAL and with JVP from MTP (JVP-MTP) and JVP-SA + 5.  We measured JVP-MTP and JVP-SA + 5 in appropriate reclining positions and subsequently CVP-MTP and CVP-MAL in the supine position blindly in 150 patients. We compared the pressures by Pearson correlation and Bland–Altman plots. p = 0.129), strong positive linear relationship (r = 0.908), and good agreement (near-zero mean difference) with each other. JVP-MTP was about 1 cm higher than JVP-SA + 5 (p < 0.001). JVP-MTP displayed higher correlation coefficients and better agreements with both CVPs than JVP-SA+5. Correlation coefficients and mean differences of both CVPs with JVP-MTP were almost equal, about 0.83 and 1 cm, and with JVP-SA + 5 also almost equal, about 0.72 and 2 cm, respectively.  CVP-MTP and CVP-MAL demonstrated similar means , and MAL can be used as MTP to measure CVP in the supine position. Our findings indicate the way to explore the matching of CVP and JVP to the full extent possible by standardizing their measurements from other identical ERPs to that from the zero-reference level MTP. Their further study in similar higher reclining positions from identical ERPs, such as MTP, MAL, and SA with the addition of higher numbers instead of 5 cm, is warranted standardizing other measurements to that from MTP. Central venous pressure (CVP) refers to the mean vena caval or right atrial pressure  and can Deol et al. reported in 2011 that JVPs measured by clinical and ultrasound collapse pressure examinations were about 5 cm lower than CVP, with both CVP and JVP measurements calibrated as the total vertical distance from MAL after initially measuring them from SA . In a prWe performed an observational study in intensive care units (ICUs) of the National Academy of Medical Sciences (NAMS) Hospitals, Kathmandu, Nepal, between January 2013 and February 2014. Conscious, spontaneously breathing adult subjects who already had a central venous catheter as part of their clinical management were potentially eligible for the study. We included in our study the patients with visible right internal jugular venous pulsations for JVP measurement and with the tip of the central venous catheter confirmed by a chest X-ray to be at the level of the carina , 22. We JVP was measured from two external reference points: the midthoracic plane (MTP) and sternal angle (SA). The MTP from the anterior fourth intercostal space to the back was marked using a ruler in the right axilla. The bed angle was adjusted for JVP measurement to yield the best views of right internal jugular venous pulsations. The observer used tangential lighting to recognize jugular venous pulsations and could strip the veins as required. The vertical distance from the marked point of MTP in the right axilla to the apex of the right internal jugular venous pulsations at end-expiration was measured as the JVP from MTP (JVP-MTP). Similarly, the vertical distance from the SA to jugular venous pulsation was measured, and 5 cm was added to obtain the value of JVP-SA + 5.The first author measured the JVPs by physical examination with the help of the JVP Meter, which was also used in the previous study . MaintaiThe first author marked the MTP in the right axilla and measured the JVP-MTP and JVP-SA + 5. Then, the ICU physicians independently measured the CVP in the supine position from the marked point of MTP as CVP-MTP and from MAL as CVP-MAL. They were blinded to each other's measurements of JVP and CVP. CVP was measured with a water column manometer. The upper level of the water column in the manometer was used to measure the CVP, and the average value between the swings observed with respiration was recorded , 25.We calculated the mean, standard deviation (SD), and confidence interval (CI) of CVP-MTP, CVP-MAL, JVP-MTP, and JVP-SA + 5. We compared the CVP-MTP and CVP-MAL with each other and with the JVP-MTP and JVP-SA + 5 graphically using Pearson correlation and Bland–Altman plot and calculated the correlation coefficient and mean difference (mean bias) with limits of agreement. A significance level of 5% was used, and 95% CIs were reported.p=0.129). Linear correlation analysis also revealed a strong positive relationship (r = 0.908), and the Bland–Altman plot demonstrated a good agreement with the mean difference (mean bias) of near-zero between CVP-MAL and CVP-MTP  subjects were admitted to medical ICU and 57 (38%) to surgical ICU. Patient characteristics are given in  CVP-MTP .p < 0.001). In Pearson correlation analysis, CVP-MTP and CVP-MAL displayed higher correlation coefficients with JVP-MTP than with JVP-SA+5 , of JVP-MTP was higher than the mean value, 7.13 (95% CI 6.84–7.43), of JVP-SA + 5  to measure the CVP and JVP, the two other factors that can affect their measurements and matching are the accessibility of the ERP and the reclining angles of the patients. We also previously discussed the difficulties in localizing the ERPs in the axilla and in using the table level in higher reclining positions and the distances relative to the thoracic diameter as ERPs for measuring the venous pressures in the day-to-day clinical practice. The obvious accessibility of the sternal angle (SA) may also be studied. However, there is hardly any report of comparing the CVP measured in higher reclining positions from the zero-reference level MTP with that from the MAL and from the sternal angle (SA) with the addition of 5 cm or higher numbers. The vertical distance between the SA and zero-reference level (ZRL) is about 5 cm in the supine position but longer in higher reclining positions where the nearer relationship of MAL with the ZRL may also vary. As indicated by our findings, further study of CVP and JVP measurements in similar reclining positions from identical ERPs such as MTP and MAL and the sternal angle with the addition of higher numbers for higher reclining positions instead of 5 cm only is warranted standardizing other measurements to that from MTP. Such standardization with the zero-reference level MTP will help clarify the correlations and agreements between the CVP and JVP measurements as well as their individual variations in similar reclining positions in relation to different external reference points.


Treatments were self-delivered at home for 15 min/morning and 15 min/evening for 14 days. Follow-up was at 2 weeks.Participants enrolled from March 2019–October 2020 and randomly assigned to active tVNS  had an 80% treatment adherence and 107 (92%) completed the study at 2 weeks; 1 participant dropped out due to adverse effects from active tVNS.Active tVNS is placed on the cymba conchae of the left ear; sham tVNS is placed on the left earlobe. Active MDB trains users in nondirective meditation with deep breathing; sham MDB trains users in open-awareness meditation with paced breathing.Primary outcome was change from baseline in ultra short-term photoplethysmography-measured cardiac-vagal heart rate variability at 2 weeks. Prior to trial launch, we hypothesized that (1) those randomized to active MDB or active tVNS would display greater increases in heart rate variability compared to those randomized to sham MDB or sham tVNS after 2-weeks; (2) a change in heart rate variability would be correlated with a change in self-reported average pain intensity; and (3) active treatments would outperform sham treatments on all pain-related secondary outcome measures.No significant across-group changes in heart rate variability were found. Furthermore, no significant correlations were found between changes in heart rate variability and average pain intensity during treatment. Significant across group differences were found for overall FM severity yet were not found for average pain intensity.These findings suggest that changes in cardiac-vagal heart rate variability when recorded with ultra short-term photoplethysmography in those with fibromyalgia may not be associated with treatment-specific changes in pain intensity. Further research should be conducted to evaluate potential changes in long-term cardiac-vagal heart rate variability in response to noninvasive vagus nerve innervation in those with fibromyalgia.https://clinicaltrials.gov/ct2/show/NCT03180554, Identifier: NCT03180554. Fibromyalgia (FM) is a chronic disorder characterized by disabling pain that lasts for 3 months or more in multiple regions of the body and is commonly associated with psychological distress . Global The presence of autonomic nervous system (ANS) dysfunction in those with FM , 13 is sVagus nerve stimulation (VNS), which typically involves electrical stimulation of the vagal nerve, is an approved therapy for both refractory epilepsy and treatment-resistant depression , 27. PreThe primary aim of this single-blinded randomized sham-controlled clinical trial was to evaluate and compare the effects of two noninvasive and portable means of electrical- and cardiorespiratory-based VNS—transcutaneous vagus nerve stimulation (tVNS) and meditative-based diaphragmatic breathing (MDB)—on photoplethysmography (PPG) measured cardiac vagal HRV and average self-report numeric rating scale (NRS) pain intensity. We hypothesized that adults with FM randomized to receive active MDB or active tVNS would display greater increases in HRV as compared to those randomized to sham MDB or sham tVNS after 2-weeks of treatment. Furthermore, we hypothesized that a change in HRV would be correlated with a change in self-reported NRS pain intensity. Lastly, we hypothesized that active treatments would outperform sham treatments on all clinical pain-related secondary outcomes.ClinicalTrials.gov (Identifier: NCT03180554) and CRISITIN (Current Research Information System in Norway). Interested participants were directed to the Oslo University Hospital website where they logged into a secure digital data collection system and filled out a brief self-report inclusion/exclusion form. Participants who met self-reported inclusion criteria received an appointment for both clinical visitation I (CVI) and clinical visitation II (CVII) at the Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital ; tVNS #2 (sham); MDB #1 (active); MDB #2 (sham). The computer-generated randomized allocation sequencer was imported into an electronic data capture system and made available to testing administrators. The randomization was stratified by sex  and cardioactive medications  with varying block size within strata. Participants were permitted to continue taking any previously prescribed pain medications during the trial period.Both treatment types (MDB or tVNS) and versions (active or sham) were self-delivered for 15 min in the morning upon waking and 15 min at night before bed for a total duration of 2-weeks [see intervention details in ]. Particvia an android smartphone-app program  and post-intervention follow-up (CVII).FM diagnostic information and cardiovascular information was obtained at baseline . Primaryvia an Android App utilized in prior research trials (Resting-state photoplethysmography (PPG)-measured HRV data was obtained h trials –44 and vh trials  at CVI ah trials : each pah trials , 48 and h trials , 49, 50.h trials ]. Due toh trials , the begTesting administrators conducted a FM clinical interview at CVI and in CVII. Participants were guided through an electronic version of the 2016 revision to the 2010/2011 FM diagnostic criteria form  which coParticipant-reported outcome measures in the form of questionnaires were completed electronically by each participant at the end of CVI and CVII [for a complete list of questionnaires see ]. The CrAdverse events were identified during intervention period and by follow-up testing administrator questions about significant discomfort, technical usability issues, or harm of any kind caused by the interventions.N =116 were formally enrolled and randomized (A sample size of at least 84 participants (21 in each group) was needed to detect meaningful differences between our four groups at 2 weeks , 55. Effndomized  for the The analyses were performed with STATA/SE for Windows, Version 16.1 and IBM SPSS Statistics version 27 , 57. Chan= 86) and full sample (N= 116).Difference in change from baseline between the four groups with and without adjusting for baseline was tested by using two linear mixed effect models for continuous outcome data and a likelihood ratio test. For the random part of the linear mixed effect model, participant identifier or identifier and time, were specified as the random variables. In the linear mixed model with two random variables (identifier and time), an exchangeable variance-covariance structure was specified. For the fixed part of the mixed model, group and time and interaction between group and time were specified to test whether the change differed between the groups over time with and without adjusting for baseline values. Highly skewed  variables were logarithmically transformed before fitting the mixed models. The analyses of average changes between groups over time were carried out for the compliant groups  which explored associative changes from CVI to CVII among HRV and pain variables showed that NRS average pain intensity in the last week had no significant correlations with changes in HRV.Treatment groups were similar in baseline characteristics and current cardioactive medication use. Significant between-group differences were found for hormonal contraceptive use among women and two items on the CEQ regarding improvement in function . The meaThere were no significant differences found across treatment groups in any of the cardiac-vagal variables of interest .n = 86)  (n = 86) .Significant across group differences were found for current pain intensity with significant within-group changes in those randomized to active tVNS  and sham tVNS  . SignifiOne participant randomized to receive active tVNS experienced chest discomfort and additional pain due to the tVNS stimulation and decided to discontinue treatment. No other serious adverse events were reported in this trial.The aim of our randomized controlled clinical trial was to establish and compare the efficacy of active and sham versions of tVNS and MDB on cardiac vagal tone and average pain intensity in adults diagnosed with severe FM. Contrary to our primary hypothesis, no significant across-group differences in cardiac vagal tone were found. Furthermore, contrary to our second hypothesis, no significant associations were found between changes in cardiac-vagal HRV and changes in average NRS pain intensity during treatment in our entire FM population; active treatments did not outperform sham treatments for clinical pain-related secondary outcomes. However, significant group differences were found for overall FM severity and current pain intensity at post-treatment follow-up.afferent activity.The presence of significant pain reductions in the absence of significant across-group differences in cardiac-vagal HRV variables may challenge the current notion that rMSSD and/or hfHRV are reliable indexes of cardiac vagal activity , 25, 58.Utilizing ultra short-term (<5 min) PPG methods for evaluating cardiac-vagal HRV could have aided in increasing participant treatment compliancy and regimen  while alSignificant changes in overall FM severity were found in all groups. Only those who received active or sham tVNS displayed significant changes in current NRS pain intensity as compared to those randomized to active or sham MDB, yet the clinical significance of these findings are questionable: overall FM severity is based on a 0–31 point scale  whereas Observational fMRI analyses , 67 showThere are several important limitations to consider. Firstly, sociodemographic characteristics including education, annual income, and employment were not collected in this trial and could have provided pertinent information for describing our findings. Secondly, even though this study was practiced as a double-blinded clinical trial, it was formally categorized as a single-blind trial because there was no way of ensuring that either the testing administrators or the participants held any prior insights into active and inactive MDB/tVNS treatment protocols. Furthermore, to sufficiently detect a difference between groups in HRV as it relates to NRS pain intensity, a sample size between 30 and 77 (depending on the HRV metric of interest) is typically recommended . HoweverIn addition to the apparent limitations of this trial, there are several important study strengths to be noted. Reducing clinical visitation time, HRV recording time, and daily treatment delivery time may have been a significant contributing factor to increasing treatment compliancy and achieving high clinical visitation attendance; MDB was self-delivered with a novel respiratory-gating device able to monitor the respiratory dynamics of each participant , 83–86. Meditative-based diaphragmatic breathing and vagus nerve stimulation had no significant across-group effects on ultra short-term PPG-measured cardiac vagal tone among adults with FM. No significant across group differences were found for changes in average self-report NRS pain intensity; active MDB as well as sham tVNS resulted in the largest improvements in average pain intensity at 2-weeks when compared to sham MDB and active tVNS. The absence of significant across-group changes in ultra short-term PPG-measured cardiac vagal tone in response to vagal-innervation treatments in those with FM may indicate that more reliable long-term recordings procedures should be utilized and/or that longer  vagus nerve innervation treatment methods should be delivered. However, finding significant across-group differences for overall FM severity and current pain intensity may indicate that meditative-based diaphragmatic breathing and vagus nerve stimulation provide differentiable yet complementary approaches to noninvasive FM pain management. Further research should be conducted on evaluating long-term noninvasive vagus nerve innervation methods for treating FM due to their useability, portability, and potential effectiveness.In accordance with institutional guidelines, anonymized data is available upon request with a corresponding application describing the intent and justification(s) for investigative analysis.The studies involving human participants were reviewed and approved by Regional Committees for Medical Research Ethics South East Norway. The patients/participants provided their written informed consent to participate in this study.The manuscript was drafted by CP. Study was conceptualized and designed by CP and HJ. Critical revision of the manuscript for important intellectual content was conducted by CP, AS, LR, and HJ. Blinded statistical analysis was performed by LD. This study was conducted as CP's Ph.D. Fellowship with the principal supervision of HJ. Co-supervision of AS and LR. Data acquisition, analysis, and interpretation of data was performed by all authors. All authors contributed to the article and approved the submitted version.Funding for a doctorate fellowship was received from the South-East Regional Health Authority, Norway (Project Number: 2017/766) to conduct and analyze data from this study. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.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.


Ensuring access to healthcare is critical to prevent illnesses and maintain health and functional abilities for older individuals. The Covid-19 pandemic is a major global public health threat that challenges healthcare availability and accessibility. The objective of the study was to compare healthcare accessibility for older individuals since and during Covid-19 pandemic. The study was based on a sample of individuals from wave 8 Covid-19 add-on and wave 9 Covid-19-add-on of the Survey of Health, Ageing and Retirement in Europe (SHARE) in the period from 2020 till 2021. The sample size was 44043 respondents from 26 European countries. Descriptive statistics, Chi-square and McNemar test was performed. Overall, in 2021 there is a statistically significant decrease in proportion of respondents who forwent medical treatment , postponed medical appointment due to Covid-19  and to whom appointment was denied by healthcare facility due to Covid-19  (p < 0.001). More often forwent medical appointment in 2021 was reported from females as well as respondents younger than 75 years, with good or very good self-rated health status and with less or no limitations due to health. Forwent medical treatment was reported more often from respondents with diabetes and hypertension. Results indicate that remote consultations are used more often than in 2020 (number of remote consultations varied between 1 and more than 100) and more often were reported by younger respondents (50-74 years). No significant association was found in self-rated health changes since and during Covid-19 pandemic for respondents who reported healthcare accessibility issues. As those issues were reported also by individuals with poor or fair self-rated health status and serious health conditions it can lead to a more rapid decline in health and functional abilities in the future.The situation with access to health care has improved during Covid-19, however further research is necessary to analyze how healthcare accessibility has affected health changes of older individuals.Telemedicine serves as a viable tool for maintaining patient care and lowering the risk of Covid-19 exposure to patients, however actions to improve digital skills for older individuals are needed.


Visceral pain (VP) is the organ-derived nociception in which increased inflammatory reaction and exaggerated activation of the central nucleus of the amygdala (CeA) may contribute to this deficiency. Considering the amygdala also serves as the integration center for olfaction, the present study aimed to determine whether olfactory stimulation (OS) would effectively depress over-activation and inflammatory reaction in CeA, and successfully relieve VP-induced abnormalities. Adult rats subjected to intraperitoneal injection of acetic acid inhaled lavender essential oil for 2 or 4 h. The potential benefits of OS were determined by measuring the pro-inflammatory cytokine level, intracellular potassium and the upstream small-conductance calcium-activated potassium (SK) channel expression, together with detecting the stress transmitters that participated in the modulation of CeA activity. Results indicated that in VP rats, strong potassium intensity, reduced SK channel protein level, and increased corticotropin-releasing factor, c-fos, and substance P immuno-reactivities were detected in CeA. Enhanced CeA activation corresponded well with increased inflammatory reaction and decreased locomotion, respectively. However, in rats subjected to VP and received OS, all above parameters were significantly returned to normal levels with higher change detected in treating OS of 4h. As OS successfully depresses inflammation and CeA over-activation, application of OS may serve as an alternative and effective strategy to efficiently relieve VP-induced deficiency. N-methyl-D-aspartate (NMDA) receptor phosphorylation through the recruitment of protein kinase A (PKA), activated neurochemical modulation would increase the excitatory drive of CeA neurons and potentiate the nociceptive signaling  were used as a mass calibration to ameliorate the potential matrix effect for ion spectrums [m/z 39.09 were used to identify and evaluate the ionic image of K+.TOF-SIMS analysis was carried out on a TOF-SIMS IV instrument  as described in our previous studies ,69. Fixepectrums . The ionn = 18) were decapitated under deep anesthesia with xylazine (10 mg/kg) and ketamine (100 mg/kg). After removal of the skull, the brain segments containing the amygdala were quickly removed and bisected equally throughout the midline. Following that, one side of the bisected segment was processed for pro-inflammatory cytokine measurements (please see below), while the other side was frozen in liquid nitrogen and then homogenized with 100 μL lysis buffer using a grinder on ice. The immunoblot procedure was processed by the methods describe previously [For immunoblotting assays, another half amount of the animals in each experimental subgroup  using the Bio-Plex cell lysis kit . After that, the total protein concentrations were determined with the Pierce BCA protein assay kit . The pro-inflammatory cytokine levels were then measured using the Bio-Plex Pro rat cytokine 23-plex assay kit on the Bio-Plex 200 system following the manufacturer’s instructions. The results are expressed as the mean pg/mg total protein ± SD of the concentrations of each factor.For measuring the pro-inflammatory cytokine levels, the total protein was extracted from the isolated CeA of the bisected segment (n = 36) were collected and processed for urinary levels of NE by the commercial kit  according to the manufacture’s guidelines.As norepinephrine (NE) is released from the nervous system and adrenal gland after autonomic excitation induced by harmful stimuli, elevated levels of urinary NE may serve as a useful biochemical marker indicating the stress level experienced by the animals. During the 2 or 4 h period of water vapor or LEO inhalation, the urine samples of all experimental animals (n = 18). The general approach for quantitative image analysis was similar to our previous studies [The computerized image analysis for quantifying the expression pattern of neurochemicals was carried out in those animals subjected to immunohistochemistry ( studies ,71. A co studies . All imapost hoc test. The statistical difference was considered significant if p < 0.05.Comparisons among the mean values obtained from different experimental groups as well as other data acquired from spectrometric, biochemical, neurochemical, and behavioral methods were subjected to one-way ANOVA analysis. The effect of each challenge compared with the vehicle-treated group was further analyzed using the Bonferroni In summary, the present study has provided for the first time that by the use of quantitative morphological, spectrometric, and functional approaches, application of OS through LEO inhalation would effectively relieve the neurochemical, biochemical and behavioral phenotypes of visceral pain. Although the detailed mechanisms participating in the beneficial effects of LEO on improving the neuronal and behavioral impairments following visceral pain are still not fully understood, effectively depressing the neuronal excitability and microglial-mediated neuroinflammation in the CeA may serve as the underlying mechanism involved in this efficacy. Considering that current options utilized for the treatment of visceral pain still exist some limiting factors, such as delay to onset or having high sedative potential , applica


Inflammatory Bowel Disease (IBD) is a chronic, debilitating collection of diseases with significant impairment to patient quality of life and hospital burden. Patients with acute flare of their disease are managed with IV corticosteroids and ultimately transitioned to an oral equivalent. Despite no formal guideline recommendation, some patients remain in hospital on oral corticosteroids, primarily for observation. Given that each day spent in hospital carries significant costs, examining this observatory period is warranted. The utility of the observatory period for patients recently switched to oral corticosteroids has not yet been studied and may be unnecessarily increasing hospital stays and costs to the Canadian medical system. - Analyse the efficacy of the in-hospital period for patients on oral corticosteroids after an acute IBD flare in preventing recurrence in the 14 and 28 days post discharge. - Assess the relationship between length of the in-hospital “observatory” period with future hospital burden.th, 2022. Patients were identified through the clinic EMR (Plexia) and hospital information was accessed via the Fraser Health Health Records Department. This study acheived ethics approval by the Fraser Health Research Ethics Board (Event: 2022376). - This retrospective cohort study identified patients with known IBD who were admitted to Royal Columbian Hospital under the Gastroenterology service primarily for acute flare of their disease from June 1, 2020 to June 30Inclusion criteria are as follows: -  - Age > 18 years old - Prior diagnosis of IBD as per CAG guidelines - Acute IBD flare is primary reason for hospitalization - Hospital management includes IV corticosteroids and discharge medications include a tapering course of oral corticosteroid.Exclusion criteria are as follows: -  - Patients found to be non-compliant on outpatient medication regimen (i.e tapering dose of PO prednisone). - Patients with a complicated course in management .-20 patients were identified, with 60 total hospital admissions.-35 visits included an observatory period, with 6 less than 24hr , and 29 greater than 24hr .-25 visits did not have an observatory period.-The relative risk of patients without an observatory period returning to hospital within 14 and 28 days compared to those with an observatory period was 4.2 and 1.75, respectively.These preliminary results suggest an increased relative risk for those without an in-hospital observatory period for short term re-hospitalization. However, we hypothesize this will significantly change once we have broadened our date range and increased our total number of hospitalizations, which is planned prior to the poster presentation date.NoneNone Declared


Current polio vaccines comprise the injectable inactivated polio vaccine  and the live-attenuated oral polio vaccine . The main limitations of the IPV are the reduced protection at the intestinal mucosa, the site of virus replication, and the high costs for manufacturing due to use of live viruses. While the OPV is more effective and stimulates mucosal immunity, it is manufactured using live-attenuated strains that can revert into pathogenic viruses resulting in major safety concerns and vaccine-derived outbreaks. During the last fifteen years, plant-based poliovirus vaccines have been explored by several groups as a safe and low-cost alternative, and promising results in protection against challenges with viruses and induction of neutralizing antibodies have been obtained. However, low yields and a high frequency in dose administration highlight the need for improvements in polioviral antigen production. In this review, we provide insights into recent efforts to develop plant-made poliovirus candidates, with an emphasis on strategies to optimize the production of viral antigens.Human polioviruses are highly infectious viruses that are spread mainly through the fecal-oral route. Infection of the central nervous system frequently results in irreversible paralysis, a disease called poliomyelitis. Children under five years are mainly affected if they have not acquired immunity through natural infection or  Poliomyelitis (polio) is a viral disease which is caused by polioviruses that are transmitted by the fecal-oral route and predominantly affects children under five years. The severity ranges from asymptomatic occurrence to meningitis and acute flaccid paralysis. Polio has the peculiarity to seriously affect the central nervous system (CNS) and damage the motor neurons located in the anterior horn of spinal nerve roots. This harm leads to muscular dysfunction or even death when vital body functions such as deglutition or respiration are compromised . Post-poPolio has a huge impact on developing countries with poor sanitation and weak public health systems. Due to worldwide vaccination efforts that began in the late ‘80s with the creation of the Global Polio Eradication Initiative (GPEI), polio has been considered almost completely eradicated. To date, polio remains endemic in two countries: Afghanistan and Pakistan . HoweverEnterovirus genus belonging to the Picornaviridae family. There are three wildtype poliovirus serotypes (WPV) and all of them are highly contagious. The WPV serotypes 2 and 3 were declared as eradicated in the year 2015 and 2019, respectively. Thus, the WPV serotype 1 has become the only wild poliovirus that remains in circulationThe causative agent of the disease is poliovirus, which is a member of the The full-length poliovirus genome has approximately 7500 bp and is composed of a single-stranded, positive-sense and non-segmented RNA. The major ORF is flanked by two untranslated regions containing a variety of secondary structures. The small viral protein VPg is attached covalently to the 5´-end and a long chain of adenine residues is attached to the 3´-end of the RNA. Both modifications are involved in replication and translation processes in association with membranous complexes . Viral RPoliovirus has an icosahedral morphology resulting from integration of 60 copies of each of the four structural (capsid) proteins named VP1, VP2, VP3 and VP4 . The VP4After ingestion, the virus replicates in the alimentary tract mucosa and is transported by macrophages and/or infected dendritic cells to deep cervical lymph nodes and mesenteric lymph nodes where the virus replicates . The virFlavivirus , hepatitis B virus (HBV), porcine reproductive and respiratory syndrome virus (PRRSV), food and mouth disease virus (FMDV), Newcastle disease virus (NDV), rabies virus (RABV), influenza virus, coronaviruses-like swine transmissible gastroenteritis virus (TGEV) and SARS-CoV-2 . These formulations are especially important to elicit a mucosal immune response at sites where polioviruses replicate. In addition, natural encapsulation and adjuvant-intrinsic effects attributed to components of plant cells can further enhance the effect of expressed viral antigens, for example, by protecting the antigen or enabling a controlled release (Plant-based vaccines can be produced by delivering a transgene into the plastid (stably) or nuclear genome (stably or transiently) or by using RNA-based viral expression systems , covering the optimization of oral vaccines and developing an affordable inactivated vaccine. Several research groups have explored plant-based production for the development of polio vaccine candidates Table 1.Chloroplast-based expression was used to produce the VP1 capsid protein fused to the cholera toxin B subunit in tobacco plants (expression level: 2.6 mg/g dry weight) . The immNicotiana benthamiana together with a polyprotein processing proteinase. Stable VLPs were generated (yield up to 60 µg/g) that retained the native, immunogenic D antigenic conformation. Transgenic mice expressing the poliovirus receptor were intraperitoneally immunized with purified plant-produced VLPs carrying poliovirus antigens. Importantly, the immunized mice showed protection after challenge with a wild poliovirus 3 strain and structural analysis of the VLPs demonstrated a morphology resembling native polioviruses  Project P31920-B32.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.


Background: There is clinical interest in determining the effects of low-load blood flow restriction (LL-BFR) resistance training on muscle strength and hypertrophy compared with traditional high- and low-load (HL and LL) resistance training in healthy older adults and the influence of LL-BFR training cuff-pressure on these outcomes. Methods: A search was performed on the MEDLINE, PEDro, CINHAL, Web of Science, Science Direct, Scopus, and CENTRAL databases. Results: The analysis included 14 studies. HL resistance training produces a small increase in muscle strength  but not in muscle hypertrophy  when compared with LL-BFR resistance training. Compared with traditional LL resistance training, LL-BFR resistance training produces small–moderate increases in muscle strength  and hypertrophy . There were greater improvements in muscle strength when higher cuff pressures were applied versus traditional LL resistance training but not versus HL resistance training. Conclusions: LL-BFR resistance training results in lower muscle strength gains than HL resistance training and greater than traditional LL resistance training in healthy adults older than 60 years. LL-BFR resistance training promotes a similar muscle hypertrophy to HL resistance training but is greater than that of traditional LL resistance training. Applying cuff pressures above the limb occlusion pressure could enhance the increases in muscle strength compared with traditional LL resistance training. Life expectancy has been increasing significantly worldwide in recent years, with an expected doubling of the population older than 60 years predicted to happen by 2050 . The agiAccording to the most recent systematic reviews, resistance training should be considered as the primary non-pharmacological therapy to manage the loss of muscle mass and strength in older adults ,7. ResisIn recent years, a promising new resistance training modality has emerged: blood flow restriction (BFR), which uses a pneumatic cuff to partially or totally occlude the arterial and venous blood flow during exercise . Among tSeveral systematic reviews ,18,19 haPrevious reviews have highlighted the large variability in BFR training protocols, especially regarding the cuff pressure, requiring further study. Several studies on healthy young adults have suggested that high cuff pressures are uncomfortable ,21 and dThe present systematic review and meta-analysis aimed to provide an update on the effects of LL-BFR resistance training on muscle strength and hypertrophy compared with traditional HL and LL resistance training in healthy adults older than 60 years. As a secondary objective, we analyzed the influence of the cuff pressure of LL-BFR training on muscle strength and hypertrophy in this population.This systematic review and meta-analysis followed the criteria of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines  and was The inclusion and exclusion of the reviewed studies relied on the clinical and methodological aspects based on the PICO (Population-Intervention-Comparison-Outcome of interest) strategy .Population: The study participants had to be healthy and older than 60 years, in accordance with the currently accepted thresholds for senescence , with noIntervention and comparison: The included studies had to compare a BFR resistance training against (1) an active HL control group in which resistance training was performed without BFR at high intensities (≥70% of 1RM) or (2) an active LL control group in which resistance training was performed at 20–40% of 1RM without BFR. The minimum training period was 3 weeks, given that this is the minimum period for physiological adaptations to occur with BFR training . BFR intOutcomes: The outcomes of interest were the muscle strength and hypertrophy; thus, all the included studies had to assess at least one of these factors. Muscle strength was assessed using maximal dynamic strength by 1RM tests (found directly or reliably estimated from 10RM ), measurStudy design: Only randomized controlled trials and crossover trials were included. Articles were included if they were published in English, Spanish, or Portuguese.The search strategy was performed following the guidelines of Russell-Rose et al. . The seaIn the first phase, two independent reviewers (RFG and MGV) screened the titles, abstracts, and keywords of the studies following the Cochrane recommendations . In the The PEDro scale was employed to assess the quality of the included trials because it is a reliable method for assessing the quality of randomized controlled trials ,38. The Two independent trained assessors (RFG and MGV) examined the quality and risk of bias of the selected studies using the same methods, and disagreements were resolved by a consensus or by consulting the third reviewer (ILUV). The inter-rater reliability was determined using the Kappa coefficient: (1) >0.81–1.00 indicated an excellent agreement between the assessors; (2) 0.61–0.80 indicated a good agreement; (3) 0.41–0.60 indicated a moderate agreement; and (4) 0.21–0.40 indicated a poor agreement .The qualitative analysis was performed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), following the recommendations of Andrews et al. .The statistical analysis was performed with RStudio 3.0 software using the ‘metaphor’ and ‘esc’ packages. All the significance tests were conducted at a level of 5%. A meta-analysis was performed only when the data for the analyzed variables were represented in at least 3 studies/comparisons. The data synthesis was categorized by groups according to the degree of limb cuff pressure: the cuff pressure near the limb occlusion pressure versus being greater than the limb occlusion pressure .To increase the accuracy and thus the generalizability of our analyses, multiple comparisons from several studies  were included in all the analyses . In the The summary statistics for all the analyses are presented using forest plots. A random-effects model was employed to determine the overall effect size (SMD). The effect size of the statistical significance of the overall SMD was examined using Hedges’ g and interpreted as follows: (1) a small effect (g = 0.20–0.49); (2) a moderate effect (g = 0.50–0.79); and (3) a large effect (g ≥ 0.80) .2) [p < 0.1) and/or the I2 was >50% [The degree of heterogeneity among the studies was estimated using Cochran’s Q statistic test and the inconsistency index (I2) . Heterogwas >50% .Influential or outlier studies were investigated according to the recommendations of Viechtbauer and Cheung . The robTo detect any publication bias, the funnel plots were visually assessed, with an asymmetric graph considered to indicate the presence of bias. Egger’s regression test was employed to quantitatively assess the publication bias ,49.The search strategy yielded a total of 664 citations. After excluding the articles not meeting the inclusion criteria and after including supplementary articles by cross-references, a total of 14 studies were considered for the final analysis. A total of 340 healthy older adults were included  . Eight sThe mean PEDro score of the included studies was 5.6 (range 4–7) . The levThe risk of bias assessment of the included trials is summarized in p = 0.012) (p = 0.60) . For both the muscle strength and hypertrophy analyses, no single study significantly affected the overall SMD, and no evidence of publication bias was detected   . There w = 0.60) . The het > 0.05) .p = 0.97). In contrast to the meta-analysis results from the subgroup with that greater than the limb occlusion pressure, the subgroup with the near limb occlusion pressure showed a similar increase in muscle strength to that obtained with HL resistance training . The Ruaro et al. [With respect to the subgroup meta-analysis according to the degree of limb cuff pressure applied to perform the training, the results showed no statistically significant differences in terms of the muscle strength between the overall SMD obtained by applying pressure greater than or near that which was required to occlude the limb and that obtained with the HL resistance training . No single study significantly affected the overall SMD obtained for this subgroup.For the muscle hypertrophy, a subgroup meta-analysis could be performed only for the studies which applied that greater than the limb occlusion pressure, given that only two studies/comparisons applied a near limb occlusion pressure. The results of the meta-analysis for this subgroup were very similar to those of the meta-analysis for all the studies, reporting no statistically significant differences between the application of HL resistance training and LL-BFR resistance training for the muscle hypertrophy  and a moderate and statistically significant increase in muscle hypertrophy  compared with traditional LL resistance training . For both the muscle strength and hypertrophy analyses, no outlier studies and no evidence of publication bias were detected   . Howeverp = 0.026). Although there is moderate-quality evidence that both LL-BFR subgroups obtained statistically significant differences compared with traditional LL resistance training, LL-BFR applied with a greater than limb occlusion pressure obtained a large overall effect size (three studies [p < 0.001), whereas LL-BFR applied with the near limb occlusion pressure obtained a small overall effect size (5 studies [p < 0.001). No single study significantly affected the overall SMD obtained for these subgroups.For muscle strength, the results of the subgroup meta-analysis showed that, compared with traditional LL resistance training, LL-BFR training applied with a greater than limb occlusion pressure produced a greater increase in muscle strength than LL-BFR training applied with near limb occlusion pressure . HoweveBased on the results of this review, LL-BFR resistance training offers superior increases in the muscle strength and hypertrophy than traditional LL resistance training. The effect sizes observed indicate a greater robustness in the results. These findings agree with those in the literature regarding older adults ,18, younOur study’s second aim was to determine the effect of LL resistance training with the effect that varying degrees of BFR cuff pressure has on the muscle strength and hypertrophy in this population. Not even the high pressures applied to the cuff during LL-BFR resistance training mimicked the benefits of HL resistance training, suggesting that the additional metabolic stress of BFR is not comparable to the mechanical and metabolic stress provided by HL resistance training. However, when comparing LL-BFR resistance training versus traditional LL resistance training, higher muscle strength increases were observed when higher cuff pressures were applied. These findings differ from those obtained in a previous meta-analysis, which indicated that the cuff pressure in BFR resistance training did not influence muscle strength and hypertrophy in older adults . NeverthBased on the results of this review, the pressure applied to the cuff during LL-BFR resistance training could affect exercise adaptations. However, given that the differences are small and based on few studies, these conclusions have been interpreted with caution. In fact, the Ruaro et al.  study coWithin the clinical implications of this review, the most effective intervention to counteract the progressive physiological deterioration that occurs with age appears to be HL resistance training. However, the use of LL-BFR resistance training could represent an alternative training method for individuals intolerant to higher-intensity training protocols and in cases where its application is contraindicated. Thus, for healthy adults older than 60 years without contraindications, LL-BFR resistance training may be prescribed in combination with HL resistance training to aim for optimal muscular strength and hypertrophy responses. It is well known that LL-BFR resistance training is more uncomfortable than traditional LL resistance training ,80. TherThis systematic review and meta-analysis presents certain limitations. The training protocols used in the included studies are widely heterogeneous in terms of their duration, type of exercise , and BFR application parameters. Optimal protocols for BFR resistance training are still to be established and are needed to standardize the trial interventions. The studies included in certain sub-analyses are scarce, which could lead to possible changes in the conclusions if new studies are added. No subgroup meta-analysis according to the degree of the limb cuff pressure could be performed for muscle hypertrophy. The small sample size and the high risk of bias in the treatment effect estimates for the selected studies could also have influenced the results of this systematic review. More clinical trials with a high methodological quality are therefore needed to overcome these limitations.There was moderate-quality evidence that, compared with HL resistance training, LL-BFR resistance training promotes lower muscle strength gains but similar improvements in the muscle hypertrophy  in a healthy population older than 60 years. The benefits in terms of the muscle strength  and hypertrophy  were greater for LL-BFR resistance training than with traditional LL resistance training in older adults. There was no difference in either the muscle strength or hypertrophy when applying pressure greater than or near the pressure required to occlude the limb blood flow compared with HL resistance training. However, it appears that applying cuff pressures above the limb occlusion pressure could enhance increases in the muscle strength compared with traditional LL resistance training . In this systematic review and meta-analysis update, we found evidence of an increased interest in the efficacy of LL-BFR resistance training on the muscle strength and hypertrophy in healthy older adults; however, the certainty of the evidence using the GRADE methodology is still low to moderate.


Positron emission tomography (PET)/computed tomography (CT) scans are widely used as a form of full body imaging and allow for the early detection of small, asymptomatic tumors that may represent cancer metastasis or recurrence. Tissue diagnosis is critical in determining the choice of ongoing targeted therapy for pediatric patients with solid tumors. These small tumors may be difficult to localize in the operating room, especially in a re-operative or radiated area of the body. An adjunct such as a PET probe, used to guide intra-operative dissection, is the ideal tool to assist in cases where an occult tumor requires an excisional biopsy.18F-fluorodeoxyglucose (FDG) is a glucose analog that acts as a marker for glucose uptake and metabolism. FDG PET scans are used in monitoring pediatric cancers. The handheld PET probe localization of FDG-avid lesions is an emerging modality for radio-guided surgery (RGS). We sought to assess the utility of PET probe in localizing occult FDG-avid tumors in pediatric patients. PET probe functionality was evaluated by using a PET/CT scan calibration phantom. The PET probe was able to detect FDG photon emission from simulated tumors with an expected decay of the radioisotope over time. Specificity for simulated tumor detection was lower in a model that included background FDG. In a clinical model, eight pediatric patients with FDG-avid primary, recurrent or metastatic cancer underwent a tumor excision, utilizing IV FDG and PET probe survey. Adequate tissue for diagnosis was present in 16 of 17 resected specimens, and pathology was positive for malignancy in 12 of the 17 FDG-avid lesions. PET probe gamma counts per second were higher in tumors compared with adjacent benign tissue in all operations. The median ex vivo tumor-to-background ratio (TBR) was 4.0 (range 0.9–12). The PET probe confirmed the excision of occult FDG-avid tumors in eight pediatric patients. Diagnostic whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET/CT) imaging is used to identify and assess metabolically active tissue. Rapidly dividing cancer cells have a high number of glucose transporters and high rates of glycolysis, increasing the uptake of FDG . PET/CT Radio-guided surgery (RGS) utilizing technetium-99 m and a handheld gamma probe was first described in 1981 and has become the standard of care for sentinel lymph node biopsy . The useThe absolute threshold for an adequate TBR has yet to be established in operative use of the PET probe. In 2000, Yasuda et al. described that a minimum TBR of 5 is required to distinguish an FDG-avid tumor from a background using the handheld gamma probe in vitro . In 2001Other options are available for intraoperative tumor localization. The literature demonstrates the successful localization of occult pulmonary lesions in pediatric patients using a variety of methods including CT-guided coil or wire placement. CT-guided microcoil placement is useful to guide surgeons to find small pulmonary nodules ,13. CT-g123-MIBG-directed surgery to aid the resection of neuroblastoma in five patients [123-MIBG was not helpful in 35% of cases, with a specificity for malignant tissue of only 55% [The use of RGS in pediatric patients with a radiotracer was first described in 1997 by Heij et al. utilizing Ipatients . There honly 55% ,18,19,20In a preclinical setting, a PET/CT calibration phantom model was used. This model was developed by the Clinical Trials Network as a method to validate PET/CT scanners for use in oncology clinical trials . The phaA clinical prospective analysis included children aged 21 years and under with suspected recurrent, primary, or metastatic PET-avid lesions who underwent tumor excision or biopsy utilizing intravenous (IV) 18F-FDG and handheld PET probe at the Children’s Hospital of Pittsburgh from 1 January 2018 to 1 March 2021. This study was approved by the Institutional Review Board (IRB) at the Children’s Hospital of Pittsburgh. The study included 9 patients who met the inclusion criteria. All participating patients underwent a pre-operative PET/CT within one month of the operation, which identified one or more occult PET-avid lesions. PET avidity was defined as SUV > 4. Tumors were defined as occult by the operating surgeon if they were expected to be difficult to find based on size and/or location.Based on prior studies, all patients received a same-day, single-dose preoperative IV injection of 18F-FDG 0.2 mCi/kg via a peripheral IV line one hour prior to the operation and approximately two hours prior to intra-operative probe use for tumor localization ,20. Per n = 17). A p-value < 0.05 is used as a threshold for statistical significance.The primary outcome of interest to evaluate PET probe utility in tumor identification is TBR. TBR was calculated in preclinical and clinical models. Data including demographics, gamma cps measurements, and TBR were reported with median values and ranges or means and standard deviations. TBR values between malignant and benign groups are compared with a nonparametric Mann–Whitney U test given the small sample size in this study , a total of 17 FDG-avid tumors were identified by pre-operative PET/CT scans. The median age was 16 years old (range 5–21 years old). Of the eight patients, six were male and two were female. The diagnoses included three patients with suspected PTLD, three with Hodgkin’s Lymphoma, one with Burkitt’s lymphoma, and one with neuroblastoma. Patient demographics are illustrated in Nine patients were included in the study. For the analysis, one patient who received IV IA handheld gamma probe was used to measure external readings from surrounding organs for the assessment of background FDG uptake . An extep-value of 0.0181 between the two groups.Probe survey of excised lesions was performed at a median of 101 min after IV FDG injection (range 65–210 min). PET probe data were collected from the prospective evaluation of nine pediatric cancer operations and in eight patients with excision of seventeen FDG-avid lesions, including ex vivo cps with calculated TBR. Eight patients underwent surgical exploration, including five minimally invasive surgeries and four open operations for the removal of PET-positive lesions. One patient underwent two separate FDG-guided procedures to remove PET-positive lesions for PTLD. Seventeen lesions in total were excised from the nine operations included in this study . Six lesGamma probes capable of detecting high-energy gamma emissions (PET probes) have been available for over 20 years . DespiteThe preclinical thoracic phantom model confirmed the ability of the PET probe to detect high-energy gamma emission from FDG decay. This was an important step in validating the probe for gamma detection with the well-established half-life of the radioisotope prior to trialing clinical use of the probe. Of note, in The patients in our series had small tumors with a minimum SUV of 4 and a median SUV of 7.0. Background FDG avidity was confirmed by an external survey and intra-operative probe use. Metabolically active organs  by an external survey demonstrated mean gamma cps > 300. This correlated well with typical PET scan findings, which note a high uptake in these metabolically active organs. This is the first description, however, of gamma activity recordings via an external survey with a handheld PET probe. Not surprisingly, the highest cps are noted at the bladder, which is a result of FDG excretion via the kidneys into the urine. The second highest cps are recorded at the brain given the high glucose requirement for neural tissue metabolism. These findings indicate a potential reason for the PET probe’s lack of specificity, as FDG uptake is seen throughout the body, with a very high accumulation in metabolically active organs. Values from these benign organs were at least 300% greater than the measurements from the small, malignant tumors. External survey data from our experiment certainly indicated that eliminating background signals would be important to allow for the routine intraoperative use of the PET probe for tumor localization. This knowledge is critical for guiding future studies that may aim to improve probe specificity and highlights the importance of tumor-specific markers as a potential future research direction.Fluorescent-guided surgery is gaining enthusiasm as a method for tumor-specific surgical guidance. The most commonly used agent, indocyanine green (ICG), is actually a non-specific, water-soluble, near-infrared (NIR) dye that can accumulate in some lesions such as lung and liver tumors . Targetep-value of 0.0181. There was a significant difference between the two groups. This is promising that even without a tumor-specific marker, FDG avidity is more apparent in malignant tissue and is detected by the PET probe.Consistent with the preclinical model, the in vivo probe performance was impacted by a lack of specificity and was unable to provide surgical guidance to tumors. The PET probe was able to confirm FDG avidity ex vivo after suspected lesions were excised. The recorded median ex vivo cps of the small FDG-avid tumors (17 lesions) was 32, compared with the median ex vivo cps of the adjacent tissue of 11, yielding a median TBR of 4.0. Sixteen of the seventeen lesions were adequately sampled in the final pathology. The final pathology was positive for the suspected malignancy in 12 of the 17 excised lesions, 4 of the 17 lesions were benign, and 1 lesion was inadequately sampled. When comparing the malignant and benign lesions, the average ex vivo TBR values were 4.7 and 2.1 with a In this small subset of patients with pediatric cancer, the PET probe RGS was safe and feasible. The standard PET scan protocol was pre-operatively used for the infusion of IV FDG. The protocol was carried out as planned with no adverse reactions or events identified in the patients who participated in the study. A PET probe intra-operative survey may add a small amount of operative time and cost but were not quantified in the present study. Radiation exposure to patients and perioperative staff from the radiotracer decay is a risk of the procedure. The literature has demonstrated that FDG PET/CT has been associated with a very small radiation exposure risk to perioperative personnel, about 4 µSv of exposure per FDG administration, which is equivalent to that of less than a single-plain X-ray film on the chest ,29,30. IWhile the PET probe is inadequate in its ability to guide surgery, it was able to confirm significantly elevated extracorporeal cps in excised lesions and served as a confirmation of FDG-avid tumor excision. More specific agents or detection systems may need to be developed to provide highly specific intra-operative guidance. FDG is not tumor-specific, and simple handheld gamma detection has a limited specificity for the presence of FDG in malignant tissue versus background tissue. The radiolabeling of a tumor-specific agent such as an antibody, known as radioimmunoguided surgery (RIGS), may allow handheld gamma probes to provide intraoperative guidance for tumor resection in pediatric cancer surgery. In 2007, Sun et al. described the use of RIGS for the excision of occult lesions in metastatic colorectal cancer by utilizing a handheld probe in combination with a radiolabeled monoclonal antibody to a glycoprotein complex overexpressed in epithelial-derived cancers . TargeteOur study is limited in its lack of broad applicability as the operations analyzed were conducted by a single pediatric surgeon experience in pediatric oncology surgery at a large, academic children’s hospital. We did not evaluate the effect of prior radiation and the number of prior operations on the success or duration of the excisions. PET probe performance can be impacted by tumor histology, FDG avidity, and size, as well as the timing of operative exploration after FDG injection and anatomic location. The PET probe demonstrated a consistent performance over broadly dispersed tumor histologies and variable anatomic locations, including cervical, intra-abdominal, and intra-thoracic operations. We did not quantify the effect of these factors on outcomes. This could be examined in future studies. Due to the low number of patients in our series, our data are insufficient for drawing comprehensive conclusions about the specificity of handheld PET probes in detecting malignant tissue. Additionally, post-operative PET scans were not reviewed to confirm the complete excision of residual disease. As with other investigations of rare diseases, it will likely be necessary for cooperative trials to be conducted with the amalgamation of multicenter data on pediatric FDG-guided surgery, in order to draw conclusions about the efficacy of the PET probe. Ideal future studies involving RIGS could potentially improve probe specificity for malignant tissue and allow for intra-operative PET probe localization.We demonstrated a successful excision of occult FDG-avid tumors in eight pediatric patients utilizing PET probe RGS. To our knowledge, this is the first case series to describe FDG-guided surgery in a pediatric patient population and the first study to evaluate the PET probe using a PET scan calibration phantom. Tumor localization is limited by lack of FDG specificity and uptake by adjacent metabolically active organs in the thoracic and abdominal cavities. The median TBR of 4.0 is promising and demonstrates that, with improved tissue specificity by novel radiolocalizing agents, a PET probe could potentially be used for in vivo localization in the future. The handheld PET probe has the potential to facilitate a successful tumor excision for diagnostic and therapeutic purposes in pediatric cancer surgery.