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Studying the prevalence of headaches at age extremes is of important clinical relevance. Pediatric studies inform us about determinants of incident disease; studies of elderly populations inform us about the long-term consequences of headaches, as well as about determinants of headache remission. As with other subspecialties of headache research, research on pediatric headache is an evolving field. However, although substantial advances have been achieved in understanding headaches in adolescents, knowledge of early childhood headaches is not as advanced conceptually. This review provides a theoretical framework for our current understanding, then summarize the results of a large, ongoing, epidemiological study in pre-adolescent children. It is clear that both in adolescents and in pre-adolescents, migraine is frequent. Diagnostic criteria for migraine and chronic migraine are certainly over-restrictive for young children. Migraine often lasts less than 1 hour in young children. A vulnerable population at risk of migraine progression also exists, likely reflecting increased biological predisposition, but also early life exposures. Indeed, it seems that even prenatal exposures of certain substances may increase the risk of migraine progression. Of relevance is the frequency of headaches within a family. Finally, migraine seems to be associated with behavioral hyperactivity, but is not comorbid with attention-deficit disorder and hyperactivity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Intestinal or hepatic ischemia/reperfusion induces acute lung injury in animal models of multiple organ failure. Tumor necrosis factor (TNF)- alpha is involved in the underlying inflammatory mechanism of acute respiratory distress syndrome. Although the inflammatory cascade leading to acute respiratory distress syndrome has been extensively investigated, the mechanical components of acute respiratory distress syndrome are not fully understood. Our hypothesis is that splanchnic ischemia/reperfusion increases airway reactivity and serum TNF-alpha levels. OBJECTIVE: To assess bronchial smooth muscle reactivity under methacholine stimulation, and to measure serum TNF-alpha levels following intestinal and/or hepatic ischemia/reperfusion in rats. METHOD: Rats were subjected to 45 minutes of intestinal ischemia, or 20 minutes of hepatic ischemia, or to both (double ischemia), or sham procedures (control), followed by 120 minutes of reperfusion. The animals were then sacrificed, and the bronchial response to increasing methacholine molar concentrations (10-7 to 3 x 10-4) was evaluated in an ex-vivo bronchial muscle preparation. Serum TNF-alpha was determined by the L929-cell bioassay. RESULTS: Bronchial response (g/100 mg tissue) showed increased reactivity to increasing methacholine concentrations in the intestinal ischemia and double ischemia groups, but not in the hepatic ischemia group. Similarly, serum TNF-alpha (pg/mL) concentration was increased in the intestinal ischemia and double ischemia groups, but not in the hepatic ischemia group. CONCLUSION: Intestinal ischemia, either isolated or associated with hepatic ischemia, increased bronchial smooth muscle reactivity, suggesting a possible role for bronchial constriction in respiratory dysfunction following splanchnic ischemia/reperfusion. This increase occurred in concomitance with serum TNF-alpha increase, but whether the increase in TNF-alpha caused this bronchial contractility remains to be determined.

An ultrasound extraction procedure for Ca, K and Mg from in vitro plant cultures is proposed, comparing cultures of different embryogenic levels of Citrus sinensis and Citrus limonia, employing ultrasound energy. Parameters related to metals extraction, such as plant material sampling, acid concentration and sonication time were investigated. For accuracy check, the proposed ultrasound extraction procedure was compared with a microwave-assisted digestion procedure and no differences in the results were verified at 95% of the confidence level. With this simple and accurate extraction procedure, it was possible to determine differences in Ca, K and Mg concentrations during Citrus embryo formation/development and between cultures (embryogenic and non-embryogenic). Finally, the ultrasound extraction method demonstrated to be an excellent alternative for handless sampling and operational costs.

Vermicompost (humic material) samples were submitted to characterization by infrared spectroscopy, X-ray diffractometry, thermogravimetric analysis, electron microscopy etc. In addition, its cation exchange capacity (CEC) was determined. Factorial experiments were designed in order to elucidate the interaction mechanisms between Cd2+ and the adsorptive sites of vermicompost. The maximum adsorptive capacity for cadmium was evaluated by a Langmuir isotherm. The characterization revealed that vermicompost exhibits high CEC values (ca. 72.9 meq per 100 g), high surface area (porous material), chelating groups and a maximum adsorptive capacity for Cd (38.6 mg g-1) at pH 5.0. This potential application was exploited in the analysis of synthetic and real (mineral water) samples with Cd concentrations of ca 5 mug L-1, requiring a preconcentration step. An enrichment factor of 100 was attained.

This work describes a factorial design for the optimization of pyrolysis and atomization temperatures in ETAAS. As examples, Cd and Pb were determined using lower pyrolysis and atomization temperatures and Al and Mo with higher pyrolysis and atomization temperatures. Good results were obtained for Cd employing Rh (m o = 1.4 pg) as a permanent modifier with pyrolysis and atomization temperatures of 640 and 1500 °C, respectively. For Zr, W or Zr+W, the Cd pyrolysis and atomization temperatures were 500 and 1500 °C, respectively, with m o = 1.4 pg using Zr or W and 1.5 pg using Zr+W. The best results for Pb were those using Rh, Zr, W and Zr+Rh, obtaining characteristic masses of 42, 37, 34 and 36 pg, respectively. Pyrolysis and atomization temperatures of 910 and 1850 °C, respectively, were achieved for this metal. For Al, the best results were obtained when Zr or Zr+W were used. Mo was also tested as a possible permanent modifier for Al, but the results were not satisfactory. The results obtained for Mo without modifier were similar to those with conventional modifiers (Mg or Pd+Mg) and the results obtained using permanent chemical modifiers were not satisfactory. In all situations, the experiments were performed faster than those using the univariate procedure.

Optimisation conditions for obtaining maximum cavitation intensity in ultrasonic baths are proposed using a simple and fast method. Parameters such as water volume, temperature, detergent concentration, horizontal and vertical positions, number of tubes in the bath, sonication time and bath water substitution were studied. The results obtained for both baths studied (Neytech and Cole-Parmer) lead to the following conditions for maximum cavitation intensity: 1 L of water at room temperature, 0.2 % (v/v) of detergent, central position on the bottom of the tank. Only one tube at a time should be used inside the bath during the ultrasound application. The cavitation intensity was linear with the sonication time up to 10 minutes and the water substitution during the sonication improved reproducibility. This system using continuous water change makes possible the sonication of 6 consecutive samples, without changes in the water volume.

An experimental procedure for direct sediment analysis was developed. Using this procedure, copper, zinc and lead were determined and quantitative recoveries for these metals were accomplished at a low cost and with minimal sample manipulation. The influence of the nitric acid concentration on the slurry preparation, as well as the sediment particle size was investigated. Sediment slurries were treated with 6.0 mol L-1 nitric acid and 2% (m/v) ammonium chloride, and sonicated for 15 minutes in an ultrasonic bath before quantification by flame atomic absorption spectrometry. Using these conditions for a certified reference material, the percentage of recovery for copper, zinc and lead were 96.4 ± 4.9, 97.0 ± 4.0 and 99.7 ± 4.0, respectively.

Two new flavones, 5 -hydroxy -7,5' -dimethoxy -3',4' -methylenedioxyflavone and 5 -hydroxy -7,3',5' -trimethoxy -4' -(3,3 -dimethylallyloxy) flavone, as well as three known flavones: 5,6,7,3',4',5' -hexamethoxyflavone, 5 -hydroxy -8,3',4' -trimethoxy -2'',2'' -dimethylpyrano (5",6":6,7) -flavone and 5 -hydroxy -8,3',4',5' -tetramethoxy -2'',2'' -dimethylpyrano (5",6":6,7) -flavone were isolated from the leaves of Ficus gomelleira. Their structures were elucidated by spectroscopic methods and comparison with literature data.

Slurry sampling in combination with flame atomic absorption spectrometry was employed for the direct determination of four essential trace elements, namely Cu, Fe, Mn and Zn in Antarctic krill. The effect of instrumental operating conditions and slurry sampling preparation on the analytical signal was investigated. For the determination of Cu, Fe and Zn, samples were suspended in a solution containing 2 mol L-1 HNO3. In the case of Mn, 4 mol L-1 HNO3 was necessary for the preparation of the slurry. The precision between sample replicates was better than 5%. The method was applied to the direct determination of Cu, Fe, Mn and Zn in Antarctic krill samples using aqueous reference solutions to prepare the calibration curves. The results obtained were in good agreement with those achieved by FAAS and ICP-AES after microwave-assisted wet digestion of the krill samples. The detection limits were 4.5, 1.0, 4.9 and 8.4 mug L-1 for Cu, Zn, Mn and Fe, respectively.

A new coumarin, 5,6-methylenedioxy-7,8-dimethoxycoumarin has been isolated from the stems of Metrodorea flavida, as well as known coumarins and alkaloids. The structures of the new and the known compounds were established by spectral data and by comparison with the literature data.

Abstract Background In order to attain a better understanding of the interactions between opportunist fungi and their hosts, we investigated the cytokine profile associated with the inflammatory response to Candida albicans infection in mice with solid Ehrlich tumors of different degrees. Methods Groups of eight animals were inoculated intraperitoneally with 5 × 106 C. albicans 7, 14 or 21 days after tumor implantation. After 24 or 72 hours, the animals were euthanized and intraperitoneal lavage fluid was collected. Peritoneal macrophages were cultivated and the levels of IFN-γ, TNF-α, IL-12, IL-10 and IL-4 released into the supernatants were measured by ELISA. Kidney, liver and spleen samples were evaluated for fungal dissemination. Tumor-free animals and animals that had only been subjected to C. albicans infection were used as control groups. Results Our results demonstrated that the mice produced more IFN-γ and TNF-α and less IL-10, and also exhibited fungal clearance, at the beginning of tumor evolution. With the tumor progression, this picture changed: IL-10 production increased and IFN-γ and TNF-α release decreased; furthermore, there was extensive fungal dissemination. Conclusion Our results indicate that solid tumors can affect the production of macrophage cytokines and, in consequence, affect host resistance to opportunistic infections.

Objective: The objective of this study is to evaluate the association of disciplinary actions by regulatory councils and unprofessional behaviour during medical graduation., Methods: A search strategy was developed using the terms: 'physicians', 'disciplinary action', 'education', 'medical', 'undergraduate' and their synonyms, subsequently applied to the electronic databases MEDLINE, Embase, Cochrane Library, LILACs and grey literature, with searches up to November 2023. The risk of bias was assessed using the Newcastle-Ottawa scale and statistical analysis was performed using the RevMan software., Results: A total of 400 studies were found in the databases, and 15 studies were selected for full-texting reading. Four studies met the inclusion criteria and were included, bringing together a total of 3341 evaluated physicians. Three studies were included in the meta-analysis, showing a greater chance of disciplinary actions among physicians who exhibited unprofessional behaviour during medical graduation (OR: 2.54; 95%CI: 1.87-3.44; I 2 : 0%; P < 0.0001; 3077 participants; physicians with disciplinary action: 107/323; control physicians: 222/2754)., Conclusions: There is a statistically significant association between unprofessional behaviour during medical undergraduate study and subsequent disciplinary actions by Medical Councils. The tools for periodic assessments of student behaviour during undergraduate studies can be a perspective for future studies aimed at reducing disciplinary actions among physicians., (© 2024 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Background: Analyses of extensive registries indicate adverse outcomes for women undergoing coronary artery bypass grafting (CABG) surgery, while randomized studies often lack representativeness., Objective: To compare adjusted hospital outcomes between men and women undergoing CABG., Methods: From July 2017 to June 2019, 3991 patients underwent primary isolated CABG, both electively and urgently, in 5 hospitals in the state of São Paulo, Brazil. To mitigate demographic differences between men and women, populations were adjusted using propensity score matching (PSM). The outcomes considered for analysis were those used by the STS Adult Database. The analyses were performed using R software, with a significance set at p<0.05., Results: After PSM (1:1), each group included 1089 patients. Regarding intraoperative variables, men exhibited longer cardiopulmonary bypass (CPB) time (p<0.001), surgical time (p<0.001), a higher number of distal anastomoses (p<0.001), and increased use of arterial grafts. Regarding outcomes, women had a higher incidence of deep sternal wound infection (p=0.006), prolonged Intensive Care Unit stay (p=0.002), increased need for an intra-aortic balloon pump (p=0.04), higher blood transfusion rates (p<0.001), higher 30-day hospital readmission rates after surgery (p=0.002) and higher mortality rate (p=0.03)., Conclusions: Although men had longer CPB times, a greater number of arterial grafts, and a greater number of distal anastomoses, immediate results after CABG were poorer in women.

Background: Identifying risk factors in cardiovascular surgery assists in predictability, resulting in optimization of outcomes and cost reduction., Objective: This study aimed to identify preoperative and intraoperative risk predictors for prolonged hospitalization after coronary artery bypass grafting (CABG) surgery in the state of São Paulo, Brazil., Methods: A cross-sectional analysis using data from the REPLICCAR II database, a prospective, consecutive, multicenter registry that included CABG surgeries performed between August 2017 and July 2019. The primary outcome was a prolonged hospital stay (PHS), defined as a postoperative period exceeding 14 days. Univariate and multivariate logistic regression analyses were performed to identify the predictors with significance set at p <0.05., Results: The median age was 63 (57-70) years and 26.55% of patients were female. Among the 3703 patients analyzed, 228 (6.16%) had a PHS after CABG, with a median hospital stay of 17 (16-20) days. Predictors of PHS after CABG included age >60 years (OR 2.05; 95% CI 1.43-2.87; p<0.001); renal failure (OR 1.73; 95% CI 1.29-2.32; p <0.001) and intraoperative red blood cell transfusion (OR 1.32; 95% CI 1.07-2.06; p=0.01)., Conclusion: Age >60 years, renal failure, and intraoperative red blood cell transfusion were independent predictors of PHS after CABG. The identification of these variables can help in multiprofessional strategic planning aimed to enhance results and resource utilization in the state of São Paulo.

Background: The pathway that links good communication skills and better health outcomes is still unclear. However, it is known that the way that physicians and patients communicate with each other has direct consequences on more "proximal outcomes", such as perceptions of physician empathy and patient satisfaction. However, which specific communication skills lead to those patient outcomes is still unknown. In this study, the authors aimed to analyze which specific patient and physician communication skills are correlated to patients' satisfaction with care and patient-perceived physician empathy., Methods: The authors classified and quantified verbal and nonverbal communication of second-year internal medicine residents and their patients through video recordings of their consultations. Patients also rated their satisfaction with care and the physician's empathy for them., Results: Using a linear regression model, the authors identified that patients' and physicians' expressions of disapproval, physicians' disruptions, and patients' use of content questions negatively correlated to patients' satisfaction and patient-perceived physician empathy. Conversely, patient affective behaviors and the physician's provision of advice/suggestion were positively correlated to at least one of the patient-measured outcomes., Conclusion: Our findings point to the importance of physicians' attentiveness to patients' communication cues. Training physicians to interpret those cues could help develop more satisfactory and empathic therapeutic relationships., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Importance: The comparison between single-incision slings (SISs) and midurethral slings has been documented in the literature, but results vary according to the SIS device., Objectives: The purpose of this study is to assess whether SIS (Solyx) is noninferior to transobturator (TOT) (Obtryx) sling for treating women with confirmed stress-predominant urinary incontinence., Study Design: A prospective, parallel, nonblinded, multicenter, noninferiority, randomized controlled study with 114 patients were randomized and followed 6 and 12 months after surgery. Interventions were midurethral TOT sling (Obtryx-halo; n = 58) or SIS (Solyx; n = 56). The primary outcome was improvement in the Patient Global Impression of Improvement (PGI-I). Secondary outcomes were the Kings Health Questionnaire (KHQ) instruments after treatment, subjective improvement, and surgical outcomes., Results: Both groups were homogeneous ( P = NS) regarding sociodemographic and clinical variables. There was improvement in the PGI-I after 6 ( P = 0.001) and 12 months ( P = 0.001) of treatment for women who underwent TOT sling. After 6 months, KHQ scores improved in the TOT group for the following domains: role limitations ( P = 0.026) and physical limitations ( P = 0.006). After 12 months, the TOT group presented better KHQ scores that were statistically significant from the SIS group in incontinence impact ( P = 0.012), physical limitations ( P = 0.001), and severity measures ( P = 0.017). Moreover, the TOT group presented higher subjective improvement after 6 months ( P = 0.006) than the SIS group. Mesh erosion was higher in the SIS group ( P = 0.006). Reoperations were not statistically different between groups., Conclusion: There were higher scores in the PGI-I score and higher subjective improvement for the TOT sling after 6 and 12 months of treatment when compared with the SIS group., Competing Interests: The authors have no conflict of interest to disclose, except for Luiz Gustavo Brito, who received a donation from Boston Scientific regarding the slings and minislings. However, the company had no influence on the protocol and manuscript writing or at any phase of the study development., (Copyright © 2023 American Urogynecologic Society. All rights reserved.)

The Sanger Excellence Fellowship has been established to increase the representation of researchers with Black-heritage backgrounds at a leading research centre in the UK., Competing Interests: SA, DA, MH, AM, MA No competing interests declared, (© 2024, Ahmed et al.)

There is limited contemporary prospective real-world evidence of patients with chronic arterial disease in Latin America. The Network to control atherothrombosis (NEAT) registry is a national prospective observational study of patients with known coronary (CAD) and/or peripheral arterial disease (PAD) in Brazil. A total of 2,005 patients were enrolled among 25 sites from September 2020 to March 2022. Patient characteristics, medications and laboratorial data were collected. Primary objective was to assess the proportion of patients who, at the initial visit, were in accordance with good medical practices (domains) for reducing cardiovascular risk in atherothrombotic disease. From the total of patients enrolled, 2 were excluded since they did not meet eligibility criteria. Among the 2,003 subjects included in the analysis, 55.6% had isolated CAD, 28.7% exclusive PAD and 15.7% had both diagnoses. Overall mean age was 66.3 (± 10.5) years and 65.7% were male patients. Regarding evidence-based therapies (EBTs), 4% were not using any antithrombotic drug and only 1.5% were using vascular dose of rivaroxaban (2.5 mg bid). Only 0.3% of the patients satisfied all the domains of secondary prevention, including prescription of EBTs and targets of body-mass index, blood pressure, LDL-cholesterol, and adherence of lifestyle recommendations. The main barrier for prescription of EBTs was medical judgement. Our findings highlight that the contemporary practice does not reflect a comprehensive approach for secondary prevention and had very low incorporation of new therapies in Brazil. Large-scale populational interventions addressing these gaps are warranted to improve the use of evidence-based therapies and reduce the burden of atherothrombotic disease.ClinicalTrials.gov NCT04677725., (© 2024. The Author(s).)

Aim: Methylation of LDLR , PCSK9 and LDLRAP1 CpG sites was assessed in patients with familial hypercholesterolemia (FH). Methods: DNA methylation of was analyzed by pyrosequencing in 131 FH patients and 23 normolipidemic (NL) subjects. Results:  LDLR , PCSK9 and LDLRP1 methylation was similar between FH patients positive (MD) and negative (non-MD) for pathogenic variants in FH-related genes. LDLR and PCSK9 methylation was higher in MD and non-MD groups than NL subjects ( p  < 0.05). LDLR , PCSK9 and LDLRAP1 methylation profiles were associated with clinical manifestations and cardiovascular events in FH patients ( p  < 0.05). Conclusion: Differential methylation of LDLR , PCSK9 and LDLRAP1 is associated with hypercholesterolemia and cardiovascular events. This methylation profile maybe useful as a biomarker and contribute to the management of FH.

The advent of the COVID-19 pandemic forced medical schools around the world to adopt emergency remote learning as a resort to avoid interruption of courses. However, the effectiveness of online classes as an educational strategy has been questioned by medical educators and students. In a prospective observational study design, students enrolled in a renal physiology and pathophysiology course were exposed to either face-to-face or remote synchronous classes. Students taught online obtained significantly higher mean scores than the group who had in-person classes, both groups assessed with identical exams. Appropriate screening tests suggested that fraud is unlikely to have significantly influenced these results and that the observed differences in performance reflected increased learning by the remote group. These observations suggest that online classes can help to maintain the continuity of physiology and pathophysiology courses during periods of social isolation and may contribute to improving learning under normal conditions. NEW & NOTEWORTHY In this study, we were able to make a rare direct comparison of face-to-face and remote strategies for the teaching of undergraduate medical students in a specific area, namely, renal pathophysiology. Unexpectedly, students who attended the remote course had significantly higher grades than those who had mostly in-person classes.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Education mediated by simulation is a widely used method for teaching basic life support (BLS). The American Heart Association recommends protocols based on scientific evidence to reduce sequelae and mortality. We aimed to assess learning and retention of knowledge of BLS in students of the first semester of the medical course using teaching methods of dialogic expository class (group 1), expository and demonstrative class (group 2), and the two previous methodologies associated with simulated practice (group 3), and after 3 months, memory retention., Materials and Methods: This was an experimental, prospective, randomized study. Participants were assessed in terms of performance in theoretical and simulated practical tests, satisfaction with training (Likert scale), and knowledge retention., Results: The practical test results were analyzed by two experienced observers. Students had 20% progression in knowledge and 80% retention of knowledge after 3 months of exposure comparing the theoretical pre- and posttest. The students in group 3 performed better than the others ( P = 0.007) in the posttest. With the simulated practice, the knowledge acquired was maintained after 3 months with a mean performance of 90%, but in the test of the infant age group, there was a loss of learning retention by 10%. There was no difference of the results between the two evaluators ( P < 0.001). The training was positively assessed by the participants., Conclusion: The use of different methodologies promoted knowledge progression, with emphasis on simulated practice. Learning retention was maintained after 3 months. In order to teach BLS to infants, it may be necessary to improve teaching techniques., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Education and Health Promotion.)

Leishmaniasis is a parasitic disease found in tropical and subtropical regions around the world, caused by parasites of the genus Leishmania. The disease is a public health concern and presents clinical manifestations that can cause death, disability, and mutilation. The parasite has promastigote (vector) and amastigote (vertebrate host) forms and kinase enzymes are involved in this differentiation process. In the present investigation, we show, for the first time, evidence of a serine/arginine protein kinase in Leshmania braziliensis (LbSRPK). Our results show that amastigotes express more LbSRPK than promastigotes.  Analogues of SRPIN340 (a known inhibitor of SRPK) were evaluated for their leishmanicidal activity and two of them, namely SRVIC22 and SRVIC32 showed important leishmanicidal activity in vitro. SRVIC22 and SRVIC32 were able to reduce the infection rate in macrophages and the number of intracellular amastigotes by 55 and 60%, respectively. Bioinformatics analysis revealed the existence of two different amino acid residues in the active site of LbSRPK compared to their human homologue (Tyr/Leu-and Ser/Tyr), which could explain the absence of leishmanicidal activity of SRPIN340 on infected macrophages. In order to enhance leishmanicidal activity of the analogues, optimizations were proposed in the structures of the ligands, suggesting strong interactions with the catalytic site of LbSRPK. Although the evidence on the action of inhibitors upon LbSRPK is only indirect, our studies not only reveal, for the first time, evidence of a SRPK in Leishmania, but also shed light on a new therapeutic target for drug development., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a powerful predictor of perioperative outcomes. We evaluated the burden of CSA-AKI in patients with preserved baseline renal function., Methods: The data of 2,162 adult patients who underwent cardiac surgery from January 2005 to December 2020 were analyzed. Logistic regression models were used to determine predictors of CSA-AKI and their associations with hospital mortality up to 30 days., Results: The prevalence of acute kidney injury was 43.0%, and 2.0% of patients required renal replacement therapy. Hospital mortality rate was 5.6% (non-acute kidney injury = 2.0% vs. CSA-AKI = 10.4%, P&lt;0.001), and any degree of CSA-AKI was associated with a significant increase in death rates (stage 1 = 4.3%, stage 2 = 23.9%, stage 3 = 59.7%). Multivariable logistic regression analysis identified age, obesity, left ventricular dysfunction, previous cardiac surgery, and cardiopulmonary bypass duration as predictors of CSA-AKI. Moreover, CSA-AKI was confirmed as independent predictor of hospital mortality for stage 1 (odds ratio, 2.02; 95% confidence interval, 1.16 to 3.51; P=0.013), stage 2 (odds ratio, 9.18; 95% confidence interval, 4.54 to 18.58; P&lt;0.001), and stage 3 (odds ratio, 37.72; 95% confidence interval, 18.87 to 75.40; P&lt;0.001) patients., Conclusion: Age, obesity, left ventricular dysfunction, previous cardiac surgery, and cardiopulmonary bypass duration are independent predictors of CSA-AKI in patients with preserved baseline renal function. The development of CSA-AKI is significantly associated with worse outcomes, and there is a dose-response relationship between acute kidney injury stages and hospital mortality.

Clinical prediction models for deep sternal wound infections (DSWI) after coronary artery bypass graft (CABG) surgery exist, although they have a poor impact in external validation studies. We developed and validated a new predictive model for 30-day DSWI after CABG (REPINF) and compared it with the Society of Thoracic Surgeons model (STS). The REPINF model was created through a multicenter cohort of adults undergoing CABG surgery (REPLICCAR II Study) database, using least absolute shrinkage and selection operator (LASSO) logistic regression, internally and externally validated comparing discrimination, calibration in-the-large (CL), net reclassification improvement (NRI) and integrated discrimination improvement (IDI), trained between the new model and the STS PredDeep, a validated model for DSWI after cardiac surgery. In the validation data, c-index = 0.83 (95% CI 0.72-0.95). Compared to the STS PredDeep, predictions improved by 6.5% (IDI). However, both STS and REPINF had limited calibration. Different populations require independent scoring systems to achieve the best predictive effect. The external validation of REPINF across multiple centers is an important quality improvement tool to generalize the model and to guide healthcare professionals in the prevention of DSWI after CABG surgery., (© 2022. The Author(s).)

Pulmonary irritants, such as cigarette smoke (CS) and sodium hypochlorite (NaClO), are associated to pulmonary diseases in cleaning workers. We examined whether their association affects lung mechanics and inflammation in Wistar rats. Exposure to these irritants alone induced alterations in the lung mechanics, inflammation, and remodeling. The CS increased airway cell infiltration, acid mucus production, MMP-12 expression, and alveolar enlargement. NaClO increased the number of eosinophils and macrophages in the bronchoalveolar lavage fluid, with cells expressing IL-13, MMP-12, MMP-9, TIMP-1, and iNOS in addition to increased IL-1β and TNF-α levels. Co-exposure to both irritants increased epithelial and smooth muscle cell area, acid mucus production, and IL-13 expression in the airways, while it reduced the lung inflammation. In conclusion, the co-exposure of CS with NaClO reduced the pulmonary inflammation, but increased the acidity of mucus, which may protect lungs from more injury. A cross-resistance in people exposed to multiple lung irritants should also be considered., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lung physiology research advanced significantly over the last 100 years. Respiratory mechanics applied to animal models of lung disease extended the knowledge of the workings of respiratory system. In human research, a better understanding of respiratory mechanics has contributed to development of mechanical ventilators. In this review, we explore the use of respiratory mechanics in basic science to investigate asthma and chronic obstructive pulmonary disease (COPD). We also discuss the use of lung mechanics in clinical care and its role on the development of modern mechanical ventilators. Additionally, we analyse some bench-developed technologies that are not in widespread use in the present but can become part of the clinical arsenal in the future. Finally, we explore some of the difficult questions that intensive care doctors still face when managing respiratory failure. Bringing back these questions to bench can help to solve them. Interaction between basic and translational science and human subject investigation can be very rewarding, as in the conceptualization of "Lung Protective Ventilation" principles. We expect this interaction to expand further generating new treatments and managing strategies for patients with respiratory disease., Competing Interests: 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., (Copyright © 2022 Biselli, Degobbi Tenorio Quirino Dos Santos Lopes, Righetti, Moriya, Tibério and Martins.)

Cardiovascular diseases (CVD) are the most important cause of morbidity and mortality in the general population. Because the high prevalence of COVID-19 and chronic Chagas disease (CCD) where the latter is endemic, all such diseases will likely be observed in the same patient. While COVID-19 can provoke generalized endotheliitis, which can lead to a cytokine storm and a hyper-coagulable state culminating into in-site and at a distance thrombosis. Therefore, small-vessel coronary artery disease (CAD), cerebrovascular disease, thromboembolism, and arrhythmias are prominent findings in COVID-19. In CCD, small-vessel CAD, cardioembolic stroke, pulmonary embolism, heart failure and arrhythmias are frequently observed as a result of a similar but less intense mechanism. Consequently, the association of CCD and COVID-19 will likely increase the incidence of CVD. Thus, doctors on the frontline should be on the alert for this diagnostic possibility so that the proper treatment can be given without any delay., Competing Interests: 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., (Copyright © 2022 Bestetti, Bocchi, Bestetti, Issa, Furlan-Daniel and Nakazone.)

Objectives: Fragility fractures increase morbidity and mortality. Adding assessment of clinical risk factors independently or as a previous step to Bone Densitometry (BD) should provide better accuracy in fracture risk prediction. FRAX tool might be used to stratify patients in order to rationalize the need for BD and risk classification. The primary objective of this study is to describe and perform comparisons between the estimated risk of fractures in 10 years using the FRAX calculator based on clinical factors with and without BD results for women aged 40 or more with clinical diseases monitored in tertiary care service in internal medicine., Methods: Cross-sectional. Women over 40 years with BD in the previous year. After medical chart review, identification of risk factors and risk estimations using FRAX-BRAZIL with (FRAX BDI) and without (FRAX BDNI) the inclusion of T-score., Results: 239 women. Age 65 ± 10.35 years. BMI 29.68 ± 6.27kg/m 2 ., Risk Factors: 32(13.4%) previous fractures; 23 (9.6%) current smoking; 78 (32.6%) corticosteroids use; 44 (18.4%) rheumatoid arthritis; 38 (15.9%) secondary causes; FRAX scores were higher when BD was not included. Spearman correlation coefficients between FRAX BDNI and FRAX BDI for major fractures r = 0.793 (95% CI 0.7388‒0.836). For hip fractures r = 0.6922 (95% CI 0.6174‒0.75446) CONCLUSION: Using FRAX to estimate 10-year fracture risk without BD data might be a reliable tool for screening, even for patients with a high prevalence of risk factors, improving accessibility and equity in health systems. The present study's data suggest an overestimation of fracture risk with FRAX BDNI, suggesting that it is safe to be widely used as a screening tool., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Connections between epidemiological findings and children's and adolescents' mental health policies have not been properly made in Brazil, and such nationwide studies are scarce. This epidemiological study (1) estimated the prevalence and predictors of parent-reported attention-deficit/hyperactivity disorder (ADHD) (ADHD-report), (2) estimated the probable diagnosis and risk of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 5th edition, criteria (ADHD-probable), and (3) estimated current psychostimulant use (ADHD-pst) in a representative nationwide sample of Brazilian school-aged children and adolescents., Methods: Data were obtained from 7114 school-aged children (49.9% boys) from 87 cities in 18 Brazilian states. Parents and teachers were interviewed using psychometrically sound questionnaires. Data and codes are available., Results: The prevalence of ADHD-report, ADHD-probable, and ADHD-pst were 7.1%, 3.9%, and 1.9%, respectively. The agreement was low between ADHD-probable and ADHD-report (22.6%) and between ADHD-report and ADHD-pst (15.6%). Logistic regression revealed that predictors of all three categories were male gender (odds ratio [OR] = 1.71, 2.32, and 1.96, respectively), divorced parents (OR = 1.47, 1.65, and 1.68, respectively), and below-expectation school performance (OR = 3.1, 13.74, and 3.95, respectively). Socioeconomic status was a significant predictor of ADHD-report, and participants from lower classes were less frequently diagnosed with ADHD than their peers from upper classes (OR = 0.57, 95% confidence interval = 0.37-0.88, P = 0.012)., Conclusions: The present findings provide an accurate description of ADHD in Brazil. We suggest disparities in agreement between report, risk, and psychostimulant use among children and adolescents and discrepancies between socioeconomic classes concerning the prevalence of an ADHD diagnosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Executive functions (EF) are a set of high order mental abilities that regulate cognition, emotions, and behavior. This study aims to report the construction and validation of a rating scale instrument for EF in children and adolescents aged from 5 to 18 years (EFICA), as well as to report the results of a comparison between children with ADHD and their peers without it. Thus, we conducted a population-based cross-sectional study relying on a sample composed of 3,284 typical children and adolescents accessed to study the psychometric properties of the parents' inventory (EFICA-P) and the teacher's inventory (EFICA-T) within a Structural Equation Modeling framework (SEM). Exploratory and confirmatory analyses were fitted, as well as the Cronbach's alpha and the McDonald's omega reliability indices. The known-groups method was carried out by independent Welch t -tests between untreated ADHD children and their peers. We concluded that the parents' inventory is composed of three dimensions (Cool Index 1, Cool Index 2, and Hot Index): χ 2 (1,649) = 4,607.852 p  < .01, CFI = .965, TLI .963, RMSEA = .053, whereas the teachers´ inventory is composed of two dimensions (Cool Index and Hot Index): χ 2 (1,273) = 5,158.240, p  < .01, CFI = .991, TLI = .991, RMSEA = .077. The internal consistency of both inventories was >.9. Significant differences between the ADHD groups were found in all domains accessed. These findings indicate that both inventories have a high degree of validity regarding their internal structures, as well as supporting their clinical utility.

Background: The impact of left ventricular reverse remodeling (LVRR) on the prognosis of Chagas cardiomyopathy is unknown. The aim of this study was to determine whether the presence of LVRR can predict mortality in these patients., Methods: From January 2000 to December 2010, the medical charts of 159 patients were reviewed. LVRR was defined as an increase of left ventricular ejection fraction (LVEF) and a decrease of left ventricular end-diastolic diameter (LVDD) by two-dimensional echocardiography. No patient underwent cardiac resynchronization therapy or required mechanical ventricular assistance., Results: At baseline, median (25th-75th) LVDD was 64 mm (59-70), and median LVEF was 33.2% (26.4-40.1). LVRR was detected in 24.5% of patients in a 40-month (26-64) median follow-up. In the LVRR group, LVDD decreased from 64 mm (59-68) to 60 mm (56-65; p < 0.001), and LVEF increased from 31.3% (24.1-39.0) to 42.5% (32.2-47.7; p < 0.001). However, LVRR was not associated with heart failure hospitalization, cardiogenic shock, heart transplantation, or mortality (p > 0.05 for all comparisons). The Cox proportional hazard model analysis identified only cardiogenic shock (hazard ratio [HR]: 2.41; 95% confidence interval [CI]: 1.51-3.85; p < 0.001) and serum sodium level (HR: 0.91; 95% CI: 0.86-0.96; p < 0.001) as independent predictors of all-cause mortality., Conclusions: Left ventricular reverse remodeling occurs in one quarter of patients with Chagas cardiomyopathy and have no impact on the outcomes of patients with this condition.

The imbalance between pro- and anti-inflammatory immune responses mediated by Th17 and Treg cells is deeply involved in the development and progression of inflammation in chronic obstructive pulmonary disease (COPD). Several clinical and experimental studies have described the Th17/Treg imbalance in COPD progression. Due to its importance, many studies have also evaluated the effect of different treatments targeting Th17/Treg cells. However, discrepant results have been observed among different lung compartments, different COPD stages or local and systemic markers. Thus, the data must be carefully examined. In this context, this review explores and summarizes the recent outcomes of Th17/Treg imbalance in COPD development and progression in clinical, experimental and in vitro studies., Competing Interests: 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., (Copyright © 2021 Lourenço, Ito, Martins, Tibério and Lopes.)

This study aimed to evaluate the clinical evolution, functional parameters and inflammatory activity of asthma in patients who submitted to an educational intervention. 58 adult patients over 18 years of age with partly controlled and uncontrolled asthma were randomized into an intervention group (IG) (N = 32) and a control group (CG) (N = 26) and evaluated for 12 weeks. The Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), Asthma Quality Life Questionnaire (AQLQ) and Beck Depression Inventory (BDI) questionnaires were applied. Spirometry, exhaled nitric oxide (NO), exhaled breath condensate (EBC) and induced sputum (IS), measurement of the peak flow and symptoms were performed. The IG patients received an educational activity for 30 min applied by a nurse. Statistical analysis: analysis of variance with repeated intragroup measures. IG presented a decreased number of eosinophils in IS and IL-17A in EBC, an increase in the percentage of FEV 1 before and after bronchodilator and an improvement in quality of life compared to the CG. There was an improvement in depression levels and a decrease in IL-4 and IL-5 in the IS and in the EBC in both groups. Our results suggest that an educational intervention can bring benefits concerning the control of inflammation, lung function alterations, quality of life and levels of depression in asthmatic patients. Registration: ClinicalTrials.gov; NCT03655392., (© 2021. The Author(s).)

Selenium (Se) is an essential micronutrient for humans. Garlic ( Allium sativum L.) metabolises Se into important Se-amino acids like Se-methylselenocysteine (Se-MetSeCys), precursor of methylselenol, an active species for cancer prevention. Therefore, the Se accumulation and speciation in garlic were studied to evaluate their relations with growth stages and types of plant clones. Four garlic clones (Nieve INTA, Union FCA, Gostoso INTA and Rubí INTA) were fortified with a Se solution (169 g Se L -1 ). The association of Se to different molecular weight fractions was evaluated by size-exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS) detection. Also, anion exchange chromatography (AEC-ICP-MS) was used for the determination of Se-amino acids, while their identification was performed by ESI-MS/MS. The Se was incorporated into high (7-5 kDa) and low (2-4 kDa) molecular weight fractions. The presence of Se-MetSeCys was observed mostly. Se-MetSeCys increased in bulbs to a maximum value but increased, then decreased, in leaves and roots. The Se-organic species were mostly found in bulbs in the last growth stage. Garlic showed a significant ability to accumulate and metabolise Se, specially, the red clones (Gostoso INTA and Rubí INTA). Also, this work suggests that this plant may become an attractive source of Se-amino acids with important biological properties.

Triatomine assassin bugs comprise hematophagous insect vectors of Trypanosoma cruzi, the causative agent of Chagas disease. Although the microbiome of these species has been investigated to some extent, only one virus infecting Triatoma infestans has been identified to date. Here, we describe for the first time seven (+) single-strand RNA viruses (RpV1-7) infecting Rhodnius prolixus, a primary vector of Chagas disease in Central and South America. We show that the RpVs belong to the Iflaviridae, Permutotetraviridae and Solemoviridae and are vertically transmitted from the mothers to the progeny via transovarial transmission. Consistent with this, all the RpVs, except RpV2 that is related to the entomopathogenic Slow bee paralysis virus, established persistent infections in our R. prolixus colony. Furthermore, we show that R. prolixus ovaries express 22-nucleotide viral siRNAs (vsiRNAs), but not viral piRNAs, that originate from the processing of dsRNA intermediates during viral replication of the RpVs. Interestingly, the permutotetraviruses and sobemoviruses display shared pools of vsiRNAs that might provide the basis for a cross-immunity system. The vsiRNAs are maternally deposited in the eggs, where they likely contribute to reduce the viral load and protect the developing embryos. Our results unveil for the first time a complex core virome in R. prolixus and begin to shed light on the RNAi-based antiviral defenses in triatomines., Competing Interests: The authors have declared that no competing interests exist.

Background: The performance of traditional scores is significantly limited to predict mortality in high-risk cardiac surgery. The aim of this study was to compare the performance of STS, ESII and HiriSCORE models in predicting mortality in high-risk patients undergoing CABG., Methods: Cross-sectional analysis in the international prospective database of high-risk patients: HiriSCORE project. We evaluated 248 patients with STS or ESII (5-10%) undergoing CABG in 8 hospitals in Brazil and China. The main outcome was mortality, defined as all deaths occurred during the hospitalization in which the operation was performed, even after 30 days. Five variables were selected as predictors of mortality in this cohort of patients. The model's performance was evaluated through the calibration-in-the-large and the receiver operating curve (ROC) tests., Results: The mean age was 69.90±9.45, with 52.02% being female, 25% of the patients were on New York Heart Association (NYHA) class IV and 49.6% had Canadian Cardiovascular Society (CCS) class 4 angina, and 85.5% had urgency or emergency status. The mortality observed in the sample was 13.31%. The HiriSCORE model showed better calibration (15.0%) compared to ESII (6.6%) and the STS model (2.0%). In the ROC curve, the HiriSCORE model showed better accuracy (ROC = 0.74) than the traditional models STS (ROC = 0.67) and ESII (ROC = 0.50)., Conclusion: Traditional models were inadequate to predict mortality of high-risk patients undergoing CABG. However, the HiriSCORE model was simple and accurate to predict mortality in high-risk patients., Competing Interests: The authors have no conflict of interest to declare in relation to this work.

Background: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide., Objectives: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH)., Methods: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients., Summary: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To investigate the external validity of recent antihyperglycaemic trials evaluating cardiovascular outcomes in a multimorbid population., Materials and Methods: Selection criteria of 15 randomized controlled trials from the 2020 American Diabetes Association Standard of Care statement were applied in a stepwise manner to tertiary care patients with type 2 diabetes. Primary outcomes were the number of patients eligible per individual trial and for the aggregate of trials. Secondary outcomes included patient predictors of trial eligibility., Results: Of 1059 patients, the mean (SD) age was 66 (10.74) years, the median (IQR) Charlson index was 2 (2, 3) and 458 (43%) had documented cardiovascular disease. The median (IQR) number of patients included in individual trials was 263 (174.25-308.75) and 795 (75.1%) of them were eligible for at least one trial. Among those 264 ineligible, 127 (48.1%) had an HbA1c level of 7% or less and no cardiovascular disease; 53.5% and 34.4% of the patients were eligible for two and three different classes of drugs, respectively. The strongest predictor of trial eligibility was cardiovascular disease (risk ratio 2.17, 95% CI 2.01-2.35)., Conclusions: A considerable proportion of multimorbid patients would be eligible for recent antihyperglycaemic trials. This positive finding can be attributed to development guidance in diabetes trials and the different approach we took, in which we evaluated inclusion by trials as an aggregate., (© 2020 John Wiley & Sons Ltd.)

Background: Even students with previous academic success may face challenges that affect their academic performance. Many medical schools offer programs to students at the risk of academic failure, to ensure that they succeed in the course., Objective and Methods: In this report we describe a pioneering academic tutoring program developed at a Brazilian medical school and discuss the initial results of the program based on the feedback from tutors and data regarding the progression of students in the medical course., Results: In 2018, 33 students enrolled into the program. Students' performance difficulties were mainly associated with mental health problems and socioeconomic vulnerability. Of the 33 students, 27 (81.8%) were assisted by the Mental Health Support Service and 16 (48.5%) were assisted by the Social Assistance Service. In addition to the planning academic activity class load, tutors were able to assist students in solving socioeconomic issues, carrying out personal support interventions with the promotion of self-esteem, and presenting suggestions for behavioral changes in their routine. For most students (72%), the action plan proposed by the tutors was successful. Eight of the 14 (57%) students in the fourth year progressed to the final two years of in-hospital practical training (internship)., Conclusions: The Academic Tutoring Program showed positive results for most of the students. Close monitoring and tutor intervention allowed students with poor academic performance to overcome the low performance cycle. These important tasks demand time and energy from tutors, and institutional recognition of these professionals is essential for the successful maintenance of the program.

Multimorbidity requires complex and ongoing care. Understanding the subjective illness experience is critical to effective care. Literature isn't clear about illness perception in patients with multimorbidity followed in services of high complexity. This study aims to investigate the illness experience based on narratives about daily living and symptoms of patients with multimorbidity and pain in a tertiary health care service., Methods: Qualitative narrative inquiry design with framework analysis from semi-structured interviews at a tertiary internal medicine outpatient clinic. Patients with Elixhauser comorbidity index ≧3 or and pain during the last week were included. Framework analysis was performed using 3 main patterns of illness experience from a previous study: "Gliding swan" (Resilience); "Stormy Seas" (Vulnerability); and "Stuck adrift" (Disruption); and identifying subthemes. One case study was selected from each main category. 43 patients, 14 classified as "gliding swan," 12 as "stormy seas" and 17 as "stuck adrift." Within the "gliding swan" group, positive examples of how to navigate through physical and emotional factors to sustain their wellbeing based on comprehension; In the "stormy seas" group, themes revolved around vulnerability, burden and ambiguity in relation to the health team. In the "stuck adrift" group the main content was about overwhelmed feelings and limitations., Conclusions: Narratives brought the content about lacking personalized understanding of diseases, with great emotional repercussion. Some meaningful anchors were highlighted. This study reinforces multimorbidity and pain interact and that healthcare professional should be aware of the turbulences that can disturb navigation in the raging seas of long-term multimorbid conditions., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)