The COVID-19 pandemic has been accompanied by an infodemic, which includes fake news (FNs) and conspiracy theories (CTs), and which may worsen vaccine refusal (VR), thus hindering the control of the transmission. This study primarily aimed to assess COVID-19 VR in Italy and its relationship with belief in FNs/CTs. Secondarily, it explored the conviction in FNs and CTs and associated variables. An online cross-sectional study was conducted in Italy (2021). The primary outcome was VR and secondary outcomes were FN misclassification score (0% to 100%: higher score means higher misclassification) and CT belief score (1 to 5: higher score means higher agreement). There were 1517 participants; 12.3% showed VR. The median FN and CT scores were: 46.7% (IQR = 40–56.7%) and 2.8 (IQR = 2.2–3.4). Age, education, FN, and CT scores had significant associations with VR. Education, economic situation, health and e-health literacy showed significant relationships with secondary outcomes. Study/work background had a significant association only with the FN score. FN and CT scores were associated. This work estimated a VR lower than before the first COVID-19 vaccine approval. The relationship between VR and FN/CT belief represents a new scenario, suggesting the need for planning effective strategies to tackle FNs and CTs to implement successful vaccination campaigns. Vaccine hesitancy is a complex phenomenon that includes indecision, delay, and reluctance and refers to delayed acceptance or refusal of vaccination despite the availability of vaccination facilities . Indeed,In the European context, Italy may represent a particularly hesitant country. Indeed, before the pandemic, a study involving 67 countries showed that Italy was among the countries with the highest level of skepticism and doubt regarding the effectiveness of vaccinations . MoreoveIn these extraordinary circumstances, it has been highlighted that a possible relationship exists between negative information on COVID-19 vaccines seen on social media and low acceptance, suggesting a relevant role played by disinformation . Indeed,Thus, the present study primarily aimed to assess the prevalence of COVID-19 vaccine refusal in Italy and its relationship with belief in fake news and conspiracy theories. Secondarily, another aim was to explore the extent of the conviction in fake news and conspiracy theories and the variables that were potentially associated with these infodemic-related phenomena.® was used to determine that the minimum sample size was 385, based on a 5% margin of error, 95% confidence level, 50% response distribution and size of the population living in Italy. An anonymous online questionnaire was set on the LimeSurvey platform and was distributed via the main social networks . The inclusion criteria for the recruitment were an age of 18 years or more, an understanding of Italian language, and residence in Italy. Participants gave their informed consent and received no compensation.Between 12 April 2021 and 16 May 2021, a cross-sectional survey was performed in Italy through the Computer-Assisted Web Interview (CAWI) method. The Bioethics Committee of the University of Turin approved the study. RaosoftFirst, the questionnaire included items on sociodemographic information, such as age, gender, nationality, education level, perceived economic situation, and main occupation. The job/study background was further investigated, with attention to the field of health care. In addition, participants were asked whether they had close friends or family members who are health care workers (HCWs), whether they had a chronic disease, and whether they lived with/took frequently care of a frail person . Also, the survey included pandemic-related items by asking participants if they had contracted COVID-19 and if they had relatives or close friends who had contracted it and by exploring vaccine refusal.Specifically, vaccine refusal  was investigated by asking participants if they had received at least one dose of COVID-19 vaccine and if, in case of a negative response, they intended to undergo vaccination when they had the chance. Thus, participants reporting vaccine refusal were identified if they did not get the vaccine and intended to refuse it, as measured in other studies .Then, HL and eHL were assessed by using the Italian version of two validated scales: the Single Item Literacy Screener (SILS) ,27 and tLast, the secondary outcomes were explored, i.e., misclassification of fake news and belief in conspiracy theories. The misclassification of fake news was investigated by asking participants to identify if 20 statements were true or false. Among these statements, fake news were mainly selected from the website of the Italian Ministry of Health . The autDescriptive analyses were carried out for all variables. Age and scores of misclassification of fake news and belief in conspiracy theories were expressed as median and interquartile range (IQR) because the Shapiro–Wilk test indicated that these data had non-normal distributions.Then, differences in the distribution of the outcomes across the variables of the questionnaire were explored through chi-squared tests and the Mann–Whitney U test .p-value < 0.250 as the main criterion [Lastly, to explore variables associated with the outcomes, univariable and multivariable models were carried out . The multivariable models, adjusted for age, gender, and educational level, were achieved with a stepwise forward selection process, with a univariable riterion . Resultsp-value < 0.05 was considered statistically significant. Missing values were excluded.Stata (v16) was used, and a two-tailed The final sample consisted of 1517 participants . The characteristics of the sample are described in Regarding the primary outcome, 186 individuals (12.3%) reported COVID-19 vaccine refusal. Considering the secondary outcomes, the median of the score of fake news misclassification was 46.7% (IQR = 40–56.7%), and the median of the score of belief in conspiracy theories was 2.8 (IQR = 2.2–3.4).The fake news that was misclassified more frequently were as follows: “taking vitamins C and D prevents SARS-CoV-2 infection” (69.5% of misclassification), “the effectiveness of the mask is not affected by the length of the beard” (68.7%), and “ibuprofen administration in patients who have developed COVID-19 significantly worsens the disease” (55.0%). All details are shown in Considering the chi-squared analyses, certain variables resulted in association with COVID-19 vaccine refusal . For insConsidering the multivariable model, several variables resulted to be significantly associated with the primary outcome vaccine refusal . Indeed,Regarding the secondary outcomes, multivariable models are shown in The present paper had the primary aim of studying the prevalence of COVID-19 vaccine refusal in Italy and its relationship with belief in fake news and conspiracy theories. Secondarily, it aimed to describe convictions in fake news and conspiracy theories and the factors that were potentially associated with such beliefs.We found a COVID-19 vaccine refusal of 12%. Compared with data collected before the approval of the first vaccine by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) ,5, this Regarding the main socio-demographic characteristics associated with a higher vaccination hesitancy, the results of this study confirmed findings from relevant systematic reviews. Specifically, most studies suggested an association between COVID-19 vaccine hesitancy and a low level of education or a young age ,25,41,42The study on the two secondary outcomes was therefore of particular interest. First of all, it is worth noting that the median score for fake news misclassification was 46.7%, suggesting a poor ability in classifying news and a low level of information on SARS-CoV-2. Secondly, some of the most frequently misclassified fake news could lead to health damage. For instance, nearly 70% of our sample stated that vitamins C and D should be taken to prevent COVID-19. However, an improper use of dietary supplements can be potentially dangerous, as highlighted in a document published in 2020 by the Italian National Institute of Health following the increased interest in supplements during the pandemic . RegardiFurthermore, some variables were associated with the increase of both the secondary outcomes, e.g., lower education level and poor/insufficient economic situation, i.e., factors already identified by other studies as associated with poor recognition of incorrect information ,54,55. IIt is also worth noting that gender had a significant association only with belief in conspiracy theories. Because it has been found that anxiety levels correlate with higher propensity to believe in conspiracy theories  and womeIn addition, inadequate HL was associated with an increase in the two secondary outcome scores, as similarly suggested by other authors . ConversLastly, it should be noted that the two secondary outcomes were significantly associated with each other, showing a strong relationship and potentially common determinants that deserve to be further investigated in future studies.The present study had some limitations that should be acknowledged. Among the main limitations of the study, it is necessary to highlight the cross-sectional design, which only allows us to formulate hypotheses but not to establish causal links, and opportunistic sampling. In addition, the choice of using a survey instead of in-depth interviews may limit the research results. Furthermore, the distribution of the questionnaire via social media may have excluded a certain subpopulation, and no information was collected on individuals who refused to participate in the study. In addition, the prevalence of foreign people participating in the study was lower than the one of foreign people living in Italy, partially because the questionnaire was only in Italian . SimilarThe present paper estimated an COVID-19 vaccine refusal lower than the prevalence detected before the approval of the first vaccine by the FDA and EMA. Among the several variables that were significantly associated with a greater probability of vaccine refusal, it is worth highlighting the association with a poor ability to recognize fake news and the belief in some conspiracy theories. These relationships, probably amplified by the infodemic, represent a novelty in the vaccine hesitancy scenario, thus suggesting an urgent need to plan effective strategies to address fake news and conspiracy theories to achieve successful vaccination campaigns. Therefore, together with the pandemic, a further challenge arises. The research agenda to address this challenge, as defined by the WHO, offers many ideas for researchers worldwide, who can contribute to the solution by measuring the impact of the infodemic, detecting the spread of the infodemic, testing and evaluating interventions that protect against infodemics and mitigate negative effects, and promoting the development, adaptation, and application of shared tools .


Early hematoma growth is associated with poor functional outcomes in patients with intracerebral hemorrhage (ICH). We aimed to explore whether quantitative hematoma heterogeneity in non-contrast computed tomography (NCCT) can predict early hematoma growth.We used data from the Risk Stratification and Minimally Invasive Surgery in Acute Intracerebral Hemorrhage (Risa-MIS-ICH) trial. Our study included patients with ICH with a time to baseline NCCT <12 h and a follow-up CT duration <72 h. To get a Hounsfield unit histogram and the coefficient of variation (CV) of Hounsfield units (HUs), the hematoma was segmented by software using the auto-segmentation function. Quantitative hematoma heterogeneity is represented by the CV of hematoma HUs. Multivariate logistic regression was utilized to determine hematoma growth parameters. The discriminant score predictive value was assessed using the area under the ROC curve (AUC). The best cutoff was determined using ROC curves. Hematoma growth was defined as a follow-up CT hematoma volume increase of >6 mL or a hematoma volume increase of 33% compared with the baseline NCCT.P = 0.040, odds ratio [OR]: 0.824, 95 % confidence interval [CI]: 0.686–0.991), “heterogeneous” in the density category , and CV of hematoma HUs  were independent predictors of hematoma growth. By evaluating the receiver operating characteristic curve, the CV of hematoma HUs (AUC = 0.750) has a superior predictive value for hematoma growth than for heterogeneous density (AUC = 0.638). The CV of hematoma HUs had an 18% cutoff, with a specificity of 81.9 % and a sensitivity of 58.1 %.A total of 158 patients were enrolled in the study, of which 31 (19.6%) had hematoma growth. The multivariate logistic regression analysis revealed that time to initial baseline CT (The CV of hematoma HUs can serve as a quantitative hematoma heterogeneity index that predicts hematoma growth in patients with early ICH independently. Spontaneous intracerebral hemorrhage is difficult to treat and continues to be a significant cause of morbidity and mortality globally , 2. OnlyWe used data from the Risk Stratification and Minimally Invasive Surgery in Acute Intracerebral Hemorrhage (Risa-MIS-ICH) trial, which was a prospective multicenter cohort study. This study was registered in ClinicalTrials.gov (No. NCT03862729). The present study utilized retrospective data from this database, from January 2015 to October 2021. Patients with the time to baseline NCCT less than 12 h and time to follow-up CT less than 72 h were included. The exclusion criteria were as follows: (i) CT at baseline was not NCCT; (ii) surgical intervention was performed before follow-up CT; and (iii) CT image quality was not optimum. The study was authorized by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University . Furthermore, this study adhered to applicable Chinese laws, rules, and guidelines, in addition to the tenets of the Declaration of Helsinki.Heterogeneous density of ICH was measured on a 5-point visual analog scale along with an incremental continuum. The density category of hematoma was described as “heterogeneous,” when there were at least three hypodense lesions within the dense hematoma, and “homogeneous,” when there were less than three hypodense lesions within the dense hematoma, as assessed on an axial section showing the maximum cross-sectional area of the hematoma , 17. TheInitial and follow-up CT scans are performed using normal clinical techniques. For future processing and evaluation, all image data were archived in the Digital Imaging and Communications in Medicine (DICOM) format. To determine the volume and density of the hematoma, two independent researchers (Mingpei Zhao and Wei Huang) examined the baseline NCCT markers of 158 patients by workstation software . The researchers were unaware of the patients' clinical history and follow-up CT findings. Hematomas were detected layer by layer on the axial section using a semi-automatic edge detection method. The region of interest (ROI) included the entire hematoma and was processed using the auto-segmentation function to obtain the histogram of HU, the mean of HU, and the coefficient of variation (CV) of HU . Detailet-test. The median (25th−75th quartile) of skewed data was used to compare them using the Mann–Whitney U test. We utilized univariate analysis to identify potential relevant determinants of hematoma growth. We then used multivariate logistic regression to determine the independent determinants of hematoma growth. In the multivariate analysis, factors with P < 0.05 in the univariate analysis and those known to be associated with hematoma growth as confounders were included. The optimal cutoff was determined using the receiver operating characteristic (ROC) curve analysis, and the predictive value of the discriminant score was determined using the area under the receiver operating characteristic (AUC) curve analysis. SPSS version 26.0  and R version 4.1.0  were used for analysis. Two-tailed P-values were reported, and P < 0.05 was considered statistically significant.Categorical variables were described as percentages, and the chi-square test or Fisher's test was used to determine the distribution differences across groups. Continuous variables with a normal distribution were presented as means and standard deviations, compared using a two-tailed Student's P = 0.101), a smaller mean HU of hematoma (P < 0.001), a larger CV of hematoma HUs (P < 0.001) and were more likely to have diabetes mellitus (P = 0.045), a black hole sign (P = 0.045), and heterogeneous density (P < 0.001) than those without early hematoma growth. Age, sex, hypertension, oral anticoagulants, oral antiplatelet drugs, admission systolic blood pressure (SBP), baseline Glasgow Coma Scale (GCS) score, deep ICH, relevant laboratory indicators, swirl sign, baseline ICH volume, and standard HU of hematoma did not differ significantly between patients with and without hematoma growth.This study enrolled a total of 158 patients with ICH . There wDiabetes mellitus, heterogeneous density, black hole sign, blend sign, mean HUs, and CV of hematoma HUs were all linked with hematoma growth in univariate logistic regression . UnivariIn comparison to heterogeneous density (area under the curve = 0.750), the CV of hematoma HU (area under the curve = 0.638) has a significantly stronger predictive value . The optOur study revealed that heterogeneous density of hematoma was a significant predictor of hematoma growth. The quantitative heterogeneity of hematomas as characterized by the CV of hematoma HUs was more predictive of hematoma growth than the traditional qualitative heterogeneity score. Diabetes mellitus, the black hole sign, a shorter time to baseline CT, and a smaller mean HU of hematoma were also found to be related to hematoma growth.The reason for heterogeneity on NCCT is unclear. We postulate that this could be a sign of either persistent bleeding or local coagulopathy, and the available explanations from previous studies are given in the following text. A hematoma develops following the rupture of a brain vessel . In the The presence of active contrast extravasation within a hematoma is referred to as a CTA spot sign, and it is frequently used to forecast hematoma growth , 26. TheIn comparison to the CTA spot sign, the NCCT is easier to obtain. As a result, NCCT markers have been routinely employed in clinical practice to predict hematoma growth. NCCT markers are classified into two groups based on their shape and density . The swivia machine learning, thereby allowing for automatic recognition and segmentation of hematomas. Clinicians would be able to import the imaging data to extract critical hematoma characteristics such as hematoma volume and CV of hematoma HUs; it can also be incorporated into the imaging workstation as a useful tool for the radiologist. Further large-scale randomized control trials are necessary to further validate our findings and to inform policy guidelines to implement this promising idea of an open-source, freely available software.The clinically relevant findings of our study are as follows: First, we identified a quantifiable objective predictor of hematoma growth, contrary to other NCCT markers that are subjective. We believe that our predictor may guide the stratification of hematoma risk. Second, our findings have translational potential for clinical applications. For example, our technology makes it possible to create relevant software that can be used to assimilate a large amount of data and establish predictive models This study has certain limitations. First, this is a retrospective analysis with a small sample size; therefore, our findings require further confirmation using the entire data from the Risa-MIS-ICH prospective trial. Second, we included patients with a 12-h baseline CT in our study, as opposed to patients with a shorter baseline CT, which may have resulted in missed cases of possible hematoma growth. Third, with an increase in sample size, the optimal cutoff representing the CV of the hematoma HU value for predicting hematoma growth may change. Finally, the segmentation and processing of hematoma require specialized software, which may be difficult to obtain in some hospitals and institutions.In conclusion, our study established that the heterogeneity of hematomas may be a predictor of early hematoma growth in patients with ICH. Moreover, the quantitative hematoma heterogeneity index utilized in this study has a significantly greater predictive value than that of the conventionally used heterogeneous density markers on NCCT. At the next stage, the RIS-MIS-ICH project will validate the research findings using prospective multicenter large-sample size data.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Fujian Medical University's First Affiliated Hospital . Written informed consent from the patients/participants or patients/participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.MZ, WH, SH, and FL: acquisition of data and critical revision of the manuscript for intellectual content. QH, YZ, ZG, LC, and GY: study supervision. RC, WF, DW, and YL: study concept and design. SH and SW: guidance on statistics. DK and LY: analysis and interpretation of data and study supervision. All authors have reviewed the final version of the manuscript.This study was supported by the project on research and application of effective intervention techniques for a high-risk population of stroke from the National Health and Family Planning Commission in China (GN-2018R002) and the National Cerebrovascular and Nervous System Difficult Diseases Diagnosis and Treatment Capacity Improvement Project, Fujian Province High-level Neuromedical Center Construction Fund (Grant No: HLNCC-FJFY-003), as well as Fujian Province Science and Technology Innovation Joint Fund Project (2019Y9118).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.


Staphylococcus aureus growth. In the presence of light, BNC/MB hydrogels completely inhibited the microorganism. Therefore, the results suggest potential materials for the prevention or treatment of Staphylococcus aureus infections in wounds.With the aim of contributing to the development of more efficient materials for wound care, new topical formulations based on bacterial nanocellulose (BNC) hydrogels containing propolis were produced. Characterizations confirmed the incorporation of propolis into the BNC matrix, maintaining its structure and properties. Rheological analysis confirmed that the hydrogels showed thixotropic behavior appropriate for topical application. Chromatographic profiles showed sustained release of propolis biomarkers for at least 20 h. The formulations did not present mutagenicity. For application in photodynamic inactivation (PDI), BNC/propolis hydrogels were prepared with the photosensitizers methylene blue (MB). Spectroscopy and confocal fluorescence microscopy confirmed the interaction of MB and propolis in BNC hydrogels, as well as the formation of a new composite material. In the antibacterial assays, formulations containing MB and propolis significantly reduced  Wound healing is a complex and dynamic process influenced by local and systemic factors that involve reactions and interactions between cells, biomolecules, and mediators occurring in proper sequence and time . The norInfection is one of the main causes of delay or impediment in wound repair because it generates an intense immune response and tissue damage as a consequence of excessive microbial proliferation at the injury site. In addition, the bacterial biofilm present in most chronic wounds hinders the penetration of antimicrobials and contributes to antibiotic tolerance and resistance, which further complicate treatment ,5. ChronTraditional treatments for wound infections are based on systemic or topical administration of antimicrobial and antiseptic agents, which are, in general, associated with dressings or coverings in the form of hydrogels, hydrocolloids, polymeric films, gauze, foams, and alginates ,8,9. HowKomagataeibacter genus, is already used as dressing in the treatment of wounds and can act as a temporary skin substitute , . (2013) ,64.It is noteworthy that the TGA curve of the hydrogel with the highest concentration of propolis (BNCH/P3) is similar to the profile of pure propolis, while the thermal behavior of the hydrogel with the lowest proportion of the extract (BNCH/P1) corresponds to the mass loss events of BH and BNCH. These data corroborate the SEM and FTIR results, confirming the new composite formulation.Rheological flow properties are related to the deformation of the material when it is subjected to shear stress, providing information about its behavior and stability, which is fundamental for quality control, material acceptance, and effectiveness ,66. All The viscosity of hydrogels decreases with increasing shear rate. When this rate is removed, the hydrogels gradually recover their values through microrestructuring of formulation elements. Furthermore, an area of hysteresis is formed between the upward and downward flow curves, which characterizes thixotropic behavior . This isIn general, in the presence of BNC, there is an increase in complex viscosity compared to pure BH for all hydrogels. Specifically, for formulations containing propolis, the behavior is very similar between samples with different concentrations . There is a slight gradual increase in viscosity associated with an increase in propolis contents . Further® was performed to confirm the composition of propolis extract according to the methodology previously published by Berretta et al. (2012) [p-coumaric acid, (2) artepillin C, and (3) baccharin, the amounts of which are listed in A chromatographic analysis of biomarkers from EPP-AF. (2012) . The obt® [The results are comparable to the chemical profile of EPP-AF® , confirmp-coumaric acid and artepillin C identified in the hydrogels are evidently proportional to the concentration of propolis extract used in each formulation . However, the proportion was not maintained for baccharin, possibly due to its degradation during the protocol, as well as lower stability or greater difficulty in extracting the compound. The release study was carried out with propolis hydrogels to evaluate its biomarker release over time  [The maximum release of , (2018)  producedThe release kinetics of propolis biomarkers from BNC hydrogels were determined based on mathematical functions that describe the release profile through correlation coefficients (r). The values obtained for each formulation are shown in r values, it is possible to infer that both biomarkers follow the Higuchi model, which is characteristic of all BNC/propolis hydrogels. This profile suggests the diffusion type of biomarker release from the BNC matrix [According to the C matrix , which oC matrix .S. typhimurium after treatment with hydrogels according to experiments without and with metabolic activation .All experiments presented MI values below 2.0, which indicates that the hydrogels did not induce a statistically significant increase in the number of revertants compared to the negative control (DMSO), both in the presence and absence of metabolic activation. BNCH/EPP3 generated more sensitivity to the used strains, as evidenced by the reduction in the number of revertants compared to the negative control and the decrease in MI values. Nevertheless, data demonstrate the absence of mutagenic activity of all formulations under the applied conditions. The non-mutagenic effect of propolis was confirmed in other works ,75. The ® hydrogel (BH) and the light scattering caused by the high content of cellulose nanofibers in the BNCH [the BNCH .®, it is possible to observe a slight shift of the bands from 670 and 610 nm to 680 and 620 nm, respectively, probably caused by the interaction between MB and propolis.BNC hydrogels containing MB present two main absorption bands, with maxima centered around 670 nm and 610 nm, with the highest and the lowest intensities, respectively, in the less concentrated formulation (BNCH/MB1). However, in the most concentrated formulation (BNCH/MB2), these bands have their intensities inverted, suggesting an MB dimerization process . AccordiThe BNC/propolis hydrogel also does not present absorption bands in this region of the spectrum. Some previous studies on the ethanolic extract of propolis have reported maximum absorbance around 295 nm, as well as absorption of phenolic compounds under UV light ,75. HoweIn the fluorescence spectra of the formulations B, there ® and MB, the band at 675 nm appears more discrete, and bands around 700 nm are absent, which indicates a probable suppression of fluorescence due to the interaction of propolis with MB.The band at 675 nm appears only in the spectrum of the BNCH/P1 formulation, which is assigned to emission from the propolis extract. In hydrogels containing EPP-AF® and MB , even in the experiments without light (p < 0.05). This result confirms the toxicity of MB in the dark [p = 0), suggesting that these are the most suitable formulations for PDI against S. aureus.BNCH/MB1 and BNCH/MB2 formulations showed a significant reduction in the dark . HoweverS. aureus.The microdilution results are in agreement with the disk diffusion experiment results . It was S. aureus and P. aeruginosa [The photodynamic activity of MB occurs through type I reactions, which produce reactive oxygen species such as hydroxyl, and through type II reactions, which generate singlet oxygen. This species is considered the main cause of antimicrobial photodynamic activity, and the phenothiazine dye is well known for its high quantum yield of singlet oxygen ,81. Accoruginosa .p > 0.05). This confirms that the antimicrobial activity of EPP-AF® is not influenced by the presence of light [S. aureus growth, generating an inhibition zone of 8 ± 0.58 mm [Regarding the BNCH- and BH-based hydrogels, the formulation containing only propolis (BNCH/P1) significantly reduced bacterial growth (reduction of 2.15 log CFU/mL and inhibition zone of 3 ± 0.1 mm), but there was no significant difference between these formulations in the treatments with and without light  compared to those containing only MB, maintaining values close to 2 log CFU/mL of reduction for both in the dark. After light irradiation, the reduction in microbial growth increased to 4.30 log CFU/mL. Despite the favorable results of these formulations for PDI application, they suggest that propolis decreased the photodynamic action of MB against the bacteria. This may be related to the shift in MB maximum absorbance in the presence of propolis, as demonstrated by the UV-Vis spectra, which may have reduced the formation of reactive species responsible for the inactivation of the microorganism. Unlike the results obtained in this work, Wang et al. (2017) [Hydrogels containing MB associated with propolis (BNCH/P1/MB1 and BNCH/P1/MB2) had significantly reduced PDI efficacy (. (2017)  achieved1O2, acting as a sequestering agent and protecting bacteria from photodynamic effects.In addition to the absorbance shift, there is the possibility of a reaction between MB, which has a positive charge , and the® at the concentrations used. This may have hampered light transmission through formulations containing propolis, decreasing the amount of energy supplied to the PS, thereby reducing the formation of reactive species. The difficulty in performing antimicrobial tests for propolis has been reported in other works due to its turbidity [The most accepted idea by the authors of this work regarding the reduction in the antimicrobial activity of BNCH/P/MB in relation to BNCH/MB concerns the turbidity of EPP-AFurbidity . However® and/or MB showed antimicrobial activity against S. aureus and may be possible future alternatives for wound care, since they may prevent or heal infections. The eradication of the microorganism by hydrogels containing MB after exposure to light expands the application of BNC formulations to PDI, supporting wound healing by eliminating infections.Nevertheless, all formulations containing EPP-AF® and MB photosensitizer were developed. The formulations maintained the BNC structure of a three-dimensional network of nanofibers, as well as its molecular organization and thermal stability. Furthermore, they presented pseudoplastic thixotropic behavior, making them suitable for topical applications. The quantity of propolis biomarkers in the formulations correspond to the concentration of the EPP-AF® extract used, and their release was sustained for at least 20 h, representing a possible extended-release system. The obtained hydrogels did not present mutagenicity. In order to apply the formulations to photodynamic inactivation, BNC/propolis hydrogels containing MB were produced. Optical characterization showed maxima centered at 670 nm and 610 nm for pure MB formulations. In the most concentrated formulation, these bands have their intensities inverted, suggesting an MB dimerization process. There was a slight shift in the maximum absorbance of the dye with propolis to 680 nm and 620 nm, which may have led to a decrease in the PDI efficacy. Nevertheless, all formulations containing propolis and/or MB were able to reduce S. aureus growth on some scale. As an advantage, the BNC/MB hydrogels completely inhibited the growth of the bacteria after exposure to light, demonstrating great efficacy for application in PDI. We conclude that the new formulation of BNC produced in this study can potentially support wound healing by treating or preventing infections.New formulations of BNC hydrogels containing EPP-AF


The difference of patients' baseline characteristics such as sex, age, Eastern Cooperative Oncology Group performance status (ECOG PS), and smoking status may influence the immune response. However, little is known about whether these factors affect the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we performed this systematic review and meta-analysis to investigate the relationship between patients' baseline characteristics and survival benefits in immunotherapy-treated NSCLC.  We performed a systematic search of PubMed, the Cochrane Library, and Embase for randomized controlled trials (RCTs) of NSCLC immunotherapy. We also searched abstracts and presentations from the proceedings of the American Society of Clinical Oncology and the European Society of Medical Oncology to identify unpublished studies. These studies have available data based on patients' baseline characteristics . We take the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS) as the effect index and use the random effect model to pool the results. P < 0.05) and female patients ; for both younger  and older patients ; and for both patients with ECOG PS = 0  and ECOG PS ≥ 1 . Moreover, there was no significant difference in the efficacy of ICIs among different sex , age , or ECOG PS . However, in patients with different smoking status, the application of ICIs significantly prolonged the OS of smokers  but could not significantly improve the OS of never smokers .  We included 18 phase II/III RCTs with a total of 14,189 participants. The benefits of ICIs were found for both male (pooled OS-HR 0.77, 95% CI 0.72-0.82,  ICIs could significantly improve prognosis in patients with advanced NSCLC, regardless of sex, age, or ECOG PS. But among patients with different smoking status, the survival benefits of never smokers treated with ICIs were no better than that of controls. The impact of these factors on immunotherapy should be considered in the future clinical practice and guidelines. As we all know, lung cancer has long been one of the most common malignancies with the highest mortality rate all over the world , 2. ClinICIs could enhance the body's antitumor immunity by restoring exhausted T cells in the tumor microenvironment, thus improving the durable response rate of some advanced cancer patients and providing a longer overall survival . So far,The immune system of the human body is affected by many external environment and self-factors. Patients may achieve different benefits from ICIs because of their different immune responses, but it is not clear which patients will benefit more from immunotherapy. It is known that sex and age are important variables affecting the human immune system. In general, both innate and acquired immunity are stronger in women than in men, leading to faster clearance of pathogens and a higher risk of autoimmune diseases in women . As the Given that the influence of the above factors on the efficacy of immunotherapy remains hugely controversial, we performed this meta-analysis, incorporating the latest phase II/III clinical trials and establishing subgroup analyses to comprehensively research the relationship between advanced NSCLC patients' baseline characteristics with survival benefits of immunotherapy.We performed the study in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines , and theFirst, we conducted a comprehensive literature search from three electronic databases  to collect phase II/III randomized controlled trials (RCTs) of immunotherapy for advanced NSCLC from database establishment to June 1, 2021. Second, to identify unpublished studies, we searched abstracts and presentations from conference proceedings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO). The following terms were used for searching: non-small-cell lung neoplasm, cancer, or carcinoma; NSCLC; Immune Checkpoint Inhibitors; immunotherapy; PD-1; PD-L1; CTLA-4; nivolumab; pembrolizumab; atezolizumab; ipilimumab; avelumab; durvalumab; tremelimumab; ICIs; randomized controlled clinical trial; and RCT.The following five criteria need to be met for inclusion: (1) RCTs of immunotherapy for advanced NSCLC; (2) data on the hazard ratio (HR) for death of overall survival (OS) reported based on participates' sex, age, ECOG PS, or smoking status must be available; (3) the intervention group received single ICI therapy or ICI combined with non-ICI therapy; (4) the control group should be treated without ICIs; and (5) phase II/III clinical trial published in English. If multiple reports of a study were available, we only included reports that contain the latest and most comprehensive data.Two authors independently extracted the data and resolved differences through discussions involving a third author until agreement was reached. We mainly extracted the following information from the studies: first author, journal name, number of participants, year of publication, trial name, pathologic type, treatment arms, and line of therapy. We also extracted the HR and 95% CI of the OS of the following predefined subgroups: sex , age (<65 y vs. ≥65 y), ECOG PS (0 vs. ≥1), and smoking status (never smokers vs. former/current smokers).Q test to determine the heterogeneity between studies and calculated the I2 values. The results were assessed using forest plots and presented as HRs for the main outcome. Egger's test and Begg's test were used to detect whether there is publication bias.Random-effects models were used for all meta-analyses because of the clinical heterogeneity inherent in the data. The HR and 95% CI of the OS were used as effect sizes. We used the We further performed subgroup analyses to explore the impact of patients' different baseline characteristics on the survival benefits of immunotherapy. And the subgroups were line of therapy, intervention therapy, and pathologic types.P value (two-sided) was less than 0.05, the results was considered to be statistically significant. All analyses were performed using STATA 16.0.If the According to the research strategy, we retrieved a total of 3,581 articles, and after strict screening, a total of 14,189 participants from 18 studies met our criteria and were included in this meta-analysis , 26–38. In addition, there is a study that needs further explanation. In the Impower150 trial , particiP < 0.05) and female patients , there was a significant interstudy statistically heterogeneity among female patients , but not in male patients  , and 4,430 were female (33.3%). It was observed that the survival advantage of the immunotherapy was better than that of the control therapy in both male  .P value for interaction = 0.955). No significant difference was observed in subgroup analyses by different line of therapy, interventional therapy strategies, or pathological types  and older patients ; there was a significant interstudy statistically heterogeneity among younger patients , but not in older patients  , and 5,715 were 65 years or older (44.6%). The survival benefits of the immunotherapy were better than that of the control therapy in both younger  .P value for interaction = 0.17). And no significant difference was observed in subgroup analyses by different line of therapy, interventional therapy strategies, or pathological types  and ECOG PS ≥ 1 ; interstudy statistically heterogeneity was not significant in either group   with ECOG PS = 0 and 8,414 patients (63.4%) with ECOG PS ≥ 1. The survival advantage of immunotherapy was superior to that of control therapy both in patients with ECOG PS = 0  .P value for interaction = 0.765), and no significant difference was observed in subgroup analyses by different line of therapy, interventional therapy strategies, or pathological types  versus control therapy. However, among never smokers, no significant survival benefit was observed  compared with control therapy. Interstudy statistically heterogeneity was not significant in either group  , and 1,439 were never smokers (14.2%). Our results suggested that immunotherapy significantly prolonged the OS in smokers  .The same results were observed in subgroup analyses. Except in nonsquamous treatment settings and ICI combination therapy settings, the survival benefits of the immunotherapy group were superior to that of the control group in both smokers and nonsmokers. .P = 0.148 for Egger's test; P = 0.184 for Begg's test)  . Sensiti's test) .In the past decade, the rapid development of immunotherapy has brought a revolutionary breakthrough in the treatment of advanced NSCLC, showing a better effect than standard chemotherapy in certain patients. Currently, the primary contradiction is the lack of reliable biomarkers to identify which patients can benefit better from immunotherapy. Now, the most widely used makers are PD-L1 expression level, tumor mutation burden (TMB), and microsatellite instability (MSI) –43. In aIn terms of sex, our results suggested that both men and women with advanced NSCLC benefit from immunotherapy, and no statistically significant differences were observed between the two groups. Furthermore, sex-related differences in efficacy were not observed when we performed subgroup analyses by different line of therapy, interventional therapy strategies, or pathological types. In a previous meta-analysis reported by Conforti et al. , the risSeveral previous meta-analyses reported that younger (<65 y) and older (≥65 y) patients treated with ICIs had no significant difference in survival benefit , 47. OurRecently, it has also been reported that ECOG PS may affect the immune response . To our In the end, we also evaluated the relationship between patients' smoking status and survival benefits in immunotherapy-treated NSCLC. Although similar researches have been conducted in several previous meta-analyses , 22, 48,Our meta-analysis suggests that the survival benefits from immunotherapy in patients with advanced NSCLC with different sex, age (<65 y vs. ≥65 y), or ECOG PS (0 vs. ≥1) are similar to those in the control group, so they should not be limited by these factors when using ICIs. In patients with different smoking status, although ICIs can significantly improve the prognosis of smokers, for never smokers, ICIs have an advantage only in patients with nonsquamous NSCLC and patients treated with ICI combination therapy. The effect of this factor on immunotherapy of NSCLC patients should be taken into account in future clinical practice and guidelines.As far as we know, our meta-analysis is the latest and most detailed assessment of the relationship between immunotherapy and various baseline characteristics in patients with advanced NSCLC. We included 18 phase II/III RCTs with a total of 14,189 participants. Supported by extensive clinical data, we comprehensively analyzed the effects of sex, age, ECOG PS, and smoking status on the survival benefits of immunotherapy for NSCLC and performed detailed subgroup analyses by patients' different line of therapy, intervention therapy, and pathologic types.There are also some limitations in our results. First, because our analysis is based on published clinical trial data and lacks individual patient-level data, these factors hinder more in-depth analysis and may have potential publication bias. Second, there were few data reported by progress free survival (PFS) in the included trials, so we did not conduct further analysis based on PFS, which may require further discussion in future studies. In addition, since most of the studies did not include patients with ECOG PS ≥ 2 and older than 75 years old, our conclusions could not be well targeted at these two groups of people; more clinical data and further analysis are needed to improve this part in the future.


Optically pumped magnetometers (OPM) are quantum sensors that enable the contactless, non-invasive measurement of biomagnetic muscle signals, i.e., magnetomyography (MMG). Due to the contactless recording, OPM-MMG might be preferable to standard electromyography (EMG) for patients with neuromuscular diseases, particularly when repetitive recordings for diagnostic and therapeutic monitoring are mandatory. OPM-MMG studies have focused on recording physiological muscle activity in healthy individuals, whereas research on neuromuscular patients with pathological altered muscle activity is non-existent. Here, we report a proof-of-principle study on the application of OPM-MMG in patients with neuromuscular diseases. Specifically, we compare the muscular activity during maximal isometric contraction of the left rectus femoris muscle in three neuromuscular patients with severe (Transthyretin Amyloidosis in combination with Pompe’s disease), mild , and without neurogenic, but myogenic, damage (Myotonia Congenita). Seven healthy young participants served as the control group. As expected, and confirmed by using simultaneous surface electromyography (sEMG), a time-series analysis revealed a dispersed interference pattern during maximal contraction with high amplitudes. Furthermore, both patients with neurogenic damage (ATTR and CMT2) showed a reduced variability of the MMG signal, quantified as the signal standard deviation of the main component of the frequency spectrum, highlighting the reduced possibility of motor unit recruitment due to the loss of motor neurons. Our results show that recording pathologically altered voluntary muscle activity with OPM-MMG is possible, paving the way for the potential use of OPM-MMG in larger studies to explore the potential benefits in clinical neurophysiology. The hallmark of most neuromuscular diseases is muscle weakness, which often emerges because of motor neuron loss . To compAn elegant alternative to EMG is magnetomyography (MMG), which uses optically pumped magnetometers (OPM). MMG measures the magnetic fields generated by the electrical current flowing in the muscles. As the magnetic companion of EMG, it does not require skin contact as a source of potential noise, is contactless and, compared to nEMG, is therefore completely painless. Although MMG was already described by Cohen and Gliver in 1972, the field of the MMG was not pursued due to the technical limitations of the conventional superconducting quantum interference device (SQUID) magnetic sensors, which require cryogenic cooling to −269°C, are bulky and lack spatial flexibility. OPMs, on the contrary, are small, do not require cryogenic cooling, and enable recording muscle activity in individual anatomical situations, which leads to a revival of the field of MMG , Transthyretin Amyloidosis in combination with Pompe’s disease (ATTR), and Charcot-Marie-Tooth disease, type 2 (CMT2), were included in our study  and took place inside a magnetically shielded room . All participants were placed in a comfortable chair, extending their legs on the chair at a controlled knee angle of 150°. During the experiment, a counterpart would press down the left ankle, and the participants were asked to continuously push back with maximum force possible. Participants performed a total of three isometric contractions of the left rectus femoris muscle with a duration of 60 s and a pause of 30 s in between each block  For a m. In patiPrior to the measurement, an ultrasound  was conducted by a qualified examiner (JM) to determine the longitudinal axis of the left rectus femoris muscle. Four optically pumped magnetometer (OPM)  were placed in line from distal to proximal along the longitudinal axis of the muscle, with a distance of 6 cm between each sensor. The first sensor was placed 6 cm proximal to the patella, and within 1–3 cm (mean distance 2.03 ± 0.65 SD cm) to the skin. The OPMs were held with a custom-built plastic frame attached to an aluminum structure. Utilized OPMs could record only two orthogonal components of the magnetic field vector at a time, Y and Z, respectively, the Y-axis being aligned to the longitudinal axis of the left rectus femoris muscle, and Z representing the orthogonally perpendicular component of the magnetic field  and its included EEG channels for EMG data. Both the OPM and sEMG data were sampled at 2,343.8 Hz. The utilized OPMs provide a magnetic field sensitivity of 15 fT/Hz and a bandwidth of 3–135 Hz, an operating range below 200 nT, and a dynamic range of a few nT. To adapt to a non-zero magnetic background field, the sensors are equipped with internal compensation coils  to canceDuring maximum contraction, single muscle fibers are firing at different frequencies and amplitudes, which overlap. Electrophysiologically, the interference patterns of many muscle fibers and many different frequencies can be recorded. The interference was qualitatively evaluated by experienced clinicians (JM and MSB), referring to density and amplitude. In healthy individuals, this interference pattern is dense, and amplitudes are of similar sizes; in neurogenic patients, the interference pattern is expected to be dispersed and to have high amplitudes .Data preprocessing was performed using Matlab R2019b . In addition, the FieldTrip toolbox  was usedn = 309 windows for HC, n = 8 windows for MC, n = 13 windows for ATTR, and n = 11 windows for CMT2.For both healthy controls and patients, periods of contraction in the sEMG and OPM recordings were manually selected. Then, these data segments were divided into 3 s non-overlapping windows. To characterize the signal properties in each of these windows, two parameters in the time-frequency domain were calculated. After calculation of our parameters, outliers were removed using the function “rmoutlier” in Matlab. These are the power spectral density (PSD) in the interval 20–100 Hz, where we consider most of the muscle activity to take place, and the signal standard deviation (SD) as a proxy for signal variability. For the calculation of the discrete Fourier transform, we used the “fft” algorithm implemented in Matlab. Altogether, we extracted p ≤ 0.05. In the case of statistical significance, a multiple comparison test was performed to identify differences between the groups using the “multcompare” function in Matlab. Bonferroni correction for multiple comparisons for n = 6 different contrasts was applied setting the significance level to p ≤ 0.008.The low number of windows extracted from our patients prevented us from verifying whether our extracted parameters were normally distributed. Therefore, we performed the Kruskal–Wallis test. We compared PSD and SD between groups  and within sensors . This resulted in a total of six tests. The tests were considered statistically significant if In total, we analyzed a set of 1,260 s (180 s in each of the seven subjects) for HC, 38.23 s for MC, 52.35 s for ATTR, and 55.98 s for CMT2.We visually compared the timeline of the signal of the sEMG and OPM-MMG between the HC and the three neuromuscular patients. Differences were most pronounced in the severely affected ATTR, especially in OPM Y, and to a smaller extent in OPM Z see . The intp < 0.001], OPM Y , and OPM Z  recordings  = 32.98, p < 0.001], and OPM Z . See First, we performed a general analysis, which revealed that PSD was different between our groups in the EMG [H(3) = 47.28, cordings . SD was p < 0.001). PSD in the OPM Y was higher in HC compared to CMT2 (p < 0.001), and PSD in the OPM Z was higher in HC compared to ATTR (p < 0.001) and to CMT2 (p < 0.001). For descriptive information regarding the median and interquartile range (IQR) of PSD, see Reduced PSD was detected in both patients with neurogenic muscle damage (ATTR and CMT2) compared to HC. Especially in ATTR, this correlates with reduced muscle mass due to progressive atrophy. PSD in the EMG was higher in HC compared to ATTR (p < 0.001). In the OPM Y, SD was higher in HC compared to CMT2 (p < 0.001), and higher in ATTR compared to CMT2 (p < 0.001). The same patterns were observed in the OPM Z. For detailed information regarding the IQR of SD, see In OPM-MMG, both patients with neuropathic muscle damage (ATTR and CMT2) showed a marked reduction in the variability of the power spectra, indicated by the very narrow SD. In the EMG, SD was higher in HC compared to ATTR  of neurogenic muscle damage can already be visualized by a simple one-channel sEMG , giving To gain information about the single motor unit, more complex methods, i.e., high-density sEMG , are neeFurthermore, as stated above, OPM is not dependent upon tissue conduction and can measure the electrical activity of deeper sections of the muscle. Besides a more representative measurement of pure muscle activity, it is also helpful to detect deep muscle fasciculations, i.e., ALS, and also might potentially be used for a more accurate motor unit number estimation (MUNE).We hypothesized that OPM-MMG is a non-invasive method for detecting pathological changes in muscle activity in neuromuscular patients. Therefore, we designed this proof-of-principle study including only three patients, nevertheless paving the way for additional studies in a larger number of patients, including early-and late-state patients with neuromuscular muscle damage. We also wanted to address the aspect that, besides the necessity of large studies gaining standard values, finding a diagnosis is always an individual process dealing with data from only a single patient. Besides the option of replacing conventional nEMG with a non-invasive method, new, and objective parameters might also be developed to detect early and subtle changes in muscle activity.The patient MC served as a quasi-non-neurogenic control patient, and we did not expect any of the typical changes in neurogenic muscle damage. Visual inspection of the interference pattern revealed a dense pattern with uniform amplitudes, and SD did not show significant differences between HC and MC. However, statistical analysis of the PSD revealed a significant difference between HC and MC in EMG, which was reduced in MC. The differences are not powerful and on the margin of significance but might be due to subtle weakness. Unfortunately, we did not integrate force measurements in this paradigm, an aspect to be addressed in future studies, and might even provide further information about the correlation between clinical and electrophysiological changes.As previously elaborated, the MMG signal originates from the ionic current of multiple muscle fibers. However, muscle fibers are not always arranged in parallel, but, depending on the examined muscle, can also be fusiform, convergent, or even circular, affecting the signal and causing interference phenomena. Based on the anatomy of the examined muscle, a geometric source model might be established (work in progress), comparable to modeling methods being used in MEG/EEG, to delineate individual sources, i.e., single muscle fibers, contributing to the signal. Besides this aspect, the signal is also secondarily dependent on the distance between the source and the sensor. The pure contraction of the muscle alternates this distance and, due to the muscle belly, even causes differences between the individual sensors. A standardized measure of the distance between the muscle and source needs to be established.The spectral bandwidth of physiological muscle activity ranged from approximately 20–300 Hz. Due to the physical properties of the sensors, sensitivity and bandwidth behave in an opposite way, with high sensitivity of the magnetic field narrowing the bandwidth, and with a broad measurable bandwidth reducing sensitivity. In our experiment, we decided to use OPM sensors combining a high sensitivity of the magnetic field (15 fT/Hz) and a bandwidth located in the lower frequency spectrum (3–135 Hz), where we expected most muscle activity to be located, however, limiting the detection of high frequency muscle activity. The balance between sensitivity and bandwidth is one of the main limitations of the application of magnetometers in MMG. Furthermore, OPM sensors are limited to recording only two orthogonal components of the magnetic field vector at a time (Y and Z, OPM sensor coordinates, In this proof-of-principle study, we introduced OPM-MMG as a non-invasive method to detect neurogenic muscle damage in patients. As we demonstrated, it is not only possible to adapt visual-qualitative analyses, but also to establish new parameters by using standardized analysis algorithms that offer quantitative evaluation. The small sensor size and the option of only small shielding devices needed for the limbs might help manage the transition from purely scientific to the clinical application of MMG.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by Ethik-Kommission der Universität Tübingen. The patients/participants provided their written informed consent to participate in this study.LS conceptualized and conducted the analysis, prepared the figures, and drafted the manuscript. MSB prepared the figures, drafted the manuscript, and supervised the work. JM performed the recordings, drafted the manuscript, and supervised the work. TM provided and set up the OPMs and revised the manuscript. DS helped to conduct the study and revised the manuscript. SB, HC, AG, HL, PM, CK, CB, PB, and MS revised the manuscript. All authors read and approved the revised manuscript.


A biopsychosocial rehabilitation is recommended for chronic nonspecific low back pain (CNLBP); however, its effectiveness compared to the traditional supervised exercise therapy of CNLBP treatment is still unclear.n = 59), supervised group-based combined exercise therapy and education , and a control group receiving usual care (n = 58). Interventions were administered for 4 weeks (8 sessions). The primary outcome was pain intensity. Outcome measures were collected baseline, after interventions (4 weeks), and during two follow-up periods (3 and 6 months).This was a parallel-group randomized controlled clinical trial. The sample consisted of 180 participants of both sexes, aged ≥18 years, with CNLBP for ≥3 months. Using web randomization and concealed allocation, they were assigned to three groups; graded activity receiving cognitive-behavioral therapy, group-based combined exercise therapy and education , as well as SET compared with the control group , without significant difference between two intervention groups. At 3 and 6 months of follow-up, GA had a statistically significantly better effect in reducing pain, disability and fear-avoidance beliefs, and improving spinal extensor endurance, range of extension and quality of life compared to SET and the control group. A statistically significantly better effect of SET compared with the control group was found in reducing pain, disability, fear-avoidance beliefs, and improving the physical component of quality of life. Harms were not reported.After the intervention, GA had a significant large effect on pain reduction compared to the control group .The online version contains supplementary material available at 10.1186/s12891-022-05908-3. Low back pain (LBP) is a major public health problem worldwide; it has been a leading cause of population disability for decades . The mosExercise therapy (ET) is an evidence-based intervention for CNLBP , 9. The Several ET interventions were endorsed in clinical guidelines, including supervised exercise therapy (SET), and graded activity (GA) exercises, among others .SET is a well-known physical therapy intervention. It is carried out under the direction and supervision of a physical therapist. It uses a pain-contingent and practice-centered approach, which focus on physical pathology and addressing pain symptoms and physical impairments . There aGA is a biopsychosocial intervention that consists of combined exercises with a gradual increase in intensity based on quotas that are based on the actual functional capacity of the patient and the ability to meet the goals set in the patient-therapist collaboration. In GA, the approach is time-contingent, instead of pain-contingent, combined with cognitive-behavioral principles, with the main goal to increase activity tolerance through an exercise program during which negative pain-related behavior is neglected, and positive behavior strengthened –18. ThisSystematic reviews (SR) from 2010 and 2016 reported no difference in the effectiveness of GA and ET in the short, medium, and long-term follow-up periods. Furthermore, there is also limited evidence that GA is more effective than the control group  in reducing pain, disability, catastrophizing, and quality of life. However, those findings were based on limited, low-quality and heterogeneous studies, which could have affected the results , 24.Given this state of evidence, the main goal of this study was to compare the effectiveness of SET and GA in the treatment of CNLBP on pain intensity, disability, the range of spinal movement, the strength of the spinal extensor muscles, the degree of depression and anxiety and the quality of life in the period immediately after the intervention (4 weeks), and in the 3rd and 6th month of follow-up.This was a parallel-group prospective randomized controlled clinical trial (RCT). This study was approved by the Ethics Committee of the Health Center of Mostar, Mostar, Bosnia and Herzegovina (No: 4458-37-2004/18). Only participants who signed informed consent were included in the study. The study protocol was registered at Clinicaltrials.gov . All methods were performed in accordance with the Declaration of Helsinki and the trial was reported based on the Guidelines for Consolidated Standards of Reporting Trials (CONSORT).The study took place from July 2019 to March 2020.Recruitment of participants was conducted over 5 months in the primary medicine setting, among outpatients. Eligible participants were adults of both sexes, aged ≥18 years, suffering from CNLBP lasting ≥3 months and with a feeling of pain most days of the week; diagnosis of CNLBP was confirmed by a family medicine specialist. Participants had to have minimum pain intensity of 40 on the visual analog scale (VAS) ranging from 0 (no pain) to 100 (worst pain). Additionally, participants had to agree to avoid any physical therapy treatments during the study period, except those prescribed by the lead investigator. Eligible participants were either newly diagnosed with CNLBP or those diagnosed with CNLBP in the participating primary care clinic in the last 6 months.The exclusion criteria were: other subtypes of LBP, history of spine surgery, the presence of other comorbidities , and participation in an ET program in the past 6 months.Randomizer.org (www.randomizer.org). Generated numbers were exported in Microsoft Excel. Allocation concealment was done by a blinded family medicine specialist who determined the participants’ eligibility and enrolled participants in the trial, without knowledge of which code was linked to which intervention.Sequence generation randomization was conducted using the random number generator on the website Implementation: Random sequence was generated by the lead investigator (AH). Three sets of unique numbers, one set for each group, were generated . The meaning of numerical codes  was known only to the lead investigator. A numerical sequence with the randomized numbers from 1 to 180, divided into three sets, was sent to the family physician, who conducted allocation concealment. The patient considered eligible was assigned a sequential number, and the family physician followed the randomization sequence to see to which numerical code  the patient was assigned. The family physician informed the lead investigator (AH) that a new patient was assigned to a certain numerical code. Then, the lead investigator contacted participants and scheduled participant enrollment, depending on the group in which participants were assigned.Participants of intervention groups and physical therapists could not be blinded due to the nature of the interventions of ET. To minimize potential bias, participants and physical therapist in the SET group were not provided with more detailed information about the type of intervention in the GA group ; they only knew that the exercises were applied in the other group as well. Measurements were conducted by the outcome assessor (IB), who was blinded to the nature of the intervention, the study hypothesis, and participants’ allocation per group to prevent observer bias during the collection of performance-based measures . Observer bias could not be applied to self-reported measures since the participants were evaluators, and they could not be blinded to the interventions.http://www.stat.ubc.ca/~rollin/stats/ssize/, for comparing means for two independent samples; All sample size calculations were checked with the GPower program (Version 3.1.9.4.), using t-test; Means: the difference between two independent means (two groups). Based on the post-treatment results of this study  . Th= 0.146) . The res= 0.146) . ParticiBaseline participants’ characteristics are shown in Table p = 0.508), baseline pain , as well baseline disability .In the post-intervention measurement, 3 participants 1.7%) were lost, in the 3-month follow-up 9 (5%) participants, and in the 6-month follow-up 16 (8.9%) participants. The flow of participants throughout the study was shown in Fig. .7% were The graph of results of the primary outcome (pain intensity) is shown in Fig. At baseline, there were no significant differences between the groups in the primary outcome and the secondary outcomes. None of the participants reported adverse effects of treatment.Both intervention groups had a large significant effect in reducing pain compared to the control group in all repeated measurements Fig. , Table 3p < 0.0001).Significant group-time interaction was also found for all secondary outcomes , while in other psychosocial outcomes there was no significant difference. However, in the follow-up period, more significant GA effectiveness was found in both quality of life components (SF 12) and beliefs about how physical activity and work affected their LBP (FABQ) (See Table p = 0.829).In satisfaction with the intervention and economic cost-effectiveness, there was no significant difference between GA and SET Table . BesidesThe results of this study indicate that both intervention groups, GA and SET, were more beneficial than the control group in reducing pain and disability, as well as other outcomes in the treatment of CNLBP. Immediately after the intervention, there was no difference between the two intervention groups in reducing pain and disability. However, in the follow-up period, GA was more beneficial than SET.A recent Cochrane systematic review  reported moderate-certainty evidence that exercise therapy is probably effective in treating chronic low back pain compared to no treatment, usual care, or placebo for pain. However, the authors concluded that the observed treatment effect of exercise on pain and functional limitation was small and not clinically important. Adverse effects of exercise treatment were seldom reported; they mainly included increased low back pain and muscle soreness . In our A significant effectiveness of both interventions, GA and traditional exercise therapy, on reducing pain and disability, but with the better clinical effect of GA immediately after interventions  was reported by Khan et al. in 2014 . HoweverMagalhaes et al. reported that there was no significant difference between GA and group-based ET in pain, disability, quality of life and other relevant outcomes immediately after interventions , as well as at 3 months and 6 months follow-up , 50. HowSeveral SRs reported that different ET might have a different effect on treatment outcomes in CNLBP , 51–53. The beliefs and attitudes of the therapists who performed the interventions may have a potential impact on the outcome. In recent years, there has been a shift in the field of physical therapy and rehabilitation from a biomedical and practitioner-oriented approach to a biopsychosocial and person-centered approach , 54. In In our study, GA was performed by experienced MPT with the current knowledge of back pain and pain pathway. Positive beliefs of the biopsychosocial model were assessed with the Pain and Attitudes and Beliefs Scale for Physiotherapists (PABS-PT). The MPT also underwent practical training to implement GA 4 months before the start of the study. We ensured that one MPT performed interventions each, one for SET and the other for GA. Also, to more clearly determine the effectiveness of both intervention groups, we formed a third, “control” group.We were motivated to conduct this study due to unclear or insufficient evidence about the studied interventions reported in earlier SRs , 56. ForEducation about pain and its assessment, according to the principles of the biopsychosocial approach, improve the therapeutic alliance (therapist-patient relationship), which can also have positive effects on the outcomes in painful conditions , 58. In In any case, comparing GA and traditional exercise therapy requires additional, high-quality studies. During the design of future studies, the attitudes and beliefs of physical therapists should be considered and measured . Likewise, as a direction for future studies, Foster and Dellito (2011) state that regardless of advances in understanding the psychosocial aspects of LBP management, several study directions can make a significant contribution in this area. The recommendations include, for example, a clear set of variables to accurately identify patients in need of more intense and comprehensive management, clearly establishing which psychosocial factors are most appropriate as prognostic factors, treatment effect modifiers, and treatment mediators, accurate and systematic psychosocial screening protocols that are feasible for use in clinical practice, evidence on approaches to better target treatment interventions using more defined dosages and high-quality studies that test education strategies at both entry and postgraduation levels . The devThis randomized trial had high internal and external validity; in designing our study, we used methods that reduced the risk of bias, and we reported interventions in a detailed and transparent manner. Thus, our interventions should be reproducible. Our results could change the findings of future SR regarding the benefits of biopsychosocial approach in physical therapy. This study also had a high participant completion rate, and it included both short-term and intermediate-term follow-ups. The limitation of the study is the duration of the intervention (4 weeks). Future studies should explore the effect of long-term interventions described in this study. Also, an effect beyond 6 months was not measured in this study. We presented results from the subgroups in results, but we would like to emphasize that the study was not powered for detecting differences between any subgroups. Furthermore, we did not use any outcomes regarding daily activities in our trial; thus, we cannot comment on functional connection with daily activities.This study suggests that graded activity and group-based supervised exercise therapy have beneficial effectiveness in the treatment of chronic nonspecific low back pain. However, graded activity has significant effectiveness in the follow-up period. Both interventions were more effective than usual care in patients suffering from chronic nonspecific low back pain. Future trials should investigate which of these two exercises therapy is superior.Additional file 1. Description of Graded Activity.Additional file 2. Program of exercise therapy in Supervised Exercise Therapy group and Graded Activity group.Additional file 3. Education intervention in Graded Activity and Supervised Exercise Therapy groups.Additional file 4. Recommendations of home-performance therapy exercises and instructions on proper posture during daily life activities in the control group.Additional file 5. Sociodemographic Questionnaire and Treatment Satisfaction Questionnaire.Additional file 6. Outcome measurement instruments.


Breast thickness showed a better correlation with all the mammography dose quantities than patient age, which showed a poor correlation. Moreover, a strong correlation was found between the calculated MGD and both the ESD (R2 = 0.929 for the CC view and R2 = 0.914 for the MLO view) and OD (R2 = 0.971 for the CC view and R2 = 0.972 for the MLO view). Furthermore, it was found that the MLO scan views yield a slightly higher dose compared to CC scan views. It was also found that the glandular absorbed dose is more dependent on glandularity than size. Despite being more reflective of the dose absorbed by the glandular tissue than OD and ESD, MGD is considered labor-intensive and time-consuming to estimate.Breast cancer is the leading cause of cancer death among women worldwide. Screening mammography is considered the primary imaging modality for the early detection of breast cancer. The radiation dose from mammography increases the patients’ risk of radiation-induced cancer. The mean glandular dose (MGD), or the average glandular dose (AGD), provides an estimate of the absorbed dose of radiation by the glandular tissues of a breast. In this paper, MGD is estimated for the craniocaudal (CC) and mediolateral–oblique (MLO) views using entrance skin dose (ESD), X-ray spectrum information, patient age, breast glandularity, and breast thickness. Moreover, a regression analysis is performed to evaluate the impact of mammography acquisition parameters, age, and breast thickness on the estimated MGD and other machine-produced dose quantities, namely, ESD and organ dose (OD). Furthermore, a correlation study is conducted to evaluate the correlation between the ESD and OD, and the estimated MGD per image view. This retrospective study was applied to a dataset of 2035 mammograms corresponding to a cohort of 486 subjects with an age range of 28–86 years who underwent screening mammography examinations. Linear regression metrics were calculated to evaluate the strength of the correlations. The mean (and range) MGD for the CC view was 0.832 (0.110–3.491) mGy and for the MLO view was 0.995 (0.256–2.949) mGy. All the mammography dose quantities strongly correlated with tube exposure (mAs): ESD (R Breast cancer is reported as one of the leading causes of mortality for women worldwide . It has Thus far, mammography is considered the most effective means of early detection of breast cancer . With thMammography mean glandular dose (MGD), which is used synonymously with average glandular dose (AGD), has been widely accepted as the most appropriate measurement for predicting the risk of radiation-induced cancer . Most adIn addition to the ESD dose quantity reported by the mammography machine, organ dose (OD) is another dose quantity that is reported by mammography machines. However, MGD and OD are not the same. A strong significant difference between the MGD and OD was reported in .Estimate the MGD per view, breast thickness, and age group for every subject enrolled in this study,Evaluate the impacts of mammography acquisition parameters, age, and breast thickness on the estimated MGD and other machine-produced dose quantities using a multilinear regression model,Conduct a correlation study between the ESD and OD, and the estimated MGD for each image view,Compare the findings of this study with other studies conducted on samples selected from different demographic regions.Thus, it is important to have a good understanding and an accurate estimation of the parameters that can affect the glandular absorbed dose, as it provides an indication of the radiation risk to the breast during exposure. The objectives of this paper are as follows:The proposed study was applied on breast screening mammogram images captured from the UAE population. All mammography screening examinations were performed using a Siemens Mammomat Inspiration . A dataset of 2035 mammograms from a cohort of 486 subjects with an age range of (28–86 years) who underwent screening mammography examinations was collected from the University Hospital of Sharjah, UAE, and retrospectively analyzed. This study was approved by the Institutional Review Board (IRB) committee of our university and hospital ethics committees. Mammography acquisition parameters, including image view, number of views, target and filter combination, compressed breast thickness, ESD, organ dose, and other acquisition parameters (kVp and mAs), for all the patients were extracted from the digital imaging and communications in medicine (DICOM) headers and used in this study. The HVL for our Tungsten (W)/Rhodium (Rh) spectra was 0.45 mm Al. A dedicated ned from ,11 for e----found in  in a simThe MGD was estimated per view, breast thickness, and age group for every subject enrolled in this study using Dance et al.’s method ,11. The Multilinear regression models were built to quantify the impacts of mammography acquisition parameters, age, and breast thickness as input parameters on output parameters related to the mammographic organ dose. A linear equation representing the regression model assigns a scale factor  to each input parameter, with one additional coefficient  added to the equation. The input parameters considered in this work were the age of the patient, the compressed breast thickness, and the acquisition parameters, namely, X-ray tube voltage (kVp), exposure time (msec), exposure (mAs), and X-ray tube current (mA). The output parameters considered in this work were the entrance skin dose (ESD) and organ dose (OD), which were reported after each mammography scan in addition to the estimated MGD, as described in Equation (1). A regression model was estimated for output parameters individually. The multilinear regression model could be represented as a function of the input and output parameters, as follows:Moreover, the individual correlations between each of the input parameters and each output parameter (dose quantity) were assessed by fitting each pair of these input and output parameters to a linear regression model, as shown in the equation below:The correlations between different mammography dose quantities, namely, machine-provided OD and ESD and calculated MGD, were also investigated. To achieve this purpose, the individual correlations between these dose quantities were assessed by fitting each pair of them to a regression model similar to what was proposed in Equation (3).R2), mean square error (MSE), mean absolute error (MAE), and mean absolute percentage error (MAPE). The coefficient of determination, or R-squared  Digital Mammographic Imaging Screening Trial (DMIST) reported an average MGD of 3.7 mGy from two-view digital mammography (1.86 mGy per view) . Herein,2 = 0.315 and 0.351 for the CC and MLO views, respectively). The positive correlation between MGD and compressed breast thickness demonstrated in the present study has been illustrated in previous studies. Riabi et al. [p < 0.01). Du et al. [Breast compression seemed to contribute to MGD. i et al.  showed au et al.  also repu et al.  analyzedu et al.  reportedp < 0.05).Age also seemed to be a factor that could impact MGD, as it was associated with glandularity and density. Herein, we observed a lower MGD for subjects 64 years and older. Similar findings were reported by Pwamang et al. , where p2 = 0.980 and R2 = 0.972 for CC and MLO, respectively) were seen between the MGDs and the mAs. Weak correlation  were also seen between the MGDs and the applied kVp. These results are in agreement with the results reported by Riabi et al. [p < 0.01) was seen between the MGD and each of the applied kVp and mAs amounts, with a correlation coefficient of 0.829 between MGD and kVp and of 0.890 between MGD and mAs.Image acquisition parameters such as kVp and mAs seemed also to impact the resulting MGDs, with X-ray tube current showing a substantial impact comparing to tube voltage (kVp). Strong correlation . Patients with radiation dose values above the diagnostic reference value had large breasts of dense composition.Baek et al.  conducte2 = 0.929 for the CC view and R2 = 0.914 for the MLO view) and OD (R2 = 0.971 for the CC view and R2 = 0.972 for the MLO view). This also showed that OD had a stronger correlation with MGD despite the strong significant difference between MGD and OD that was reported by Suleiman et al. [To our knowledge, limited studies have investigated the correlation between OD and MGD, with most studies focusing only on ESD and MGD ,21. UsinThis study proposes an estimation and good understanding of parameters that could affect the glandular absorbed dose. The MGD was estimated per view, breast thickness, and age group for every subject enrolled in this study. Moreover, an evaluation of the impacts of mammography acquisition parameters, age, and breast thickness on the estimated MGDs and other machine-produced dose quantities using a multilinear regression model was conducted. Furthermore, a correlation study between the ESD and OD, as well as the estimated MGD, for each image view was discussed. This retrospective study was conducted on mammography scan data for subjects who underwent screening mammography examinations. The findings of this study were compared to the findings of other studies conducted on samples selected from different demographic regions. It was found that the mean MGD for the MLO view was slightly higher than that of the CC view. The findings of the regression analysis showed that all the mammography dose quantities, namely ESD, OD, and MGD, were strongly correlated with tube exposure (mAs). However, patient age showed poor correlation with all the mammography dose quantities. Breast thickness showed better correlation with all the mammography dose quantities compared to patient age. Moreover, it was found that there was a strong correlation between the calculated MGD and the ESD and OD values reported by the mammogram unit, with OD showing a stronger correlation with MGD.