Participants used a triaxial accelerometer for 4–7 days to obtain MVPA. Mediation analyses were performed considering the CRF as a mediator, MVPA as an independent variable, and FVC and FEV1 as dependent variables with adjustment for age, sex, and cardiovascular risk score. We aimed to investigate the total (path c) and direct  effects through the regression coefficients. We also examined the indirect effect, which was obtained from the product of the coefficients (path ab). Our sample was composed mainly of overweight and middle-aged women. MVPA was positively related to CRF (path a), as well as CRF and lung function (path b). MVPA also presented a significant positive total effect (path c) in the lung function. However, this relationship became non-significant when CRF was included in the model for both FVC and FEV1 (path c’). We did not observe a direct effect of MVPA on the lung function. In contrast, the indirect effect was significant (path ab). Lastly, CRF mediated 60% of the total effect of MVPA on FVC and 61.9% on FEV1. CRF mediates the relationship between lung function and MVPA in asymptomatic adults. Therefore, our results reinforce the need to include CRF assessment in practice clinical routine and suggest that strategies focusing on CRF might be more promising to prevent respiratory diseases in adults.We investigated whether cardiorespiratory fitness (CRF) mediates the association between moderate-to-vigorous physical activity (MVPA) and lung function in asymptomatic adults. We examined the cross-sectional results of 1362 adults aged 18–80 years from the Epidemiology and Human Movement Study. Participants were submitted to spirometry to obtain forced vital capacity (FVC) and forced expiratory volume in 1s (FEV1). Additionally, we used cardiopulmonary exercise testing to obtain peak oxygen uptake ( Since the prevalence of physical inactivity has increased worldwide ,2, the l2) and provides other equally relevant clinical measures [Only a few studies directly obtained MVPA and CRF, which introduce potential biases for the generalizability. Cardiopulmonary exercise testing (CPET) is the gold standard to obtain CRF , and the underestimating of causal effects  . DespiteMediation analysis emerges as an alternative for understanding these possible mechanisms and contributes to establishing the cause-and-effect, regardless of study design . AccordiWe conducted a cross-sectional study from 2013 to 2016 with a convenience sample selected from the Epidemiology and Human Movement Study (EPIMOV Study). The EPIMOV Study is a prospective cohort study whose main purpose is to investigate the association between low PA and fitness levels and the development of chronic diseases, especially cardiovascular and musculoskeletal diseases .Subjects from both sexes, aged 18 to 80 years and free from previously diagnosed pulmonary, cardiovascular, musculoskeletal, or neuromuscular diseases, were recruited through advertisements in social media, local universities, and newspapers. The EPIMOV Study excluded subjects with recent respiratory infections, abnormalities during CPET or spirometry, and refusal to participate. In the present study, we included only participants with valid triaxial accelerometry data. Participants with difficulty in comprehending or performing the study protocol or those with alterations or operational problems during the CPET  were excluded. All participants provided written informed consent before participation. The Ethics Committee of the Federal University of São Paulo approved the present study (#186.796).The EPIMOV Study protocol was performed during two visits a week apart. On the first visit, we carried out a clinical health screening followed by an anthropometric evaluation, and CPET . Lastly, we provided instructions for triaxial accelerometer-based habitual PA level  during 7 consecutive days starting from first visit. On the second visit, participants returned the devices. Then, they underwent body composition assessment , among other measurements from EPIMOV Study protocol, including isokinetic muscle function and a six-minute walk test. The first and second visits were located at Angiocorpore Cardiovascular Medicine Institute and EPIMOV Laboratory, respectively. In the present study, we analyzed the results of the following assessments.Participants underwent a clinical health screening, including age, sex, educational level, long-term use of medication, and current diagnosis of diseases. Then, we obtained risk factors for cardiovascular disease by self-report as follows: age , family history of cardiovascular diseases , arterial hypertension, diabetes, dyslipidemia, obesity, and current smoking. Lastly, we calculated the 10-year cardiovascular risk score (CVRS) based on sex, age, BMI, systolic blood pressure (treated and untreated), smoking, and diabetes as recommended ,28.2.We obtained height (m) and weight (kg) using a digital scale with a stadiometer. Then, we calculated body mass index (BMI). Participants were classified as obese when BMI > 30 kg/mWe determined body composition through the bioelectrical impedance  according to previously described . We calcSpirometry was performed using a calibrated spirometer  according to the criteria established by the American Thoracic Society . We obta2 max predicted by using the Vivacqua and Hespanha equation [2 max, on average, in 10 min. We obtained ventilatory, cardiovascular and metabolic variables breath-by-breath using a gas analyzer  and a 12-lead ECG  during the test. The data were filtered every 15 s for further analysis. The peak 2 was considered the average value obtained in the last 15 s at the peak of the incremental exercise, being expressed as an absolute value (mL/min), corrected by weight (mL/min/Kg) and as percentage of predicted (% pred.) [Participants were submitted to a CPET on a treadmill under a ramp protocol . Initially, the participant remained at rest period for 3 min followed by an individualized incremental protocol. Briefly, speed and grade started at 3 km/h and 0%, respectively, and were automatically increased in a linear and individualized way based on equation . The pre% pred.) ,35. 2) > 1.0 [We discontinued the test in cases of potentially lethal arrhythmias, hyperreactive systolic blood pressure response , signs or symptoms suggestive of myocardial ischemia, or the participant’s request. The tests were considered as maximal effort when they filled at least two of the following parameters: heart rate ≤ 10 bpm under the maximal heart rate predicted or 5% under than the value obtained with the equation (220-age), respiratory exchange ratio (carbon dioxide output/2) > 1.0 ,37.We evaluated the PA level through triaxial accelerometers  previously validated ,39,40. PThe thresholds for the sedentary behavior and the intensity of PA were as follows: sedentary behavior ; light-intensity ; moderate-to-vigorous . We considered those participants with less than 150 min per week of MVPA or less than 75 min per week of vigorous PA as physically inactive . Since tStatistical analysis was performed by using STATA, version 14. The data were analyzed descriptively and expressed as mean and standard deviation for continuous variables and as frequency and percentage for categorical variables. 2 (mL/min/kg) was used as a mediator, MVPA  as independent variable and FVC (% pred.) and FEV1 (% pred.) as dependent variables. We included age, sex, and Framingham CVRS as covariates. We estimated the total, direct and indirect effects of MVPA on lung function  was mediated by CRF. In the present study, the peak function . path c) and direct (path c’) effects through the regression coefficients and significance between each model’s independent and dependent variables. We also examined the indirect effect, which was obtained from the product of the coefficients (path ab)  . path c) represents the correlation between PA and lung function without considering the mediating potential. After the structural equation modeling elaboration, which considered the CRF as a potential mediator, we can observe the effect a, which represents the correlation between the independent variable and the mediator . The effect b represents the correlation between the mediator and the dependent variable . After adjustment by confounders [path ab represents the indirect effect of PA on lung function, i.e., the effect mediated by the CRF in this example. The mediated effect is, simply, the multiplication of effects found in paths a and b. Therefore, the direct effect c’ represents the effect of the independent variable after considering the mediated effect, i.e., ab-c [The total effect ; (2) the independent variable (MVPA) has to correlate significantly with the mediator (CRF) (path a); (3) the mediator (CRF) has to correlate significantly with the dependent variable (FVC and VEF1); and (4) the mediation is complete when the direct effect c’ is zero and became non-significant when controlled by the mediator.Conducting a mediation analysis in the present study requires: (1) the independent causal variable (MVPA) has to correlate significantly with the dependent variable (FVC and VEF1)  and using full-information maximum likelihood, which allows valid inferences assuming that the data are missing at random.The mediation analysis was performed based on all available data (2), as well as calculating the values of the Comparative Fit Index, for which we consider values above 0.9 as evidence of adequate adjustment.In order to increase the statistical power of the multivariate models, we calculated the Framingham CVRS. We did a sensitivity analysis and, due to the strength of the correlation, we chose the CVRS as a covariate instead of inserting each cardiovascular risk factor. Briefly, CVRS expressed as a percentage can be calculated based on sex, age, SBP, treatment for high blood pressure, current smoking, diabetes, and BMI. Also, we checked the correlations between chosen covariates to avoid multicollinearity. Since we found no strong correlations among then, we were able to include age, sex and CVRS in the same model, despite the use of age and sex in the CVRS. Considering the fundamental influence of height on lung function variables, this was also considered for adjustment in the models in which FEV1 and FVC were the dependent variables. We evaluate the fit of the models by calculating the coefficients of determination of the equations (Rpath c’ was non-significant (approximately zero). As a general rule, a complete mediation is considered only if b/c > 0.80 and partial mediation in cases where the influence of the independent variable on the dependent variable (path c’) has been reduced, but still remains significant and different from zero to introduce the mediator [We evaluated model fit with the comparative fit index, where we considered values above 0.9 as evidence of adequate fit. Lastly, we used the Sobel–Goodman test to investigate the proportion of total mediated effects. Complete mediation was considered in the case where mediator . We set We considered 1592 participants eligible from the EPIMOV Study, but 1362  were included in the present study .Our sample was composed mainly of overweight and middle-aged women (46.7 ± 14.2 years). We observed a low prevalence of self-reported hypertension, but a high prevalence of physical inactivity and obesity. The prevalence of diabetes and current smoking was similar to values observed in the Brazilian population .Thirty-four percent of participants reported regular use of medication. The most commonly reported medications were classified as biguanides, betablockers, angiotensin receptor antagonists, statins, angiotensin converting enzyme inhibitors, and thiazide diuretics.2 pred., suggesting exercise tolerance and regular-to-good CRF. Regarding CPET data, we included in our analysis only valid and maximal tests. According to sex, males presented peak 2, on average, 40.1 ± 11.0 and females, 26.7 ± 8.5. Maximal heart rate was, on average, 171 ± 16 (94.6 ± 6.9% pred.) and 162 ± 19 (92.3 ± 7.9% pred.), respectively, for males and females. Lastly, the respiratory exchange ratio was higher than 1.0 for both males and females . As can be seen in n = 368, 27%). The PA level in detail can be seen in Among our participants, we obtained 1040 (76.3%) valid accelerometry data. Almost 30% of our sample was classified as physically inactive (path a) in both A and B. In turn, CRF was associated with both FVC (A) and VEF1 (B) (path b). MVPA also presented a significant positive total effect (path c) in FVC (A) and VEF1 (B). However, these relationships became non-significant for FVC (A) and FEV1 (B) (path c’) when controlled by CRF. Therefore, we did not observe a direct effect of MVPA on the lung function (path c’). In contrast, the indirect effect was also significant (path ab) in A and B. Lastly, the Sobel–Goodman test confirmed that CRF mediated 60% of the total effect of MVPA on FVC and 61.9% on FEV1  and lung function or even between sedentary behavior and lung function remains unknown and could be further addressed.CRF mediates more than 60% of the relationship between MVPA and lung function in asymptomatic middle-aged adults. Preventive strategies that prioritize CRF may be more promising to prevent respiratory diseases and reinforces the importance of adding the CRF assessment in clinical practice routine. Future studies should address this mediation prospectively.


In Europe, meningococcal (Men) vaccines are available against 5 of the 6 serogroups responsible of nearly all cases of invasive meningococcal disease (IMD). Meningococcal vaccination has been introduced in the national immunization programs (NIPs) for children and adolescents of numerous European countries, but with no consistent strategy across countries.To describe IMD epidemiology, NIPs, and vaccination coverage rates (VCRs) in children and adolescents in 8 Western European countries.Epidemiological data (from 1999 to 2019), NIPs regarding meningococcal vaccination status, and VCRs were collected from the European Centre for Disease Prevention and Control (ECDC) and/or national websites.via MenC only (countries: N = 3), MenACWY only (N = 2), or MenC (infants/children) and MenACWY (adolescents) (N = 3) vaccination. VCRs were higher in children than adolescents.MenB was the most common serogroup. In Belgium, Spain, France, the Netherlands, the United Kingdom (UK), and Portugal, incidence was greater for MenW than MenC. In 2019, MenB risk was covered in 2 countries . MenC risk was covered in all countries, Our study confirmed the diversity of NIPs, including in neighboring European countries with similar factors like economic resources and epidemiological risk, thus indicating that other factors underlie NIPs. Convergence toward a more common immunization program including MenACWY and MenB vaccination would promote equity and safe travel regarding infectious diseases for young people, and possibly improve the understanding of vaccination by patients and healthcare professionals. With 3,233 confirmed cases in European Union/European Economic Area (EU/EEA) member states (30 countries) and 324 deaths in 2018, invasive meningococcal disease (IMD) is an uncommon but life-threatening disease  in developed countries are usually highest in infants <1 year), followed by toddlers (1–4 years), with a second peak in young people 15–24 years)  or multivalent (MenACWY) formulations. Protein-based vaccines have been developed for MenB, because the MenB capsular polysaccharide was too similar to human neural adhesion molecules to be used as a vaccine antigen. A MenB vaccine made from 4 common proteins found on the surface of MenB meningococcal bacteria, combined with the outer membrane vesicles (OMV) from 1 MenB strain, was approved in Europe in 2013  reviewed NIPs for the 4 main disease-causing serogroups  in France and surrounding EU countries, in relation to epidemiology. Vaccination coverage was analyzed, as achieving a high VCR is the key to effective vaccination programs.via carriage prevention in adolescents, and/or presumed upcoming changes in IMD epidemiology.Each vaccination strategy was assessed in terms of direct protection against the most frequent serogroups in the appropriate age groups (children and adolescents), indirect protection objectives (herd immunity) The following countries were selected: Belgium (BE), Germany (DE), Spain (ES), France (FR), Italy (IT), Portugal (PT), the Netherlands (NL), and the UK (UK).Selection criteria comprised: (i) EU member in 2019, which facilitated data collection; (ii) geographically situated around France, which facilitates interactions that could lead to similar epidemiologies, and (iii) similar per capita gross domestic product (GDP), to avoid bias linked to economic factors influencing recommendations. Luxembourg, which is an EU member neighboring France, was excluded due to its exceptionally high per capita GDP  .The Eurostat database was used to collect economic and demographic data for selected countries .The latest epidemiological data were obtained from the ECDC website; the ECDC monitors infectious diseases for the EU member states, including for the UK until 2018. NIPs for meningococcal vaccination were obtained from the ECDC and the national UK websites , 23. VCREpidemiological data from 1999 (date of the introduction of the conjugate MenC vaccine in the UK) to 2019 (before the COVID-19 pandemic) or the latest available data for national meningococcal vaccination recommendations and VCRs were collected for each of the 8 countries.In 2019 , all countries belonged to the EU-28. Altogether, they included about two-thirds of the EU population, being some of the most highly populated countries. Their per capita GDP was close to the EU-28 average, ranging from €18,670 (PT) to €41,980 (NL). Based on demographic indicators and as compared with other selected countries, Spain and Italy had the oldest population and lowest crude birth and infant mortality rates .In 2019, in the EU/EEA member states, the IMD NR was 0.57/100,000: 7.24/100,000 for infants, 2.00/100,000 for toddlers, and 0.88/100,000 cases for young people.N = 28), France (N = 45), and the UK (N = 51)  . Since 2(N = 51) . The NR (N = 51) . NR shar(N = 51) . In 2019(N = 51) . No MenCWith an NR of 0.10/100,000, W was the second most frequently reported serogroup in Europe. The highest NR was reported in the Netherlands  and the lowest in Italy  . MenW NRMenY NR averaged 0.06/100,000 in 2019 in Europe, ranging between 0.04/100,000 and 0.15/100,000. The annual MenY NR remained low over time in the studied countries, with only slight variations over time ; howeverRoutine meningococcal prevention strategies were introduced between 1999 and 2012, starting with MenC vaccine. Routine strategies were then updated on 1 occasion in 3 countries , 2 occasions in France and Portugal, 3 occasions in Spain, and 4 occasions in the UK. The German strategy has remained unchanged since its introduction in 2006 .Meningococcal C vaccines were introduced in the late 1990s early 2000s, first in the UK then in Belgium, Spain, and the Netherlands . At the MenB recombinant protein vaccines were first introduced in the UK in 2015 and then in Italy in 2017 . At intrAs a result of increased MenW incidence worldwide, including Europe, several countries used quadrivalent MenACWY vaccines . The UK via MenC monovalent vaccines for infants (FR) or toddlers  with no adolescent program, 3 with a mix of MenC for infants (ES) and toddlers and MenACWY for adolescents , and 2 via MenACWY vaccines for toddlers and adolescents   .In 2021, in countries with only MenC programs, by the age of 24 months (2 years), 91% and 80% of children were vaccinated with MenC conjugate vaccine in France and Germany respectively. In Germany, 90% of 4–7-year-old children were vaccinated against MenC. In Portugal, in 2019, the VCR was 99% in 2-year-old children .via a MenACWY vaccine. Finally, in Italy, 79% of children aged 24 months were vaccinated against MenC, including 47% via a MenACWY vaccine. Regarding adolescents, in the UK, 87% of adolescents received a MenACWY vaccine in 2019. In Spain and the Netherlands, NIPs were updated from C to ACWY vaccine that same year, with a catch-up program for the latter: 89% of adolescents in Spain were vaccinated against MenC (including 13% via a MenACWY vaccine); 86% of adolescents in the Netherlands received a MenACWY vaccine. Finally, in Italy, 75% of adolescents aged 16 but 58% of 18-year-olds received a MenACWY vaccine.In 2019, in countries with MenACWY vaccine programs, 91% and 94% of 2-year-olds received MenC vaccine in the UK and in Spain, respectively. In the Netherlands (where 2019 was the year of the NIP update from MenC to MenACWY), 93% of toddlers were vaccinated against MenC, including 9% Regarding MenB, in 2019, 69% and 90% of children aged 24 months were vaccinated in Italy and the UK, respectively. No data were available for Portugal or France, as vaccination was not introduced until 2020 and 2022, respectively.The WHO “Defeating meningitis by 2030” global roadmap aims to reduce cases of vaccine-preventable bacterial meningitis by 50% and deaths by 70% . AlthougIn Europe, there is no uniform IMD immunization program except in epidemic situations . In somein the UK resulted from epidemiological considerations, starting in November 1999, facing high fatality rates due to the rapid expansion of a hypervirulent clone belonging to cc11. The NIP included a 3-dose vaccination schedule  without booster dose, and a catch-up campaign (1 dose in children aged 1 to 18 years and then up to 25 years). The VCR reached ≈85% (88% for infants and 96% for children) within 18 months following the start of the vaccination campaign, and MenC incidence decreased by more than 80% in the targeted population  of all 14-month-old toddlers and a catch-up campaign for all 1- to 18-year-old children, in order to target the meningococcal reservoir age group (adolescents). VCR rapidly reached 94%, and a 92% reduction in MenC incidence (99% in children aged between 1 and 18 years) was observed 2 years after introduction of MenC vaccination in the NIP. The decreased MenC IMD incidence in children aged <1 year (-92%) and >18 years (-80%) also supported a collective protective effect beyond the targeted population (herd immunity). This drastic NIP impact was attributed to the high VCR, particularly in adolescents, who are the reservoir for meningococcal carriage  was below the level expected to trigger introduction of IMD vaccination in the NIP. A few years later, thanks to the vaccination programs, MenC incidence had decreased in most European countries, leaving France among the top countries for MenC incidence  and leading to the introduction of MenC vaccination in 2010  issued an interim position statement for consultation that did not advocate introducing MenB vaccine, based on cost-effectiveness evaluation  for all children by the National Health Authority. In February 2021, the National Health Authority recommended not changing the vaccination strategy, mainly because MenB cases were uncommon and based on the absence of epidemiological increasing trend and on an unfavorable cost-effectiveness analysis  and MenB (2017) vaccinations have been included in the NIP, although incidence of both serogroups is extremely low, suggesting that the Italian NIP program is more “preventive” than “curative” from a public health perspective.Non-epidemiological factors may also underlie NIPs. Reviewing methodologies, frameworks and decision-making processes for economic evaluations of vaccines, with a focus on evaluation of vaccines targeting IMD, Christensen et al.  showed taluation , whereasaluation . The decanalysis . Howeveranalysis . In thisanalysis , 44. Howanalysis , 45. In N = 29). In addition, in most countries, the vaccination schedule follows the school cycle; differences in school systems could explain the differences observed in the age groups targeted by the NIPs. Another limitation is the differences in governance between EU countries. NIPs are usually organized at national level, whereas the regional level tends to be in charge of overseeing implementation of vaccination and monitoring VCR  also decided to switch from MenC to MenACWY for toddlers (12–15 months). In Germany, the NIP has included MenC in toddlers since 2006 but, in the region of Saxony, the Saxon Vaccination Commission (SIKO: Sächsische Impfkommission) decided to switch to MenACWY for infants/toddlers, and has additionally recommended a booster for adolescents since January 2019. A similar stepwise approach is seen in Italy: since the authorization of MenB vaccine by the European Medicines Agency (EMA) in 2013, and prior to the introduction of the vaccination in the Italian NIP in 2017, MenB vaccine was provided free of charge in a few Italian regions  to issue vaccination recommendations, or the time needed to move on from recommendations to effective access for the population . In addiIn conclusion, the present study confirmed the diversity of NIPs, even in neighboring countries with similar factors like economic resources and epidemiological risk, highlighting other factors driving NIPs. Although various factors are considered for updates, current NIPs should aim at prevention against circulating serogroups using MenB and MenACWY vaccines. Convergence toward a common European immunization program would improve equity between countries, promote safe travel regarding infectious diseases in the European area, and possibly increase understanding among healthcare professionals and the lay public. For example, European convergence on an IMD immunization program could start with MenACWY vaccination in adolescents, continue with general vaccination of infants and toddlers against serogroup B, and extend to vaccination against other serogroups (ACWY) in this age group. A consensual approach would be required to overcome expected implementation difficulties, as was successfully done for COVID-19 vaccination.


This study is aimed at exploring the efficacy of transarterial chemotherapy embolization (TACE)+radiofrequency ablation+sorafenib in the treatment of patients with recurrent liver cancer and at constructing its prediction model.  A total of 60 patients with recurrent liver cancer treated in our hospital from March 2020 to March 2022 were enrolled and divided into two groups according to treatment methods, with 30 patients in each group. Group A adopted TACE+radiofrequency ablation+sorafenib therapy while group B adopted TACE+radiofrequency ablation therapy. Clinical efficacy, complications, and adverse reactions of the two groups were observed. A total of 30 patients with nonrecurrent liver cancer in the same period were enrolled. 60 patients with recurrent liver cancer and 30 patients with nonrecurrent liver cancer were taken as the recurrence group and the nonrecurrence group, respectively. The baseline data and clinical data of the patients were queried by the Hospital Information System. The data included age, gender, Child-Pugh grade, HBV/HCV infection, portal vein tumor thrombus, degree of differentiation, vascular invasion, serum alpha fetal protein (AFP) level, number of tumors, maximum diameter of tumors, and number of nodules. The logistic regression analysis was used to analyze the independent risk factors for liver cancer recurrence. The Hosmer-Lemeshow test was used to analyze the degree of fitting between the prediction model and the standard curve. The ROC curve was used to analyze the predictive value of the model for liver cancer recurrence. P < 0.05). There were no significant differences in the incidence of complications such as embolism syndrome, hand and foot skin reaction, gastrointestinal reaction, hypertension, diaphragmatic injury and bleeding, and biliary leakage and fever between the two groups . The proportions of patients in the recurrence group with portal vein tumor thrombus (PVTT), medium and high degree of differentiation, combined with vascular invasion, serum AFP level ≥ 400 ng/dL, multiple tumors, maximum tumor diameter ≥ 5 cm, combined with cirrhosis, and polynodules were all higher than those in the nonrecurrence group; the differences were statistically significant . Complication of PVTT, the degree of medium and high differentiation, and the maximum tumor diameter ≥ 5 cm were independent risk factors for recurrence of liver cancer . The prediction model of liver cancer recurrence was obtained by multiple regression analysis, P = 1/[1 + e−(−5.441 + 6.154∗PVTT + 3.475∗differentiateddegree + 3.001∗maximumdiameteroftumor)]. The Hosmer-Lemeshow test showed that χ2 = 1.558 (P = 0.992). According to the ROC curve analysis, the AUC, SE, and 95% CI value of the prediction model for liver cancer recurrence were 0.977, 0.012, and 0.953-1.000, respectively.  The objective effective rate and disease control rate in group A (33.33% and 70.00%) were higher than those in group B (10.00% and 43.33%), and the differences were statistically significant (both  TACE+radiofrequency ablation+sorafenib is effective in the treatment of recurrent liver cancer, and the prediction model established based on the risk factor has high predictive value for patients with recurrent liver cancer. Primary liver cancer (PLC) is a common malignant tumor disease in clinical practice. Its mortality and morbidity of liver cancer rank the second and third, respectively, among all malignant tumor diseases, and its morbidity is relatively high in Asia , 2. PLC P > 0.05). This study was approved by the Hospital Ethics Committee.A total of 60 patients with recurrent liver cancer treated in our hospital from March 2020 to March 2022 were enrolled and divided into group A and group B according to treatment methods, with 30 patients in each group. In group A, there were 19 males and 11 females. The age ranged from 39 to 64 years, with the average age of 54.30 ± 6.28 years. Complications included hypertension in 8 cases, diabetes in 3 cases, and others in 19 cases. In group B, there were 17 males and 13 females. The age range was 39-77 years, with an average of 55.43 ± 10.79 years. Complications included hypertension in 12 cases, diabetes in 5 cases, and others in 13 cases. During the same period, a total of 30 patients with nonrecurrent liver cancer were enrolled as the nonrecurrence group. There were 18 males and 12 females. The age range was 38-72 years, with an average of 55.36 ± 7.52 years. Complications included hypertension in 10 cases, diabetes in 4 cases, and others in 16 cases. The general data of the three groups were comparable  age > 18, (2) all patients were diagnosed with recurrent liver cancer by clinicopathological diagnosis, (3) the maximum diameter of the tumor was 1-7 cm, (4) the life expectancy > 3 months, and (5) all patients participated in this study voluntarily.The exclusion criteria of this study are as follows: (1) patients with other malignant tumor diseases, (2) patients with Child-Pugh grade C for liver function, (3) patients with severe organ dysfunction such as heart, lung, and kidney, (4) patients who cannot tolerate TACE and radiofrequency ablation or were allergic to sorafenib, and (5) patients with severe coagulation dysfunction that were uncorrectable.Group A was treated with TACE+radiofrequency ablation+sorafenib, and group B was treated with TACE+radiofrequency ablation.The femoral artery was punctured with Seldinger technique routinely, and the 5F catheter was placed. The catheter was placed at the opening of the celiac trunk artery for angiography to determine the tumor target vessel. Superselective intubation was performed into the tumor supplying artery. The tumor target vessel was embolized with fluorouracil 1000 mg, cisplatin 50 mg, pirarubicin 50 nmg+super liquefied lipiodol 5~10 mL. After the operation, hepatoprotective hydration treatment was performed.After the TACE treatment for 2-4 weeks, radiofrequency ablation was performed. First, CT scanning was performed to determine the puncture point, and then, lidocaine was used for local anesthesia. Percutaneous puncture of intrahepatic lesions was performed under the guidance of the CT, and tumor ablation was performed according to the protocol. After that, CT scanning was performed to see whether the scope covered the target tumor. If it was not completely covered, radiofrequency ablation could be performed immediately. During radiofrequency ablation, all lesions should be ablated in one ablation process, including single nodule and polynodule patients.Seven days after intervention, sorafenib was given orally, 400 mg/time, twice a day for 4 weeks.(1) The clinical efficacy of group A and group B was evaluated according to the efficacy evaluation criteria. (2) There is a comparison of complication rate between group A and group B. (3) A total of 30 patients with nonrecurrent liver cancer in the same period were selected, and 60 patients with recurrent liver cancer and 30 patients without recurrent liver cancer were divided into the recurrence group and the nonrecurrence group. The baseline data and clinical data of patients were queried by hospital information system. Age, gender, Child-Pugh grade, HBV/HCV infection, portal vein tumor thrombus, differentiation degree, vascular invasion, serum AFP level, tumor number, tumor maximum diameter, number of nodules, and other data were included. Baseline data and clinical data were compared between the recurrence group and the non-recurrence group. (4) Logistic multivariate regression analysis was used to analyze the independent risk factors of HCC recurrence. The baseline and clinical data of the recurrence group and the nonrecurrence group were statistically different. (5) Logistic regression was used to analyze the risk factors of HCC recurrence and establish a regression model. (6) The receiver operating characteristic (ROC) curve was used to calculate the discrimination of the prediction model.The treatment effects of the two groups were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST)  proposeds). When the measurement data conform to the normal distribution and the variance was homogeneous, a t-test was adopted. The counting data were described by N and %. The disordered classification data were compared by the χ2 test or Fisher's exact probability method. The logistic regression analysis was used to analyze the risk factors of liver cancer recurrence. The Hosmer-Lemeshow test was used to analyze the fitting degree between the prediction model and the standard curve. The ROC curve was used to analyze the predictive value of the model for recurrence of liver cancer. All tests were two-sided, and the difference was statistically significant when P < 0.05.All the data in this study were entered into Excel form without communication between two persons and analyzed and processed with statistical software SPSS 24.0. The measurement data were expressed in mean ± SD  were higher than those in group B (10.00% and 43.33%). The differences were statistically significant (both P > 0.05) as shown in There were no significant differences in the incidence of complications such as embolism syndrome, hand and foot skin reaction, gastrointestinal reaction, hypertension, diaphragmatic injury and bleeding, and biliary leakage and fever between the two groups , as shown in The proportion of patients in the recurrence group with PVTT, medium and high degree of differentiation, combined with vascular invasion, serum AFP level ≥ 400 ng/dL, multiple tumors, maximum diameter ≥ 5 cm, combined with cirrhosis, and polynodules was higher than that in the nonrecurrence group; the differences were statistically significant , as shown in Complication of PVTT, the degree of medium and high differentiation and the maximum tumor diameter ≥ 5 cm were independent risk factors for recurrence of liver cancer ]. The Hosmer-Lemeshow test showed that χ2 = 1.558 and P = 0.992  [P < 0.05). Group A was given TACE+radiofrequency ablation+sorafenib, and group B was given TACE+radiofrequency ablation. These results indicated that the combination of TACE+radiofrequency ablation+sorafenib was more effective in the treatment of recurrent liver cancer, which may be related to the synergistic therapeutic effect of sorafenib with TACE and radiofrequency ablation. There were no significant differences in the incidence of complications such as embolism syndrome, hand and foot skin reaction, gastrointestinal reaction, hypertension, diaphragmatic injury and bleeding, and biliary leakage and fever between the two groups . Although sorafenib was added in group A, there was no increase in the incidence of serious adverse reactions and complications indicating that sorafenib are safe for treatment.Most recurrent liver cancer cannot tolerate secondary surgery because of specific tumor location, multiple recurrent foci, and complicated with severe cirrhosis. TACE is the preferred treatment for nonsurgical treatment of recurrent liver cancer –8. TACE r (2022)  indicater (2022) . TreatinP < 0.05). The results showed that the complication of PVTT, medium and high degree of differentiation, vascular invasion, serum AFP level ≥ 400 ng/dL, multiple tumors, maximum tumor diameter ≥ 5 cm, cirrhosis, and polynodules were related to the recurrence of liver cancer. The recurrence of liver cancer is generally caused by multicentric canceration, and the high recurrence rate after surgery also seriously affects the therapeutic effect. Early recurrence was mainly related to tumor size, vascular invasiveness, and higher AFP level in muscle serum of the primary tumor, while late recurrence was mainly related to etiology and cirrhosis background. Vascular invasion can lead to worse tumor stage and tumor progression in patients, and PVTT is a common complication in patients with liver cancer, indicating poor prognosis [P < 0.05). PVTT, serum AFP level ≥ 400 ng/dL, multiple tumors, cirrhosis, and polynodular were not the independent risk factors for liver cancer recurrence. This result may be related to the small number of cases in this study.Comparison of baseline and clinical data between the two groups showed that the proportion of patients in the recurrence group with PVTT, medium and high degree of differentiation, combined with vascular invasion, serum AFP level ≥ 400 ng/dL, multiple tumors, maximum diameter ≥ 5 cm, combined with cirrhosis, and polynodules was significantly higher than that in the nonrecurrence group (all rognosis . Tumor grognosis , 18, whirognosis . The numrognosis –22. The The identification of patients with recurrent liver cancer by predictive model is conducive to the timely intervention by clinicians and the development of individualized control programs for high risk factors, which is conducive to further reducing the recurrence rate of liver cancer and improving the prognosis of liver cancer patients. In this study, a prediction model was established based on various risk factors. The Hosmer-Lemeshow test and ROC curve analysis showed that the model had high predictive value for liver cancer recurrence and could be used in the early prediction of liver cancer recurrence.In conclusion, TACE+radiofrequency ablation+sorafenib has a good clinical effect in the treatment of recurrent liver cancer, and the prediction model established based on risk factors has a high predictive value for the recurrence of liver cancer.


The chronotype refers to the individual differences related to the preference toperform activities or to rest during the wake or in the preferences for acertain period of the day. In this study, we evaluated how the chronotype can beconsidered a variable of interest for individual personality differences. Still,it was verified how the positive and negative effects and self-esteem interactwith the quality of sleep and the circadian personality according to the BigFive personality factors. This study included 150 volunteers of both sexes (41men and 109 women) aged between 16 and 44 years old .The analysis of variance showed significant differences for Horne and Ostberg usual sleep efficiency  and the sleep quality index .Morning subjects had better behavioral indexes of sleep quality when compared toevening subjects. Regarding positive affects ,morning subjects had a higher score than afternoon subjects (p=0.34) andconsequently had higher scores in kindness traits  and emotional stability . Thechronotype is associated with personality factors and sleep behavior  and variablessuch as sleep efficiency and quality of sleep can be moderators of thisbehavior. However, it is not clear the validity of generalization of thesestudies, it is still unclear whether the circadian typology affects the personalityor if some third factor influences both. Chronobiology points out that circadianrhythms have two main properties, the first being the neurobiological parameters orbiological clocks of circadian rhythms3, which consists of three chronotypes 1. MT subjects have a preference for going to bed early and wakingup early and tend to reach their peak mental and physical performance earlier in theday. In contrast, ET subjects have a preference for going to bed and waking up late,and for performing better at the end of the day and late at night. However, a largepart of the adult population is classified with an intermediate chronotype4. There is evidence to suggest thatCT is influenced by individual factors, such as age and sex5-7, environmental factors, including exposure tolight8,9, and also to cognitive skills andpersonality traits10-15.Chronotypes are commonly known as circadian typology [CT]14 was verified. They pointed out that theparticipants’ diurnal preference was associated with the difficulty of carrying outavoidance strategies to deal with academic stress as high school approaches the end;however, the subjects with a neurotic trait were able to deal with an aversion toclasses, distracting with night activities, such as using the internet. ET subjectsare associated with sleep problems, anxious/depressive symptoms, smoking, caffeineconsumption, alcohol consumption, and suicidal behavior13. Still, it argues that the nocturnal type of bothmales and females have patterns inferior to the behaviors of extraversion and socialdesirability16.CT is associated with different lifestyles. Recently the effect of the five majorpersonality factors with CT in Polish high school students11. Thishypothesis was supported for extroverted nocturnal subjects showingdisproportionately high satisfaction with life, while introverted nocturnal typesshowed the lowest levels of satisfaction. The level of extroversion can influencewhether nighttime types choose to engage in adaptive social activities that increasewell-being at night.Studies show that that extroversion would moderate the association between chronotypeand satisfaction17 used the fivefactors of Zuckerman (AFFM) and CT and suggested that ETs are more outgoing,impulsive, and in search of new things, while MTs tend to be more introverted,conscientious, pleasant, and emotionally stable. They also suggest that MT typesubjects are more conscientious than ET subjects. ET types are more neurotic thanmorning ones7. Also, they validatedtheir hypothesis by suggesting that women of the ET type are more impulsive and lookfor new actions18.Muro et al. (2009)10.This model considers four dimensions of temperament, damage prevention, news search,reward dependence, and persistence; and three dimensions of character. The authors showed thatindividuals of the nocturnal type had a greater search for novelties, but lowerscores for damage prevention, persistence, and self-direction. Also, CT modulatedgender differences in relation to damage prevention and search for novelties, thatis, only men of the nocturnal type had a lower damage prevention score.The relationship between CT and the Cloninger model of the seven dimensions ofpersonality was also explored19 was investigated. The use of different tools andmediating factors has methodological limitations related to sleep qualityinstruments and processes12,20. Thus,this study sought to identify mediating factors such as mood and self-esteemassociated with personality, quality of sleep, and circadian typology.The relationship between personality and CT shows some inconsistent results and thehypothesis has been raised that the model used to measure personality may have amoderating effect on this relationship. Also, a mediator of depression betweenmorning behavior and the five great personality traits21.This research was carried out by the Laboratory of Neuroscience, Behavior andSleep Psychology (LPNeC), located at the State University of Minas Gerais.However, the data collected refer to all regions of Brazil during the periodfrom August to September 2020, which is equivalent to the winter and springseasons according to the geographic layout of the southern hemisphere. Photicfactors and geographic location are important markers for the circadiandisposition of living organismsThis study included 150 volunteers of both sexes (41 men and 109 women) agedbetween 16 and 44 years old . All participants wereundergraduate students, 80.1% from public institutions and 19.1% from privateones. Furthermore, 82.8% of the participants were from the southeast region ofthe country, 10.6% from the northeast region, and 3.4% from the southern region.Participants were subdivided into three groups according to the circadiantypology: ET ; NT ; and MT . Exclusion criteria were participants who used alcohol orillicit drugs, used psychotropics, had a known autoimmune disease that affectshypothalamic areas associated with homeostatic and circadian sleep control. Inaddition to neuropsychiatric mood disorders or disorders that were related tosleep or that alter the sleep-wake cycle.22. Itshould be noted that its validation in Portuguese was performed with a highdegree of sensitivity (65%).Pittsburgh sleep quality index (PSQI): it is a subjective measure that evaluatesthe quality of sleep-in relation to the last month. This instrument consists of19 items that are ordered by seven factors: 1) subjective sleep quality, 2)sleep latency, 3) sleep duration, 4) usual sleep efficiency, 5) sleep disorders,6) use of sleeping medications, and 7) daytime dysfunction. This questionnairehas a total score of 21 points, being distributed on a scale of 0 to 3 pointsper item, and it demonstrates that the higher the score, the worse the qualityof sleep. In this study, the translated version and the validation for theBrazilian population23. The purpose was to assess the individual’spreference to carry out their activities during the 24 hours. The questionnaireconsists of 19 questions about habitual situations in the individual’s dailylife. The results classify individuals into five chronotype categories: evening(16 to 30 points); moderately evening (31 to 41 points); indifferent orintermediate (42 to 58 points); moderately morning (59 to 69 points); andmorning (70 to 86 points).Horne and Ostberg matutinity and evening questionnaire: questionnaire preparedand validated/adapted to the Portuguese languageHamilton anxiety assessment scale (HAM-A): the instrument is an objective methodof tracking anxiety. The version used in this study has 7 partial items and 7general items, which in all verify mood, tension, fears, insomnia, intellectualdifficulties, motor somatizations, sensory somatizations, symptoms, and behaviorduring the interview. They must be answered with scores from 0 to 4 . Its score rangesfrom 0 to 56, and the final result classifies individuals into 3 categories:mild anxiety (18 to 24 points); moderate anxiety (25 to 30 points); and severeanxiety (30 or more points).Hamilton scale for depression assessment (HAM-D): the version of the instrumentto be used in this study has 11 items, which verify aspects such as depressedmood, guilt, suicide, insomnia, delay, agitation, anxiety, work, and activities.The response scores increase according to the severity of the symptomspresented. In the end, the scores classify individuals in mild depression (15 to24 points); moderate depression (25 to 30 points); severe depression (31 to 43points); and very severe depression (44 or more points).24. The items aregrouped into five factors: openness, conscientiousness, extraversion, kindness,and neuroticism.Inventory of the five great personality factors (IGFP-5): IGPF-5 has 44 items,structured in simple sentences that are answered in five points on a scale ofLikert-type responses that vary from totally disagree (1) to agree (5). Itsvalidation for the Brazilian population was carried out in a sample of 5,089,male and female participants aged 13 to 67 years old from five different regionsof Brazil23. Their scores are evaluated ona Likert-scale format in five points, with the following gradation: “not alittle”, which equals 1 point, “a little”, “more or less”, “quite” and “verymuch”, which equate to 5 points.Positive and negative affection scale (PANAS): this instrument measures positiveand negative subjective effects using 32 adjectives. Validation of factoranalysis was used, which has the best solution for two orthogonal factors:positive affect (α=0.88) and negative affect (α=0.86)25,26. The response options weredistributed on a four-point Likert scale: “I totally disagree”, “I disagree”, “Iagree” and “I totally agree”. The higher the score obtained, the higher therespondent’s self-esteem index.Rosenberg’s self-esteem scale (EAR): it has 11 items, which investigate globalaspects of self-esteem. The version adapted of the original scale was used,which showed an internal consistency index above 0.80 for Cronbach’salphaInitially, the contact with the participants was made out of convenience afterthe study was published on social networks. After agreeing with the volunteers,all instruments were adapted in the form of online platforms via forms for datacollection, open access, to avoid as much contact as possible betweenresearchers and interviewees during the COVID-19 pandemic. The division of thegroups according to the circadian typology was established according to Horne& Ostberg’s Morning and Evening Identification Questionnaire. In the secondmoment, all the instruments used in the study were presented and explained. Theparticipants took an average of 20 minutes to answer the scales andquestionnaires and the participants were recommended to remain assiduous intheir responses.Data were plotted in spreadsheets according to the CT description and categories.Descriptive and inferential statistical analyzes were performed using SPSS, version 20. Descriptive analyzeswere verified using frequency and measures of central trend. Data normalityconditions were verified by Komogorov-Sminorv within the 95% confidenceinterval. Parametric analyses of variance (ANOVA One-Way) statistics were usedand, consequently, multiple comparisons of factors through ANOVA. Onceidentified the interaction between categories through chi-square tests.The study was approved by the Research Ethics Committee of the University of theState of Minas Gerais (Protocol No. 38327020.8.0000.5115) complying withResolution No. 466/12 and 510/16 of the National Health Council. Participationwas voluntary, confidential and anonymous; the data obtained from theparticipant followed the guidelines and standards of research involving humanbeings.Initially, it was identified that 91.4% of the participants were under socialisolation due to the COVID-19 pandemic; however, 100% of the volunteers were dailyperforming remote academic activities, of which 66.2% in day shift activities and33.8% in evening shift. Still, in relation to remote education, 33.1% were studentsgraduating in an academic course and 25.2% undergraduate students. Regarding healthfactors, 43% performed daily physical activities. According to the eligibilitycriteria, the participants were free from neuropsychiatric disorders; however, 26.5%had a first-degree relative with the presence of psychological disorders. Regardingbehavioral sleep patterns, 67.5% had four of their own, of which 13.2% shared a bedwith one person.p=0.138). A cross-reference analysis was performed withCramer V correction between the groups of circadian typologies and the periodsof study of the  students and thestudy shift, however; teste ꭓ2test showed no difference, (p=0.982) and(p=0.901), respectively.The analysis of variance (ANOVA) for independent groups showed significantdifferences for HO , as expected by Horne andOsterg (1976) . The datp=0.018) ETs(p=0.022). ANOVA also pointed out a significant differencebetween groups for the total PSQI score , witha marginally significant difference between MT subjects when compared to ET(p=0.044). The data also pointed out a significantdifference for sleep latency measured in minutes , in which MT subjects have less latency to initiate sleep whencompared to ET (p=0.016).ANOVA indicated a significant difference between groups for C4  and the post hoc Bonferroni test showed that MTs have betterhabitual sleep efficiency when compared to NTs (p=0.34). Regarding CT and personality components, theyobserved significant differences for kindness and stability . ET (p=0.014)and NT (p=0.002) subjects had a higher score for kindness thanMT subjects. Similarly, NT subjects (p=0.003) had a higherstability score than MT subjects.ANOVA showed a significant difference for positive affect  in which subjects with ET had a higher score than subjects withMT (p=0.079)was no wlonger significant, the same did not occur with the kindness variables and stability. Similar to thePSQI, the sleep latency variable also showed control for positive affect(p=0.075), but maintained the significant difference forkindness  andstability .Regarding the control of the habitual sleep efficiency variable, the analysiscontinued to point out a significant difference for positive affect , kindness  and stability .A simultaneous analysis of joint variables was performed to verify how the usualsleep efficiency, latency and PSQI influence the mood and personality traitsaccording to the CT. Multivariate analysis using CT as a fixed factor andcontrolling the PSQI showed that the positive affect  = 4.69; p=0.004;η2=0.88] and emotional stability . The same results occurred forpositive affect ,the kindness , andstability  whencontrolling the students’ study shift so much.Simultaneous analysis of joint variables was also carried out, controlling thestudents’ study period and shift. Multivariate analysis using CT as a fixedfactor and controlling the study period maintained the significant differencefor positive affection [F = 2.95; Typological differences in circadian activity have been characterized as anontogenetic factor of personality. The results of this study strengthen thehypothesis that the chronotypes of adult subjects are related to specificpersonality traits, for example, morning subjects are characterized by greateremotional stability and higher levels of kindness when compared to evening subjects.Another fundamental point in this comparison is that this difference is accentuatedby the construction of positive effects in morning individuals. It is important tonote that previous studies do not indicate the existence of an interaction ofpositive and negative affects with personality traits and circadian typology.27. Theinfluence of social zeitgebers (synchronizers) on behavior variation may beassociated with clues intrinsic to the sleep-wake cycle of the circadian period inthe personality structure.The chronotype as a human characteristic is based on self-reported daytime ornighttime preference criteria, using patterns of activity in usual waking time asindicators28. That is, the discussion about circadian typology andpersonality traits remains contradictory. The nature of these conclusions can beassumed by future interactions, lack of consistent personality trait testing, andstudies with internal reliability measures about temperament and personality traitsassociated with sleep behavioral patterns during the subject’s ontogeny.The influence of sex on the distribution of morning and evening preferences amongstudents was not observed. The differences in processes underlying the genders andthe circadian timing system remain undefined28. It is important to note thatsleep delay, common among adolescents, can be attributed, at least in part, tosocial changes in the development of mechanisms that regulate sleep time.The results also did not point out any associative differences between the shift andthe study schedule of the participants. However, gender differences and the timearrangements for class and study shift must be taken into account in morning-eveningstudies that assess subjects’ behavioral or cognitive performance17), this conceptdepends on the theory adopted by the researcher. There is a panacea of personalitytheories that are used in the literature. A key point for this perspective was touse the factorial model of the “Big Five Personality Factors”, a large number ofstudies point to the validity and reliability of this measure in different contextsand cultures24,27,29. It used multiple regressions among gender,neuroticism and affability did not observe differences related to thechronotype12. Differently,it was pointed out that individuals with more nocturnal habits had higher scores inextraversion and kindness29.Similar results were found in this study; however, differences were observed foraffable or loving behaviors in subjects with morning preference and, consequently,greater emotional stability for morning subjects. These results are similar to thefindings7, which suggestthat morning subjects are more conscientious than nocturnal subjects13. Refer that the sense of restraintand practical sense is consistent with practices of sensitivity and confidence ofthe kindness trait. It is important to highlight that the morning subjects had abetter sleep quality index. However, we can associate these results with the hoursfor work and study that are socially determined, most of the time, in a daytimesociety. Thus, the preferences of the morning individual end up being consistentwith this reality, presenting a higher quality of sleep and lower barriers in socialadaptation. Thus, it is pointed out that the quality of sleep can be an importantcontrol variable to maintain a positive effect according to the CT.It is important to consider the variety of personality definitions . Theseconstructs are mainly related to positive affect and affable or emotionally stablebehaviors for morning subjects. Although this study presents new associations of CTand emotional and personality behavior, studies of this nature have contributed withideas about social behavior around everyday social experiences, such as positive andnegative affect, for example, cohabitation with family members, interaction withfriends and occupational roles. Future research may focus on differentmethodological measures of personality measurement , use different chronotype measures, or objectivelyassess the actual sleep-wake cycle using actigraphy. Still, a three-dimensionalresolution interaction between circadian typology, personality traits, and cognitiveprocess models, for example, memory and attention models, can contribute to supportthe interaction of these patterns. However, it is argued that personalityassessments, when treating sleep behavioral patterns and their typologicalvariables, are of paramount socio-environmental importance.


Hypertension and cancer are two of the leading global causes of death. Hypertension, known as chronic high blood pressure, affects approximately 45% of the American population and is a growing condition in other parts of the world, particularly in Asia and Europe. On the other hand, cancer resulted in approximately 10 million deaths in 2020 worldwide. Several studies indicate a coexistence of these two conditions, specifically that hypertension, independently, is associated with an increased risk of cancer. In the present study, we conducted a meta-analysis initially to reveal the prevalence of hypertension and cancer comorbidity and then to assess which organ-specific cancers were associated with hypertension by calculating the summary relative risks (RRs) and 95% confidence intervals (CIs). Our analysis shows that hypertension plays a role in cancer initiation. Our extended analysis on how the hypertension-associated angiogenesis factors are linked to cancer demonstrated that matrix metalloproteinases 2 and 9 appear to be two key factors facilitating cancer in hypertensive patients. This work serves as an important step in the current assessment of hypertension-promoted increased risk of 19 different cancers, particularly kidney, renal cell carcinoma, breast, colorectal, endometrial, and bladder. These findings provide new insight into how to treat and prevent cancer in hypertensive patients. Hypertension, also known as high blood pressure, is a complex chronic condition that affects approximately 45% of the United States population  and is aA previous meta-analysis showed an association between hypertension and kidney cancer, colorectal, liver, endometrial, esophageal adenocarcinoma, and a borderline significance of breast cancer . The stuAfter further analysis, previous studies have shown that not only does hypertension possibly promote incidental cancer risk, but prehypertension (SBP: 120–139 mmHg or DBP: 80–89 mmHg) and antihypertension treatment may also promote increased risk of incidental cancer ,30. One Carcinogenesis, or the initiation of cancer, is understood, but a universal theory as to why it occurs is unclear. One possible theory may be associated with hypertension. In addition to cancer initiation, previous studies have also shown that hypertension may also play a role in cancer progression as well. In a study involving bladder cancer, high blood pressure was associated with increased risk and mortality among men, and blood pressure showed a graded increase in strength of association from overall bladder cancer, NMIBC, MNIBC, and bladder cancer mortality . Dose-deWith newer studies being introduced relating to the development of cancer in hypertensive patients, the aim of this study was to conduct a meta-analysis of the data up to the present (June 2021) to evaluate the association of untreated hypertension and increased risk of developing patient-specific, organ-specific cancer and the possible pathologies behind the association.Previous works have used machine learning on cancer and hypertension as keywords; however, for this study, we wanted to include only studies showing hypertension and an increase in incidental cancer risk. Therefore, a manual search was conducted to find data, which took five months. To conduct the literature review needed for this study, databases, such as PubMed and Embase, were used to identify studies published up until June 2021. The study used the following search criteria: (hypertension OR high blood pressure OR metabolic syndrome) AND . This search process was used to identify all qualifying studies that involved clinical cohort and/or case-controlled studies that considered the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and their relation to any organ-specific cancer sites. After the initial search that took place from January 2021 until the end of March 2021, the search was then specified for articles from 2017 until the present to find new data on the topic, since the previous meta-analysis included data up until 2017. This manual search was concluded in June 2021.If the study was on metabolic syndrome, which is a combination of factors, such as BMI, high triglycerides, and hypertension, only hypertension data were examined and extracted. Hypertension was defined as being higher than the baseline blood pressure given in each individual study, and the data were given either by measurement, medical history, or from a questionnaire. The study criteria included the following guidelines: (1) case-control or cohort study design; (2) the study reported either a relative risk, hazard ratio, or odds ratio that could be converted to a relative risk; (3) the exposure was hypertension, and the outcome was incidental cancer risk.The data were extracted manually by the reviewers, who first read the abstract and title of the study. The author’s name, location of study, year of publication, design of study, and the definition of hypertension were all independently extracted. In total, there were 30 cohort studies, 16 case-control studies, and 1 unknown.I2 test for studies with two or more exposure and outcomes [The data from previous studies on the individual cases were provided by statistical software and either gave relative risks or an odds ratio, depending on what the individual study analyzed. Primary analysis calculated summary relative risks and confidence intervals of 95%. A few studies that were included used odds ratios, but in this case, they were then converted to relative risks ,43. A suoutcomes ,45. The outcomes .The included studies ranged from 1998 to 2021. In these studies, there were 678,949 patients and 35,499,496 participants. Hypertension was then defined in 41 of the studies (87%) using WHO criteria , NCEP-ATPIII criteria ; 13 (32%) used self-reporting data; 9 (22%) used other criteria. To obtain the exposure (hypertension) assessment in the studies, blood pressure was either measured , administered through a questionnaire , or obtained from medical records . Only 45 (96%) of the 47 studies included these measurements. The studies were located in Europe , North America , Asia , and South America .The overall analysis for the meta-analysis included 47 studies, and the combined overall effect estimate (RRs) and heterogeneity of these studies are presented using a relative risk model for each individual cancer. In total, 19 different cancers were analyzed for the overall meta-analysis, as seen in I2: 94.4%) [I2: 58.1%) [I2: 94.4%) and a smaller between-study heterogeneity for kidney cancer in women (I2: 58.1%). RCC also saw an increase in risk (I2: 57.3%). [I2: 0%) [There were associations made between almost every cancer site evaluated, but when accounting for the number of studies involved , those with only one study were not included in our results as a positive association. When looking at the data with numerous studies involved, we found statistically significant associations between hypertension and risk of incidental kidney cancer for both men (: 94.4%) ,7,22,27 : 58.1%) ,22. We o 57.3%). ,28,64 in[I2: 0%) ,64 in wo[I2: 0%) .I2: 69.1%) [I2: 69.1%). One study was not included because it did not include data on the confidence intervals, but it did observe an odds ratio of 2.5 for women with hypertension developing breast cancer [I2: 64.3%) [I2: 73.2%) [I2: 0%) [I2: 0%) [Breast cancer also showed a positive association between hypertension and cancer risk I2: 6.1% [9,11: 69.1%) ,20,21,23t cancer . There w: 64.3%) ,18,19,22: 73.2%) ,24. Furt[I2: 0%) ,51. Blad[I2: 0%) ,56.I2: 92.9%) [I2: 0%) [I2: 90.8%) [In the subgroup analysis of SBP and DBP per 10 mmHg, SBP showed a positive dose-dependent association with RCC (: 92.9%) ,65 and m[I2: 0%) ,32. DBP : 90.8%) ,65.This meta-analysis observed hypertension and its association with increased cancer risk in 19 different cancers. A strong positive association was observed for the following: kidney, RCC, breast, colorectal, endometrial, and bladder. There also was a positive association of SBP per 10 mmHg for MIBC and DBP per 10 mmHg. With the other cancers only containing one study each, a valid and generalized association could not be made.Several other studies have investigated this association and have shown positive results, especially hypertension and the risk of RCC ,71,72,73The extracellular matrix (ECM) is a type of noncellular structure that regulates most of the cellular functions of tissues and organs. It impacts cell behavior . More specifically, the microvascular ECM structure is essential for tissue repair and wound healing . On the A large-scale retrospective study looked at the overall survival outcome of patients with hypertension and the prognosis of nasopharyngeal carcinomas (NPC). Not only did the results show that those patients with hypertension stage II had a worse overall survival rate than those without, but vascular endothelial growth factor (VEGF) expression also increased in patients with advanced NPC . VEGF isMetabolic syndrome components possibly promote cancer by generating reactive oxygen species (ROS), increasing hormone production and availability, which includes estrogen, insulin-like growth factor (IGF-1), and adipokines. On the other hand, when looking at the individual components of hypertension, it has been related to insulin resistance and, hence, to IGF-1, which is related to cell growth and neoplastic progression . The renMatrix metalloproteinases (MMPs) play a role in both hypertension and cancer ,85,86. MThe mechanisms involved in the activation of these MMPs is unclear, but hypertension may contribute to MMP-2 activation . This phMMPs have been shown to also be upregulated in many cancer types . One stuMMPs’ contribution to hypertension and its association for increased risk of incidental cancer is still unclear, as most studies only observe one condition (either cancer or hypertension), not both simultaneously. Therefore, a clear link cannot be concluded on how hypertension promotes patient-specific organ-specific cancers and what mechanisms drive the comorbidity of these two diseases. Our summary theory, based on an extensive review of over 102 published studies in this field, is that high blood pressure activates MMP-2, where MMP-2 has been shown to activate pro-MMP-9, and MMP-9 has been reported to increase the risk of hypertension. Hypertension-induced increased stiffness and degradation of the ECM has been widely reported. On the other hand, ECM stiffening and degradation are linked to progression of several cancer types. Understanding how hypertension and the MMPs  affect one another would be beneficial for designing cancer prevention strategies for hypertensive patients.The present meta-analysis used a wide search criteria that were specifically for studies with a positive association between hypertension and an increased risk of developing incidental cancer. The present study also did not use machine learning, because the researchers wanted to gain more in-depth information initially on the papers for their own gain and knowledge on the topics of both hypertension and cancer. Cancer and hypertension are both extremely complex and may be promoted from various cofounding parameters such as BMI, genetics, diabetes, hypertension, and high triglycerides. A previous study that did look at other factors associated with metabolic syndrome found that the strongest association with prostate cancer was a combination of obesity and hypertension, but when they studied these factors individually, hypertension, independently, was associated the most strongly with prostate cancer risk . AnotherThe present study did have limitations. It did not look at contributing factors, such as BMI or genetics, in order to gain information purely on hypertension and cancer; therefore, future studies on this research would be beneficial to observe if these contributing factors, along with hypertension, also had an association with developing or not developing incidental cancer. A majority of the studies performed multivariable adjustments, but not all, and the present study did not perform a subgroup analysis. Another possible limitation is the lack of data on the details of each malignant tumor that developed within these patients and the studies lacked information on how long these tumors developed after the initial hypertension examination. Lastly, some organ-specific cancer sites only had one included study; thus, a statistical analysis could not be made. Future research for those organ-specific cancer sites would be beneficial for this work.In conclusion, since hypertension and cancer are both extremely complex, there are several possible parameters that could also play a role in cancer initiation and progression. The present study focused on hypertension because of its pathological complexity and the lack of information on the possible crosslink between hypertension and cancer. The present study was also able to demonstrate that one of these factors  may contribute to carcinogenesis and that this association between hypertension and cancer is possibly observed between different organ-specific cancer sites. Specifically, the present study observed that individuals with hypertension were at a high risk of kidney, breast, colorectal, endometrial, and bladder cancers. It is important to note that the high complexity of hypertension and cancer makes it difficult to provide a definite remark as to why and how this is occurs, but this study was also able to give detailed evaluations of the possible mechanisms of this observed cross-linkage and attempted to enhance the understanding of this phenomenon and provide detailed information on relevant information that may have the potential to improve preventable and therapeutic treatments for these patients.


Cinnamomun verum and Thyme vulgaris EOs and their organic extracts exert numerous biological activities because of their major compounds, particularly thymol, carvacrol, eugenol, and benzoic and cinnamic acid. The structural motifs presented by these phytochemicals are responsible for their biological activities. Modification or hybridization of these structures could lead to new bio-based compounds with improved efficacy or multiple modes of action. In this work, we aimed to develop reliable methods of obtaining six hybrid molecules from the major constituents of C. verum and T. vulgaris EOs. For the first time, we tested their efficacy in the inhibition of the mycelium growth and spore germination of two of the most important phytopathogenic fungi, Fusarium oxysporum and Colletotrichum gloeosporioides, and one opportunistic human pathogen, Aspergillus niger. The cytotoxic activity of the obtained hybrids was assessed using the brine shrimp lethality assay. In addition, we report for the first time a biocatalytic process for the obtention of these bioactive hybrid molecules. The results of this work enable the possibility of using hybrid molecules based on the major constituents of EOs as active ingredients in strategic industries such as agriculture, aquaculture, and pharmaceuticals.Plants have been used by humans since ancient times due their antimicrobial and medicinal properties. Essential oils (EOs) are complex mixtures of secondary plant metabolites, including terpenoids, phenylpropanoids, and other aromatic compounds.  All secondary products were obtained by following the proposed synthesis and purification method. These results reveal that the proposed method of chemical synthesis could be reliable for obtaining further hybrid molecules based on the use of EOs in large quantities, specifically, via the esterification of different phenolic compounds with carboxylic acids, achieving good yields of high-purity products in two hours and in the absence of heat or hazardous solvents.1), (2), and (3), respectively.Although most of these hybrids were previously synthetized chemically, we have reported their obtention by means of enzymatic catalysis for the first time in absence of solvents. 4), (5), and (6), respectively.The peaks which correspond to target compounds have been pointed out with their numbers in the chromatograms. In all cases, the retention times and MS fractionation patterns coincided with those of the chemically obtained hybrids, allowing us to ensure that the chemically and enzymatically obtained compounds were the same.Enzymatic reactions carried out under the proposed conditions produced qualitatively low product yields. Substrates, either carboxylic acid or phenols, were the major compounds at the end of the reaction, and several non-identified secondary products were obtained.4) and (5), when thymol, carvacrol, and cinnamic acid were used as substrates.In view of these results, CALB lipase seems to be less specific to methoxyphenols such as eugenol and to have greater affinity for other phenylpropanoids such as cinnamic acid. The highest conversions of reactants to products were observed in reactions  and (6) at 0.5% completely prevented the growth of fungi.The mycelial growth inhibition (MGI) effects against three fungi exerted by each hybrid molecule at three different concentrations are shown in C. gloeosporioides, hybrid molecules exerted lower antifungal efficacy against F. oxyposrum. At the highest concentration assayed, MGI was potent, but this effect nearly disappeared when hybrids were tested at 0.125%. Furthermore, cinnamic esters seemed to be more effective in inhibiting the mycelial growth of F. oxysporum.In comparison with Aspergillus niger, all hybrids exerted medium to low bioactivity. At 0.125%, (4) nearly lost its activity completely, but it became clear which hybrids from cinnamic acid exerted higher antifungal effects. It should be noted that the tested molecules did not exhibit dose-dependent response behavior.In the case of In order to demonstrate the antifungal effects of the EO hybrid molecules, in A. niger can also be responsible for plant diseases, is not a strictly phytopathogen. Consequently, these results indicated which of the hybrid phytochemical-based molecules tested, were able to exert potent mycelium inhibitory growth effects on specific plant pathogens but lesser effects on opportunistic human fungi.Although To obtain solid understanding of the compounds’ antifungal activity, we determined the spore germination inhibition (SGI) as a secondary mode of action, following the method described in C. gloeosporioides than against F. oxyposrum, and with regard to A. niger most of them were completely ineffective in inhibiting spore germination.The SGI results obtained for the EO hybrid molecules can be qualitative extrapolated to describe their MGI bioactivities. All candidates exerted higher efficacy against In general terms, all the concentrations tested exerted medium to low bioactivities. Once again, the obtained phytochemical hybrid molecules were relatively good spore-inhibitory ingredients for controlling phytopathogenic fungi but not for human diseases caused by these microorganisms.C. gloeosporioides, all hybrids displayed medium efficacy at 0.5% and the benzoic esters performed the best. For F. oxysporum, all hybrids exhibited medium to low activity at higher tested concentrations, with (1), (3), and (4) being the best candidates. In the case of A. niger, the SGI results are not shown in the graph because only (1) and (2) exerted low efficacies, and the other hybrids appeared to be completely ineffective in inhibiting spore germination. Most hybrids did not present dose-dependent response behavior in the SGI assays conducted in this study.50) of the six hybrid molecules examined in this study. Experiments were conducted for nine different concentrations—600, 300, 150, 100, 75, 50, 25, 10, and 1 µg/mL solutions in DMSO (1%).BSLA is a robust bioassay that is widely used in pharmacological studies for naturally occurring and natural-related chemicals, which is capable of identifying cytotoxic and bioactive compounds. 50 values above 1000 µg/mL, whereas LC50 between 1000–500 µg/mL are lowly toxic and treatments with LC50 100–500 µg/mL and 100–0 µg/mL are moderately and highly toxic, respectively.According to the Clarkson’s toxicity criterion , plant eA. salina nauplii. The eugenol-derived hybrids, (3) and (6), exerted medium–low toxic activities and exhibited LC50 values ten times higher than thymol and carvacrol derivatives, regardless of whether eugenol was hybridized with benzoic acid or cinnamic acid. Furthermore, hybrids based on benzoic acid appeared to be slightly more active than cinnamic acid derivatives and thymol-based molecules were more active than carvacrol-related hybrids. In view of the above conclusions and supported by the experimental data, (1) was the hybrid molecule with the lowest LC50 and the highest bioactivity against A. salina.In view of these results, a clear relationship exist between the chemical structure and the mortality of C. verum seemed to result in new molecules which did not exert high cytotoxic effects. Moreover, when hybrids were obtained by means of a combination of phenylpropanoids from C. verum and phenols from T. vulgaris EO, high cytotoxic effects were noted.The hybridization of the major compounds of Cinnamomun verum and Thymus vulgaris EOs. Some recent works have demonstrated the possibility of obtaining, by other chemical methods, a few of these hybrid molecules, namely, 2-Isopropyl-5-methylphenyl benzoate (1), 4-Allyl-2-methoxyphenyl benzoate (3), and 2-Isopropyl-5-methylphenyl cinnamate (4), and their potential bioactivity as antileishmanial and insecticidal compounds has been tested [In a changing scenario, in which the traditional active ingredients in agroindustry and pharmaceuticals are gradually being displaced by nature-based ingredients, basic and industrial research on novel lead compounds is necessary in order to comply with new legal and social requirements. Notably, in the European “Green Deal” strategy, 50% of conventional phytosanitary products will be prohibited by 2030 . In the n tested ,44. For Colletotrichum gloeosporioides and Fusarium oxysporum for 4-Allyl-2-methoxyphenyl benzoate (4) and 4-Allyl-2-methoxyphenyl cinnamate (6) were potent, and we determined that 0.5% was the concentration that inhibited 100% of mycelial growth. Regarding the inhibition of spore germination activities, benzoic acid derivatives exhibited the highest efficacies against C. gloeosporioides and F. oxysporum, but all of the compounds exerted medium to low efficacies. The obtained results indicated that these could be lead compounds in novel biopesticide formulations applied in field curative applications. Moreover, the next step to validate the antifungal activity of the selected hybrids could involve well-established in vivo pot or greenhouse assays against phytopathogenic fungi. In the other hand, the efficacy of the two modes of action against Aspergillus niger was quite low. Testing higher concentrations or searching for other phytochemical hybrids could provide ingredients for the treatment of opportunistic fungal human diseases. Even though the antifungal activities of all the starting products were well established [To assess their antifungal activity, in vitro experiments were conducted using two different modes of action against the two most important phytopathogenic fungi and an opportunistic human pathogen. The inhibitory effects on the mycelial growth of ablished ,46,47,4850 value less than 1000 µg/mL. The EO-based hybrid molecules developed here exhibited a strong correlation between their toxicity against A. salina and their structural features. In all cases, they demonstrated potential as anticancer drugs, with toxicities varying between medium (LC50 ≈ 500 µg/mL) and high (LC50 ˂ 100 µg/mL). Eugenol-derived molecules were ten-fold less toxic than thymol or carvacrol hybrids, and benzoic derivatives were slightly more active. It is worth noting that the published data indicate that thymol’s activity against A. salina nauplii was LC50 = 514 µg/mL [1) and 2-Isopropyl-5-methylphenyl cinnamate (4). For validation of the data obtained in the experiments performed here, the most effective hybrids, which correspond to the hybridization of phenolic monoterpenes from T. vulgaris and phenylpropanoids from C. verum, must be tested against target tumoral cell lines. These results could also imply toxicity to aquatic life; therefore, if applied in agriculture, well-established tests [3).To examine the potential bioactivity of these EO-based molecules, the cytotoxicity was assessed by means of the brine shrimp lethality assay, a well-established method to preliminarily test the bioactivity of plant extracts and nature-related pure compounds. This easy, fast, accurate, and cost-effective bioassay is widely used for pre-screening anticancer compounds and extracts from natural sources ,26,49. T14 µg/mL , ten tim1 NMR, and the lowest yield achieved was higher than 70%. On the other hand, and although in this study we have presented the first demonstration of the enzymatic production of these hybrids, the proposed method demonstrates that they could be obtained by natural means, and thus could have the potential for industrial scalability. Further investigations could be accomplished regarding the enzymatic catalysis process. Variations in substrate ratios, temperatures, and reaction times, as well as the use of different enzymes and cost-effective purification processes, could be investigated in order to achieve higher conversion of the substrates to products or to avoid the obtention of secondary artefacts.In the present work, we have also amply demonstrated reliable, cost-effective, and industrially scalable chemical synthesis methods for EO-based hybrids. The high purity of the obtained products was demonstrated via H1) was most active as an antifungal compound and as a potential anticancer drug, and was also one of the most reliable hybrids obtained via chemical and enzymatic methods. In conclusion, in the present work, we have proposed industrially-applicable chemical and enzymatic methods for obtaining hybrid molecules based on EO constituents. We have demonstrated which of these hybrids could represent novel active ingredients in agricultural biofungicide products and, potentially, in EO-based anticancer drugs. Furthermore, we revealed and discussed some structure–activity relationships, thus enabling the rational design of new EO-based hybrid molecules which could meet the demands of industry and society.Specifically, the compound 2-Isopropyl-5-methylphenyl benzoate (