The aim of the current work was to establish if alexithymia predicts disordered eating in a non-clinical sample directly and indirectly (via negative affect).Alexithymia is an independent predictor of symptoms of eating disorders, but also influences disordered eating in clinical samples indirectly n = 248) completed measures of depression, anxiety, alexithymia, and disordered eating . Bias-corrected bootstrapping was used to conduct parallel mediation analyses to determine if negative affect (depression and anxiety) mediated the influence of alexithymia on disordered eating.A sample of healthy females (difficulty identifying feelings) and drive for thinness was mediated by depression but not anxiety. The link between difficulty identifying feelings and bulimia was mediated by anxiety but not depression. The correlation between alexithymia (difficulty describing feelings) and body dissatisfaction was mediated by both depression and anxiety. However, after controlling for negative affect, difficulty identifying feelings remained an independent predictor of drive for thinness, and difficulty describing feelings remained an independent predictor of body dissatisfaction.The relationship between alexithymia  directly predict disordered eating in healthy participants as well as indirectly  Evidence in support of this proposal comes from studies reporting no change in alexithymia levels in patients in remission from their eating disorder , 19. Howdieting, bulimia, and oral control . Mediation analyses were conducted to examine the potential role of negative affect in the relationship between alexithymia and disordered eating. The proposed mediation model is presented in via the mediators. Given that drive for thinness, bulimia, and body dissatisfaction are dimensional factors that cut across clinical and non-clinical populations (The aims of the current study were to (i) confirm findings that disordered eating is positively related to alexithymia (DIF and DDF) in non-clinical participants, and (ii) to examine if depression and/or anxiety would mediate the influence of alexithymia on disordered eating in a non-clinical sample. Participants completed self-report measures of alexithymia (TAS-20), negative affect (depression and anxiety) and disordered eating . However, given that controlling for negative affect can reduce the strength of the relationship between alexithymia and disordered eating . However, as controlling for negative affect can diminish the relationship between alexithymia and disordered eating  was expected, in line with previous work , difficulty describing feelings , and externally oriented thinking ]. Participants indicate the extent to which each item describes them using a 5-point Likert scale . Scores on the subscales range between 7–35 (DIF), 5–25 (DDF), and 8–40 (EOT) and are summed to give a total TAS-20 score, which ranges between 20 and 100, with higher scores indicating greater alexithymia. The TAS-20 has been shown to be valid , bulimia , and body-dissatisfaction . Participants rate the extent to which each statement is true of them using a 6-point Likert scale . All items are scored from 0–3 (from least to most severe disordered eating). Responses indicating the most severe symptoms are scored three, two, and one, respectively, whilst the remaining three responses are scored zero. Scores on the DFT and Bul subscales range between 0 and 21, and scores on the BD subscale range between 0 and 27. These scales have been shown to have good reliability in student samples . All data were treated as continuous variables. Spearman correlations were used to determine the significance of the associations between variables . Preliminary analysis revealed that difficulty identifying feelings and difficulty describing feelings subscales, but not the externally oriented thinking subscale, of the TAS-20 were correlated with all measures of disordered eating. Furthermore, DIF and DDF were strongly correlated (0.67) with each other, suggesting they were measuring similar constructs. Partial correlations revealed that, after controlling for DDF, DIF was still significantly associated with DFT and bulimia, but not body dissatisfaction. On the other hand, after controlling for DIF, DDF was only significantly correlated with body dissatisfaction and not DFT or bulimia. Therefore, DIF was included as the predictor in the mediation analyses for DFT and bulimia and DDF was included as the predictor in the mediation analysis for body dissatisfaction. Separate mediation analyses were conducted for each of the three eating subscales with depression and anxiety entered as parallel mediators, in line with previous research . The jMMp < 0.001; BUL (mean difference = 0.41), t(248) = 1.94, p = 0.053; and BD (mean difference = 1.29), t(248) = 2.33, p < 0.05. However, importantly, comparison of the current scores with the norms for a clinical sample , t(248) = 22.4, p < 0.001, and BD (mean difference = −7.38), t(248) = 13.3, p < 0.001, which supports the non-clinical status of the current sample.Comparison of the mean EDI scores from the current study  than that reported in a sample of clinically diagnosed patients with eating disorders , t(246) = 3.01, p < 0.01. Importantly, in comparison to a clinical sample (p < 0.001) and depressed  = 39.4, p < 0.001. Taken together the pattern is consistent with our conception of the current sample as non-clinical.Comparison of the mean TAS-20 total score with a recent UK student sample  revealedisorders ; t(205) students  revealedl sample  the partdrive for thinness, bulimia, and body dissatisfaction) was significantly positively related to alexithymia  and mood (depression and anxiety). There were also significant associations between alexithymia and mood. It is notable that age was significantly related to alexithymia, disordered eating, and mood1. As observed relationships were based on Spearman correlations the mediational analyses were conducted using the ranked data.Correlational analyses see  using Spdifficulty identifying feelings as the predictor variable, drive for thinness as the dependent variable, and anxiety and depression as parallel mediators. The paths of this model are illustrated in A regression was conducted with 1) from DIF to anxiety was significant, as was the path (a12) from DIF to depression. The path (b11) from anxiety to drive for thinness was not significant, but the path (b12) from depression to drive for thinness was significant. The total effect of DIF on drive for thinness (c1) was significant, as was the direct effect (c’1), controlling for the influence of depression and anxiety. The indirect effect of DIF on drive for thinness (a11 + b11) via anxiety was not significant. However, the indirect effect via depression (a12 + b12) was significant. This suggests that the influence of DIF on drive for thinness was mediated by depression but not anxiety. However, even after controlling for negative affect, DIF remained an independent predictor of drive for thinness.The path  from DIF to anxiety was significant, as was the path (a22) from DIF to depression. The path (b21) from anxiety to bulimia was significant, but the path (b22) from depression to bulimia was not significant. The total effect of DIF on bulimia (c2) was significant, but the direct effect (c’2) was no longer significant, after controlling for the influence of depression and anxiety. The indirect effect of DIF on bulimia (a21 + b21) via the mediator (anxiety) was significant. However, the indirect effect via depression (a22 + b22) was not significant. This suggests that the influence of DIF on bulimia was mediated by anxiety but not depression. Furthermore, after controlling for negative affect DIF no longer directly predicted bulimia.The path  from DDF to anxiety was significant, as was the path (a32) from DDF to depression. The path (b31) from anxiety to body dissatisfaction was significant, as was the path (b32) from depression to body dissatisfaction. The total effect of DDF on body dissatisfaction (c3) was significant, as was the direct effect (c’3), after controlling for the influence of depression and anxiety. The indirect effect via depression (a32 + b32) was significant. However, the indirect effect of DDF on body dissatisfaction (a31 + b31) via anxiety was only trend significant (p = 0.056). This suggests that the influence of DDF on body dissatisfaction was mediated by depression and to some extent anxiety. Furthermore, after controlling for negative affect, DDF remained an independent predictor of body dissatisfaction.The path (a3drive for thinness (DFT) was supported by the current findings. This is consistent with previous studies  via depression corresponds with evidence from clinical samples (The aims of the current study were to (i) confirm findings that disordered eating is positively related to alexithymia (DIF and DDF) in healthy participants, and (ii) to examine if depression and/or anxiety would mediate the influence of alexithymia on disordered eating in a non-clinical sample. The expectation that DIF and DDF would be positively related to  studies , 33, 35.icipants . The fin samples , 47.bulimia was supported by the current findings. This is consistent with previous studies . This is consistent with evidence that negative affect accounts for the relationship between alexithymia and disordered eating  was larger than the cohorts used in related the clinical mediation studies , with the subscales measuring difficulty identifying and describing feelings correlating even more strongly . This suggests that similar findings would have been observed had the BVAQ been used in place of the TAS-20. However, it is notable that self-report measures of emotion processing deficits like the TAS-20 and BVAQ do not always correlate with implicit measures of emotion processing. For example, a recent study showed that participants with obesity reported similar levels of alexithymia to normal weight controls, but demonstrated deficits on an implicit emotion processing task  was still an independent predictor of drive for thinness and body dissatisfaction. One implication of our work is that future studies examining the potential roles of alexithymia and negative affect in the development of disordered eating should aim for larger sample sizes (n≈400) to ensure that they are also powered to detect very small effects. Another implication is that the influence of alexithymia on disordered eating (at least drive for thinness and body dissatisfaction) cannot be entirely explained by negative affect. The current findings are cross-sectional and correlational and, thus, cannot provide evidence of the direction of causation. However, as alexithymia is considered to be a relatively stable trait that is a risk factor for disordered eating  can be found below: The data is available The studies involving human participants were reviewed and approved by the Research Ethics Committees of both Aston University and De Montfort University. The patients/participants provided their written informed consent to participate in this study.NR and DW designed and supervised the study and wrote the manuscript. Data was collected by undergraduate research assistants. NR analysed the data. Both authors contributed to the article and approved the submitted version.


CFTR-related metabolic syndrome (CRMS) is a novel diagnosis due to widespread use of and advances in the newborn screening (NBS) process for cystic fibrosis (CF) in the United States of America, allowing for the diagnosis of asymptomatic children with CF. Before 2015, a large Puerto Rican pediatric population was not screened for CF in the NBS test. Studies have shown that patients presenting with idiopathic recurrent or chronic pancreatitis have an increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We present a retrospective chart review of 12 pediatric cases (n = 12) that were presented to an outpatient community clinic with clinical manifestations associated with CF. The pancreatic insufficiency prevalence (PIP) score was calculated on CFTR mutations. The mutations considered for the calculation of the PIP score were: F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519_1521del), and L1335P (c.4004T > C). V201M mutation was classified as mild in both PIP scores, and a correlation with pancreatitis was noted. Clinical manifestations vary in cases with the V201M variant (c.601G > A). One case was diagnosed with CFTR-related disorder (CRD) and recurrent pancreatitis. It is important to consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico due to the implications and increased risk of pancreatitis and other CF-related complications.  CFTR-related metabolic syndrome (CRMS) in the United States of America. When a CF screening test does not meet the established criteria as per CF guidelines [CFTR-related disorder (CRD), should be a diagnostic consideration as part of the differential diagnosis in a patient with clinical symptoms. It is suggested that the term CRMS be used to refer to newborns with hypertrypsinogenemia on the NBS who have sweat chloride readings <60 mmol/L and up to two CFTR variants, at least one of which is not characterized as a CF-disease-causing variant, and who do not match the criteria set out by the CF Foundation for the diagnosis of CF [Advances in genetics, the implementation of newborn screening (NBS), and the availability of sweat tests allow for early diagnosis of children with cystic fibrosis (CF) and idelines , other eis of CF . CRD is is of CF . In PuerCFTR gene [CFTR variants [CFTR variants with mild phenotypic effects have a greater risk of developing pancreatitis than those associated with moderate-to-severe phenotypes. This CFTR genotype–phenotype correlation found in pancreatitis is unique compared to other organ manifestations related to the complex monogenic nature of the CF disease [CFTR gene that are now elevating the risk of pancreatitis in the Puerto Rican pediatric population.Patients presenting with recurrent-acute or chronic pancreatitis have an increased frequency of mutations in the FTR gene . A smallvariants . The pan disease . As a ren = 12) referred to an outpatient community clinic specialized in the evaluation of rare pediatric pulmonary disorders in Puerto Rico. Each pediatric patient was previously or recently diagnosed, as per CF Foundation guidelines [CFTR variants. Genetic testing results were analyzed regarding the base change, protein/intron position, zygosity, and variant classification. An electronic chart review of the enzymatic measurements of lipase, amylase, and pancreatic stool elastase levels was assessed when available. Based on the reference values, patients were classified as either exocrine pancreatic insufficient (EPI) (<200 mcg/g stool elastase) or exocrine pancreatic sufficient (EPS) (>200 mcg/g stool elastase). The pancreatic insufficiency prevalence (PIP) score was calculated and compared to those in the CFTR2 database for the same mutations. CFTR mutations found were explored in the Clinical and Functional Translation of CFTR (CFTR2) database from patients from the United States and around the world [CFTR variant name, exocrine pancreatic insufficiency (EPI) patients, exocrine pancreatic sufficiency (EPS) patients, and the total number of patients with each variant in the database was completed. The CFTR variants in the cohort with a PIP score of ≤0.25 were classified as mild. The PIP score was also calculated for CFTR2 patients and compared with those found in our retrospective cohort of pediatric patients from Puerto Rico. The Institutional Review Board of the Ponce Health Sciences University in Ponce, Puerto Rico approved data collection and analysis for the protection of human subjects. We present a retrospective chart review of 12 pediatric cases , seven were males (58%) and five were females (42%) with a median age of 7.55 years and Puerto Rican ethnicity. The most frequently reported findings were FTT, recurrent pancreatitis, and abnormal IRT. The complete data list for CFTR base change, protein/intron position, zygosity, and mutation classification is presented in From a total of 12 pediatric patients (The mutations F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519 1521del), and L1335P (c.4004T > C), which were present in two or more cases, were considered for the calculation of the PIP score. F508del obtained a PIP score of 0.25 in our cohort and 0.88 in the CFTR2 database, V201M PIP scores of 0.00 and 0.23, I507del PIP scores of 1.00 and 0.89, and finally, L1335P PIP scores of 0.50 and 0.37. V201M mutation was classified as mild in both PIP scores of 0.00 and 0.23. The CFTR2 database had a total of 53,480 EPI patients for F508del, 3 EPI patients for V201M, 529 EPI patients for I507del, and 11 EPI patients for L1335P. Our cohort had one EPI patient for F508del, zero EPI patients for V201M, two EPI patients for I507del, and finally, one EPI patient for L1335P, which are presented in CFTR gene. Physiologically, it is a disorder of chloride and bicarbonate transport through epithelial membranes resulting from the absence or inappropriate functioning of the CFTR protein [CF is a clinical diagnosis due to the broad spectrum and severity of symptoms and organs affected amongst individuals ,9,10,11.CFTR genotype [CFTR genotypes [CFTR and other missense mutations of CFTR have not yet been identified for their role in gene expression and function [Recurrent-acute or chronic pancreatitis illustrates an accurate phenotype of CFTR dysfunction . CF-disegenotype . After Penotypes . In the function . In our function ,17. CFTR genetic mutations, such as in Puerto Rico [In our study cohort, the I507del and L1335P variations were classed as moderate, as they are in the CFTR2 database. Cases 7 and 9 in our study cohort presented with the V201M variant (c.601G > A) but clinical manifestations, physical findings, and diagnoses varied between the two cases. Case 7 was diagnosed with CRMS, and clinical manifestations and physical findings were remarkable for the history of recurrent pancreatitis. Currently, case 7 is EPS, and the diagnosis of pancreatitis increases her risk of developing EPI in the future . The exarto Rico . To addrIt is essential to continue monitoring and consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico with complaints such as failure to thrive, abdominal pain, and pancreatitis. A considerable portion of the Puerto Rican pediatric population was not screened for CF prior to 2015 since IRT levels were not yet included in the NBS. At the same time, access to sweat tests on the island was limited, with only one laboratory previously available. As a result, adolescents may be at risk of complications of CFTR dysfunction, such as pancreatitis, in Puerto Rico. Our team has recently established a second laboratory for sweat test collection and analysis, which has been operating since 2021. This facility adheres to the guidelines established by the CF Foundation, makes use of cutting-edge equipment, and is fully accredited by the Clinical Laboratory Improvement Amendments (CLIA). CFTR variants associated with an increased risk of pancreatitis [CFTR variants and functions is much needed to understand and develop targeted drug treatments for underrepresented populations in research. Currently, there is no specific therapy for CF-related pancreatitis, but new and highly effective CFTR modulator therapies aiming to modulate and potentiate the CFTR function may have implications for specific mutations affecting the gastrointestinal component of patients with CF-related pancreatitis and EPI [All these efforts will help us to increase awareness about the disease, which may help to identify and recruit more patients for research in Puerto Rico. In the pediatric population, the risk of malignancy is low. However, as the age of survival continues to rise, there is an increased risk of malignancy in the gastrointestinal and biliary tracts for patients with reatitis . Insight and EPI ,25. CFTR variants in Latin America. Specific screening panels customized to their population's genetic profile were researched in Ecuador, demonstrating the need to study Puerto Rico's genetic profile to understand our unique CFTR variability [CFTR variants [CFTR variants in Puerto Rico and the Dominic Republic, showing an increased variability of the CFTR variants, with a high potential to be missed by the newborn screening [CFTR variant for Puerto Rico was F508del, congruent with our observations. A cross-sectional investigation in Uruguay found that the incidence of CF was significantly lower than the state authorities claimed [CFTR genetic variants in our population, especially in adults.Similarly, challenges with CF identification are lower in North American and European countries compared to Latin American nations due to a lack of official patient registries, universal access to newborn screening, up-to-date diagnostic technologies, and interdisciplinary and specialized clinical centers . Table 6iability . Howevervariants ,29. Priovariants ,30. The creening . In the  claimed . AdditioCFTR variants is required, as demonstrated by a study in Colombia [CFTR variants to the mixture of European, Amerindian, and African ancestry in many Latin American countries such as Puerto Rico. According to research, Mexico has one of the most diversified CFTR spectra in the world [CFTR variants in Latin America may help to clarify the complexity and segregation of rare CFTR variants in our communities. As a result of the heterogeneity of CF, a registry of Colombia , to tailhe world . This trhe world . The preCFTR variants causing recurrent pancreatitis and EPI in Puerto Rico. We described the association between V201M CFTR mutation and CRMS diagnosis with a greater risk of developing chronic pancreatitis in Puerto Ricans. High clinical suspicion of Puerto Rican pediatric and adult patients presenting with recurrent pancreatitis is needed between healthcare providers to consider CRMS or CRD in the differential diagnosis. CF screening is even more critical considering that, before 2015, NBS tests were not mandatory for CF in Puerto Rico, and a large portion of the pediatric population was not screened for an elevation of IRT nor the most common mutations of the CFTR gene. For this reason, many patients may continue to go undiagnosed with chronic pancreatitis in adulthood. Early diagnosis allows for a better prognosis and quality of life for CF, CRMS, and CRD patients, along with CF carriers. Additional basic, clinical, and translational research in underrepresented minority groups, such as patients living in Latin America, is needed to develop specific treatments for CF-related pancreatitis. A better understanding of the CF genotype–phenotype relationship is necessary for Hispanic populations such as Puerto Ricans, especially in children. Teamwork among pediatric pulmonologists and general pediatricians in Puerto Rico is vital to raise awareness about CF and to enable us to fully understand the CFTR spectrum of disease. Our study cohort of 12 Puerto Rican pediatric patients demonstrated the presence of


Thirteen males and fifteen females completed land (Wingate (WAnT)) and pool-based (TST) measures of anaerobic power and capacity previously described in the literature. Additionally, the subjects completed assessments of body composition via air displacement plethysmography. The males produced higher force than the females for Fpeak (p < 0.001) and Fmean (p = 0.008) during the TST. However, linear regression analysis determined that lean mass significantly predicted Fpeak (p = 0.002) and Fmean (p < 0.001) during the TST, while gender was no longer significant . In conclusion, increases in anaerobic power and capacity (Fpeak and Fmean) may be a function of increased lean mass in males and females, warranting future research on the impact of resistance training programs on force production and swimming performance.Consistent differences between males and females have been shown in land-based measurements of anaerobic power and capacity. However, these differences have not been investigated for a tethered 30-s maximal swimming test (TST). The purpose of this study is to explore gender differences in land and pool-based assessments of anaerobic power (F Anaerobic power and capacity are important sport-specific fitness components related to overall sports performance and injury prevention . CommonlAssessing the anaerobic power and capacity of swimmers presents a unique challenge. With research demonstrating a lack of association between land-based measures of anaerobic power and capacity and swimming performance ,12, it iAs the TST has grown in popularity over the past decade, so has its application in investigating gender differences in the aquatic environment. While a few studies have consistently reported higher peak and average force production and higher swimming performance (faster swimming speed) in male subjects compared to female ,27,28,29This study employed a randomized repeated-measures crossover design. Following the appropriate orientations, the subjects completed two experimental sessions: (1) the WAnT and (2) the TST. The order of the experimental sessions was randomized, and they were conducted on separate days with a minimum of two days and a maximum of seven days between sessions . All proSubjects. Twenty-eight healthy subjects , were included in the study. The subjects were included in the study if they met the following criteria: (1) 18–45 years old, (2) intermediate level swimmer or higher (defined as able to proficiently swim freestyle with rhythmic breathing for 15 min continuously and/or 457.2 m (500 yards)), (3) free of upper or lower extremity musculoskeletal injury or medical condition that would limit their ability to exercise on a cycle ergometer or in shallow water, and (4) comfortable exercising on a cycle ergometer and in shallow water. All subjects completed a medical inventory, the Physical Activity Readiness Questionnaire (PAR-Q) [ (PAR-Q) , and pro (PAR-Q)  were assWingate Anaerobic Test (WAnT). Force production on land was evaluated using an electronically braked Velotron cycling ergometer  during the Wingate protocol. This protocol has been well described in the literature and has been shown to be a valid and reliable measure of anaerobic power and capacity [capacity ,33. AfteTethered Swimming Test (TST). Force production in the water was evaluated using a fully tethered swimming system consisting of a Futek submersible S-Beam load cell, Model LSB210  firmly attached to a pole at the end of the pool. The load cell was connected to a PC that uses a data acquisition system, SENSIT Test and Measurement (v 2.3.4007.7), with the data sampled at 300 Hz. The load cell was connected to a 2.5 m nonelastic tether and swim belt set at a standardized angle (4°) for each test. The protocol utilized in the current investigation has been previously described in the literature in detail [n detail ,22,34 ann detail .Data Processing. The following parameters during the WAnT and the TST were identified for each subject: (a) Fpeak was defined as the highest force (N) value obtained from the individual force–time curve, and (b) Fmean was defined as the average of all force (N) values during the 30-s trial.Statistical Analysis. Following an assessment of normality  were used to determine absolute differences between males and females for Fpeak and Fmean during both the WAnT and TST. Additionally, linear regression analysis with backwards selection was used to determine the influence of gender, body weight, and body composition  on Fpeak and Fmean for the WAnT and TST. The level of significance was set a priori at p ≤ 0.05.The study sample consisted of approximately equal numbers of male and female subjects, and the demographic characteristics are presented in peak and Fmean in both the land and pool assessments (WAnT and TST), with the male subjects consistently producing higher force than their female counterparts on land and in the water , except for gender, a significant regression equation was found for all dependent variables:A stepwise multiple linear regression was calculated to predict Fpeak (N): F = 38.505, p < 0.001), with an R2 of 0.828;Fmean (N): F = 58.31, p < 0.001), with an R2 of 0.823.FWAnT:peak (N): F = 21.321, p < 0.001), with an R2 of 0.630;Fmean (N): F = 14.257, p < 0.001), with an R2 of 0.533.FTST:peak and Fmean), while gender did not significantly contribute to the prediction model. In addition to FFM, %BF significantly contributed to Fpeak during the WAnT. In summary, it was found that FFM was the best predictor of force production during the TST, which accounted for 63% and 53% of the variance in Fpeak and Fmean, respectively. Additionally, for every 1 kg of lean mass, a subject produced 5.39 N higher Fpeak and 2.596 N higher Fmean during the TST. The results of the analysis can be found in For all models, it was found that FFM significantly predicted force production (FThe aim of this study was to examine gender differences and the influence of body weight and composition on peak and average force production during land and pool-based assessments of anaerobic power and capacity. It has been well established that males have higher absolute power output than females in land-based assessments of anaerobic power and capacity ,6,7,8,9.However, gender differences in force production in the pool have received limited attention in the literature. In a recent systematic review, Santos and colleagues referenced only four studies analyzing propulsive forces between genders . BuildinOf particular interest, the current investigation sought to determine the influence of gender, body weight, and body composition on force production in the water. Similar to land-based findings, the results of this study also demonstrate that gender does not significantly contribute to predicting force production in the water during the TST. Alternatively, the data show that force production in the water was significantly influenced by the subject’s lean mass. As such, the results of the regression analysis indicate that the peak and mean power output increases linearly with the amount of lean mass. Given that the female subjects had significantly lower lean mass than their male counterparts, it can be strongly suggested that the main reason for the gender difference in absolute peak and mean force production during the TST is simply that the female subjects had less muscle mass. While this has previously not been directly studied in swimming, the results of this analysis are consistent with the findings of land-based studies ,4,7,9,10Given this relationship between lean mass, force production, and swimming performance, it may be inferred that increasing lean mass with a well-designed resistance training program would result in improved sprint swimming performance. The TST is a stationary swim test with no forward motion, and therefore, it may change swimming kinematics. It also does not account for the counteracting effects of increased drag forces and/or decreased buoyancy associated with changes in muscle mass and body composition during free swimming, as has been well described in the literature ,36,37. AWhile the aim of the current investigation was to examine the influence of gender and body composition on force production, several limitations should be noted. First, the current investigation included a relatively small sample size with a broad spectrum of inclusion criteria. While this heterogeneous sample may lend to the generalizability of the results, the influence of age, training status, and level of swimming expertise on kinematics, force production, and swimming performance has been well established ,36. TherIn summary, the results of this study indicate that while gender differences exist for absolute force production during land and water-based assessment, the main factor accounting for gender differences in peak and mean force production during a TST is the amount of lean mass. From this, it can be concluded that resistance training programs designed to increase lean muscle mass may potentially benefit sprint swimming performance, although more research is needed to better understand the optimal body weight or lean mass to power ratio in swimming.


The generation of T lymphocytes (thymopoiesis) is one of the major functions of the thymus that occurs throughout life. Thymic epithelial cells actively participate in this process. However, less attention has been paid to extracellular matrix (ECM) elements of thymus and their role in thymocyte differentiation. To clarify this topic, we selected some studies that deal with thymic ECM, its modulation, and its effects on thymopoiesis in different models. We emphasize that further studies are needed in order to deepen this knowledge and to propose new alternatives for thymic ECM functions during thymopoiesis. The extracellular matrix (ECM) is a structured and complex network composed of proteins, glycosaminoglycans, and other molecules, whose gene expression is defined as the “matrisome”. ECM is a non-cellular component present in all tissues, providing physical scaffolding for cells and biochemical cues for their differentiation and homeostasis. Similarly, it is a reservoir of several growth factors and bioactive molecules, constantly undergoing a remodeling process where its components are deposited, degraded, or modified. ECM molecules connect to cells through integrins, syndecans, and other receptors. More importantly, deregulation of ECM composition and its structure is associated with the development and progression of several physiological and pathological conditions ,2.In the context of the immune system, lymphoid organs exhibit significant cellularity; ECM is crucial for support and organization of the cellular microenvironments, subdividing the tissue into functional regions in order to achieve correct cell positioning. For instance, thymus has cortical and medullary regions with distinct molecular compositions at the level of the ECM. Thymic stromal cells (thymic epithelium and fibroblasts) actively produce ECM molecules, such as several types of collagens, laminins, and fibronectin . FurtherSchistosoma mansoni; Trypanosoma cruzi; Plasmodium bergei; cytomegalovirus infections; and diseases such as type 1 diabetes, malnutrition, myasthenia gravis, and Down’s syndrome . In therized by ,23.There is a lot of discussion about the role of thymic epithelial cells (TECs) in the differentiation of thymocytes , and participation of the ECM in this process is equally important to the function of TECs ,25,26. H+CD8+ cells. At the end of the differentiation, thymocytes become single-positive CD4+ or CD8+ cells, emigrating from the thymus [Thymopoiesis consists of a continuous production of naïve self-tolerant T cells by the thymus to ensure an immune response against antigens and homeostasis in the peripheral tissues. In this process, T cell progenitors arise in the bone marrow from hematopoietic stem cells. These cells then migrate to the thymus and enter through vasculature at the cortical medullary junction. More immature thymocytes are double-negative since they do not express CD4 and CD8 glycoproteins. In the next stage, they become double-positive CD4e thymus .During this process, thymocytes interact with thymic stromal cells through receptors and counter-receptors such as TCR-MHC, DLL4-Notch, and c-Kit-Kit ligands in the cell membranes. Furthermore, they use integrins to adhere to and receive signals from ECM components such as very late antigens (VLAs) with α and β subunits. In this case, the main obstacle in reproducing the thymic microenvironment is the complexity of its ECM composition and organization . In ordeBortolomai et al. (2019)  arrangednu/nu mice. Eight weeks after grafting, T cells were found in the peripheral blood of these animals. However, there was a delayed export of these cells into the blood circulation, which may be due to a delayed time taken to vascularize the grafts, generating a lower peripheral T-cell percentage.Seach et al. (2010)  filled a+ and CD8+ T cells were present in the periphery of the immune system.Given that matrix composition exhibits tissue specificity, using a native thymus matrix to reconstruct this complex organ could have an advantage over synthetic alternatives. With this in mind, Fan et al. (2015)  utilizedSimilar results were observed with human thymic cells; however, the authors did not mention participation of ECM molecules in their model . In thes+ SPs were relatively increased in the absence of heparan sulfate. However, no specific blocks in T-cell development were observed. This effect can be attributed to the failure of CXCL12 and CCL19/21 chemokine immobilization and defective interstitial motility.The main glycosaminoglycan-containing proteins in the thymus appeared to be damaged by all detergents (above cited) in these models, potentially impacting ECM protein and growth factor binding. Hsu et al. (2021)  demonstrWhile the vascular framework of the ECM is well preserved in the decellularized scaffold of the thymus, significant alterations in essential factors might occur. For instance, an increase in metalloproteinases was shown to delay TCR rearrangement and inhibit the proliferation and progression of thymocytes from double-negative to double-positive, as demonstrated previously . Other m−CD7+CD5+ stage in humans). These cells were injected intrahepatically into neonatal immunodeficient NSG mice. After 12 weeks post-engraftment, there was detected mature αβTCR/CD3-bearing CD4+ and CD8+ T cells in these animals. Since this in vitro system lacks stromal elements, one of its limitations is the restricted progression to mature T cells, in addition to a probable TCR repertoire with low diversity.It is important to highlight that, although ECM is crucial for correct thymopoiesis, other in vitro systems have been proposed and established. Trotman-Grant et al. (2021)  validateFrom these studies, the importance of discussing thymic ECM in the context of thymopoiesis was demonstrated. There is a lot of research to be carried out, and details about the exact function of each molecule have to be described. Ligands and receptors, stromal cells, and thymocytes interact with each other and with the thymic ECM. More attention should be paid to thymic ECM, since correct tissue orientation and functionality depend on it.Another topic of future discussion is the use of human organoid cultures, with several potential benefits, such as faster and more robust outcomes, and a more accurate representation of human tissue, such as thymus, in order to generate immunocompetent T cells.In the future, adjuvant immunotherapies (such as thymic rejuvenation to increase T cell export) might be developed for immunodeficient patients or autoimmune diseases if the thymic ECM could be seen as a potential topic for further studies.


Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge . In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD , while the diagnosis of COPD was not associated with the choice of selective β1-BB . Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations. Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide . COPD isBeta (β)-blockers (BBs) are widely prescribed β-adrenergic blocking agents, useful in reducing morbidity and mortality in patients with COPD and concomitant CVD –12. NeveAs a consequence, the European Society of Cardiology (ESC) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines suggest the safe and effective use of selective β1 BBs in patients with concurrent HF and respiratory diseases while strongly discouraging the use of non-selective BBs with vasodilating action like carvedilol , 24. DesThe proper use of BBs, mainly in fragile patients such as older adults with HF and COPD, is essential even if the evidences are inadequate. The factors affecting BB prescription and selection are not well known. Additionally, few data on BB prescriptions are available, and Geriatric and Internal Medicine Departments represent a useful field of investigation to analyze older patients with comorbidities and in polypharmacy. Moreover, hospital admissions provide an opportunity to reevaluate treatments in patients with HF and COPD. In fact, a better familiarity with BBs and their contraindications by a hospital physician, in collaboration with a pharmacologist, could help identify appropriate preventive strategies for the management of these patients at discharge.In the light of the above reasons, the aim of the study was to investigate the use and the appropriateness of different BBs in older patients affected by HF and HF/COPD, admitted to the internal medicine and geriatric wards and recorded in the REPOSI register.All data concerning patients were extracted from the REPOSI Registry database. REPOSI is a collaborative and independent registry of the Italian Society of Internal Medicine (SIMI), the IRCCS Mario Negri Institute for Pharmacological Research, and the Foundation of the IRCCS Cà Granda Maggiore Hospital in Milan. The introduction of the register was aimed at recruiting, monitoring, and evaluating older hospitalized patients aged 65 or more, admitted to 102 Italian internal medicine and geriatric wards. The register was established in 2008; information came from each single medical record and was collected every 2 years , 30. TheFor this study, all 4,713 patients recorded in the REPOSI Register between 2010 and 2016 were considered. Patients affected by HF and COPD were identified in accordance with the International Classification of Diseases 9th Revision (ICD-9-CM), as well as all other comorbidities. Drugs were classified according to ATC classification. The following clinical characteristics were evaluated: sex, age, BMI, indices of comorbidity and severity according to the cumulative disease assessment scales CIRS_C and CIRS_S , 32, mooDrugs used up to the admission and drugs prescribed during hospitalization and discharge were considered separately. BBs were grouped in β1-selective BBs and non-selective BBs, according to β1-receptor selectivity. Indication of use was considered for each molecule. Contraindications to BB use were identified according to the summary of product characteristics (SPCs), for each BB, and patients with contraindicate prescriptions were evaluated. Patients without a BB treatment at admission and discharged with a BB prescription were considered new users; discontinuers and switchers were identified as patients using a BB at admission and discharged without a BB or with a different BB, respectively. Patients using the same BB at admission and discharge were considered continuers. Patients who died during the hospital stay were excluded from the evaluation of drugs prescribed at discharge.U test for independent samples were used to compare categorical or continuous variables, respectively. The McNemar test was applied to compare the frequencies of categorical variables between admission and discharge.A descriptive analysis was performed to compare all the characteristics of the study population. All data were reported as absolute and relative frequencies for categorical variables, while medians with interquartile range (Q1–Q3) were calculated for continuous variables. The Barthel and Geriatric Depression Scale was reported as binomial variables. The Kolmogorov–Smirnov test was applied to evaluate the sample distribution. Due to the non-normal distribution of some variables, a non-parametric approach was adopted. The two-tailed Pearson's chi-squared test and the Mann–Whitney To assess the possible influence of all the considered characteristics of the study population on BB prescriptions and β1 selective BB choice, univariate logistic regression models were carried out using patients without BB or with non-selective BB prescriptions as comparators, both in patients affected by HF as a whole and in the subgroup of patients affected by HF and COPD.All predictors identified in the univariate models were included in a stepwise multivariate logistic regression model . Moreover, all variables that did not result in significant in the univariate analysis, but were considered clinically remarkable after a careful consideration based on current knowledge and clinical expertise, and with a cut-off of alpha error of 0.2 according to the Hosmer–Lemeshow test, were also included , 38. Conp-value < 0.05 was considered statistically significant. The statistical analysis was performed using SPSS version 23.0 .Odds ratios (ORs) with 95% CIs were calculated for each covariate of interest in the univariate (crude OR) and multivariate (adjusted OR) models. The goodness of fit of the regression models was assessed by the Hosmer–Lemeshow test for adequacy. A Of 4,713 patients recorded in the REPOSI register during the years 2010–2016, 942 (20.0%) were affected by HF. Of these, 274 (29.1%) also had COPD and 56 (5.9%) died during hospitalization. Patients with both HF and COPD were mostly men, with greater comorbidity indices (CIRS.S and CIRS.C) and were treated with more drugs, both at admission and at discharge, compared to patients affected by HF alone. In addition, more patients with HF and COPD were concomitantly affected by ischemic heart disease and atherosclerosis or peripheral vascular disease than patients affected by HF alone . Heart rPatients affected by HF and treated with at least one BB at admission were 444 (47.1%). Of them, 344 (77.5%) were continuers and 76 (17.1%) discontinued the therapy, while 24 (5.4%) died during hospital stay. At discharge, of 466 patients who were alive and had not previously been treated with BB, 79 (17.0%) new users were identified.p < 0.001; discharge, 38.1% vs. 51.7%, p < 0.001). Furthermore, no significant difference in BB users was observed between admission and discharge in both the HF and COPD affected patients (p = 0.864) and in those with HF alone (p = 0.999). BBs were used in 4 patients (2 non-selective BBs and 2 β1-selective BBs) admitted because of COPD exacerbation.The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge  (p = 0.017), atrial fibrillation , and chronic kidney disease (CKD) . Conversely, BB use was inversely related to age . Rehospitalizations or deaths within 1 year occurred in 3 and 11 BB users, respectively, while 6 patients were rehospitalized, and 33 died within 1 year among patients not treated with BBs. In detail, the use of BBs reduced the probability of dying within 12 months  and the rehospitalizations  compared to non-users.The probability of being treated with a BB significantly increased over time in patients affected by HF and ischemic heart disease. Furthermore, the probability of using a BB was significantly lower in patients with HF also affected by COPD  . Moreovep = 0.500). Furthermore, no significant differences were observed in β1-selective BB use between patients with HF and COPD or with HF alone, both at admission  and at discharge .The 23.8% and 25.5% of patients with HF and COPD used a non-selective BB at admission and at discharge, respectively  switched to β1-selective BBs, while 7 out of 251 users of β1-selective BBs at admission (2.8%) switched to non-selective BBs at discharge. In patients affected by HF and COPD, no patients out of the 24 admitted with non-selective BBs switched to β1-selective BBs, whereas 2 out of 77 users of β1-selective BBs at admission (2.6%) switched to non-selective BBs at discharge.Among the 79 new BB users at discharge, 61 were affected by HF alone and 18 by HF and COPD. A non-selective BB was chosen as starting treatment in 17 (27.9%) and 5 (27.8%) patients affected by HF alone or HF and COPD, respectively.p = 0.322)  . FurtherPatients with HF were treated with 7 different BBs, while patients affected by HF and COPD used 5 different BBs. The most commonly used BB in both groups was bisoprolol at admission and at discharge. Carvedilol was the second most widely used BB in patients with HF and COPD. Furthermore, the use of bisoprolol increased at discharge both in the HF or HF and COPD affected patients  as well as the use of carvedilol , while the use of other BBs decreased .Beta-blocker prescriptions were contraindicated in 49 (11.0%) BB users at admission and in 43 (10.9%) BB users at discharge. In particular, 23 (6.7%) and 17 (5.2%) patients with HF alone were treated with a contraindicated BB at admission and at discharge, respectively. In patients concomitantly affected by HF and COPD, contraindicated BB prescriptions resulted in 26 (25.7%) users at admission and 29 (29.6%) at discharge. Carvedilol was the main cause of inappropriate prescriptions in patients with HF and COPD. Moreover, in 11 patients at admission and 13 patients at discharge, the BB was contraindicated because of drug–drug interaction risk.The use of BBs was evaluated in hospitalized older patients affected by HF and COPD to implement the knowledge about the management of older patients enrolled in the REPOSI database , 40. FirPatients with both HF and COPD were treated with multiple drugs both at admission and at discharge than patients affected by HF alone. In fact, the presence of comorbidities could promote a therapeutic approach based on polytherapy, especially in older patients , 59; theDespite a clinical and pharmacological rationale suggesting the use of BBs in most of the patients with HF, in this study, fewer than half of the patients were admitted with a BB prescription and, surprisingly, no more BB users were observed after discharge. In fact, <20% of patients started a new BB treatment, while almost 20% of BB users discontinued the therapy after discharge. Moreover, in approximately 10% of BB users, prescriptions were contraindicated because of clinical conditions or drug–drug interactions, and no differences were observed between admission and discharge. Even hospital physicians in internal medicine and geriatrics wards did not properly address the treatment suggested by guidelines.Although limited to a number of patients, the use of BBs in clinical practice has significantly been associated with a decreased risk of death and rehospitalizations. This confirms once again that beta-blockade is a crucial approach to reduce morbidity and mortality in patients with HF, especially if they are concurrently affected by COPD . In factOnce again, the data obtained from the REPOSI register database showed that hospital physicians of internal medicine and geriatrics wards did not modify the treatment with BBs observed at admission; the number of BB users was significantly lower in patients affected by HF and COPD than in patients affected by HF alone; if affected by COPD, the probability of being treated with BBs was about half than that of patients affected by HF alone, and no differences were found at discharge. Moreover, in the subgroup of patients with HF and COPD, the concomitant diagnosis of ischemic heart disease, atrial fibrillation, and CKD was related to a higher use of BBs. A hospital physician prescribed more BBs in patients affected by several conditions for which the use of BBs is approved and is in accordance with guidelines, including ischemic heart disease and atrial fibrillation. On the other hand, the major prescription of BBs in patients affected by CKD is justified by the contraindication of other drugs indicated in HF, such as angiotensin-converting enzyme inhibitors (ACE-i) , 74.Interestingly, the diagnosis of COPD did not influence the choice of BBs in patients with HF, with respect to other data, which suggest a greater use of β1-selective BBs in patients with concomitant COPD than those with HF alone . More thCurrent clinical guidelines suggest that metoprolol, bisoprolol, or nebivolol should be preferred in patients with HF and concurrent COPD . The mosA discrepancy in prescribing BBs in patients with comorbidities has been observed in our study. The probability of being treated with a BB was significantly higher in patients affected by HF and concurrent ischemic heart disease, but the probability of choosing a β1-selective BB was significantly lower in this group of patients. In other studies, no substantial differences were shown for selective and non-selective BBs in the treatment of subjects with ischemic heart disease . MoreoveIn accordance with previous reports , hyperteIn this study, the expected improvement of BB prescriptions after hospitalization was not observed. Largely, the hospital physician in the internal medicine and geriatrics wards takes care of quite complicated patients at the time of admission, especially the older patients affected by different chronic comorbidities, such as cardiovascular diseases , 89. In The analysis of real-world data in older patients with a high grade of complexity, who are often not included in premarketing studies, is the major strength of this analysis. Moreover, the multicenter design based on the REPOSI register use with a large number of participating centers, which resulted in a wide sample of hospitalized older patients in internal medicine and geriatric wards, supports the novelty of our findings. Current evidence strongly promotes the hypothesis that pharmacological management of patients affected by HF and concomitant COPD should include the identification of other comorbidities and potentially co-medications. Moreover, a personalized care based on a multidisciplinary approach with the close collaboration of hospital physicians and pharmacologists has become really important in order to select the best and the most appropriate therapy. In addition, interventional educational programs may improve physicians' adherence to international guideline recommendations. Furthermore, this study provides an important overview of factors associated with the BB choice and, therefore, the BB use in a large cohort of older adults affected by HF and COPD, hospitalized in internal medicine and geriatric wards, in a long-time study period; moreover, it highlights differences in BB use between admission and discharge, underlining the hospital physicians' therapeutic approach. However, this observational study has some limitations: (i) no specific information on how the diagnosis of COPD was made , and the severity of COPD was not reported in the REPOSI database and we could not analyze how much this affects the prescription, especially primary, of BB or their discontinuation. Similarly, we could not identify patients according to severity and characteristics of HF. (ii) REPOSI concerns only older hospitalized patients; therefore, these findings could not be extended to the general population. Moreover, our findings concern only Italian population, and additional evidences are required to be generalized to other nations.salvatore.corrao@unipa.it.The dataset generated for this study will not be made publicly available. Further inquires can be directed to the author SC, The studies involving human participants were reviewed and approved by Participation was voluntary and all patients provided signed informed consent. REPOSI was approved by the ethics committees of the participating hospitals. The study was conducted according to Good Clinical Practice and the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.VA: conceptualization and writing original draft. FS and SC: writing original draft, writing—review and, editing. MR, MB, and GP: formal analysis. NI, AN, and GN: Validation. CA and GS: investigation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


High positive correlations (p < 0.01) were found between the FAS, BDI, State Anxiety and Trait Anxiety scales. Regression analysis showed that 51.7% of the variance in FAS scores can be explained by trait anxiety, an additional 6.2% by the BDI and 1.2% by state anxiety. Mediation analysis showed that state anxiety and BDI mediate the relationship between trait anxiety and FAS. Finally, BDI was found to exert a moderating role in the relationship between trait anxiety and fatigue. In conclusion, our study showed that nurses continue to experience high rates of anxiety, depression and fatigue. The variation in fatigue appears to be significantly dependent on trait anxiety. Depressive symptomatology and state anxiety exert a parallel positive mediation on the relationship between trait anxiety and fatigue, with depression exhibiting a moderating role in this relationship.The coronavirus pandemic (COVID-19) is a global health crisis with a particular emotional and physical impact on health professionals, especially nurses. The aim of this study was to investigate the prevalence of anxiety, depression and fatigue and their possible relationships among nurses during the pandemic. The study population consisted of nurses from five tertiary-level public hospitals in Athens who completed the Fatigue Assessment Scale (FAS), Beck Depression Inventory (BDI) and State–Trait Anxiety Inventory (STAI) questionnaires. Gender, age and years of work experience were recorded. The study was conducted from mid-November to mid-December 2021. The sample included 404 nurses  with a mean age of 42.88 years (SD = 10.90) and 17.96 (SD = 12.00) years of work experience. Symptoms of fatigue were noted in 60.4% of participants, while 39.7% had symptoms of depression, 60.1% had abnormal scores on state anxiety and 46.8% on trait anxiety, with females showing higher scores on all scales ( The 2019 coronavirus pandemic (COVID-19) has caused a major health crisis worldwide with a huge psychological impact . RegardiEarlier studies had suggested ,18 that From the above, it is clear that nursing staff are particularly vulnerable to developing physical and psychological problems, especially during the COVID-19 pandemic. It is worth noting that at the time of the study, Greece was experiencing the peak of the fourth wave of the pandemic with the prevalence of the Delta variant, which caused particularly high mortality rates. At that time (mid-November to mid-December 2021), approximately six to seven thousand new cases were being recorded daily, 600–700 patients were hospitalized in intensive care units and 80-100 deaths per day were attributed to COVID-19, with an increasing trend that was difficult to address by the national health system , which sThis was a descriptive correlation study. Data were collected through self-completed questionnaires that were distributed in person to the participants by the researchers. Participation in the study was voluntary. The questionnaire was anonymous, participants had the right to voluntarily withdraw from the study and were aware of the objectives and procedures to be followed.The study population consisted of a convenience sample of 404 nurses from five large public/academic hospitals in Athens. The above hospitals treated patients with and without COVID-19. The demographics of the study participants included gender and age. Professional information included years of work experience. In the invitation to nurses to participate in the study, an effort was made to make the study sample representative of Greek nurses in terms of gender, years of work and age. The Ethics Committee of the University of Peloponnese approved the study protocol (18699/11-10-2021), as did the Clinical Research Committees of the five hospitals. The study was conducted from mid-November to mid-December 2021.With a target population of 27,103 nurses  a marginThe Fatigue Assessment Scale (FAS) was used to assess fatigue. The FAS consists of 10 questions . Each question is scored from 1 to 5. Responses include “never, sometimes, often, quite often, always”. Total scores range from 10 to 50, with values ≥22 indicating fatigue. The FAS questions aim to capture fatigue over the few weeks prior to the questionnaire completion . The relThe Beck Depression Inventory (BDI) was used to assess depression. This scale measures the cognitive, emotional, behavioral and physical manifestations of depression in the individual during the week prior to the inventory completion. It consists of 21 items, which are rated on a scale of 0–3 . The iteThe Spielberger State–Trait Anxiety Inventory (STAI-Y Form) was used to assess anxiety. This scale consists of forty items, each of which is scored from 1 to 4. The scale differentiates between anxiety caused by a specific situation (state anxiety) and anxiety that is a more permanent personality trait (trait anxiety). The State Anxiety subscale (STAI Form Y-1) consists of 20 items that assess how the respondent is feeling “right now”. In responding to the State Anxiety subscale, individuals select the response that best describes the intensity of their feelings. Answers include “Not at all, somewhat, moderately and a lot”. The Trait Anxiety subscale (STAI Form Y-2) consists of 20 items that assess how the respondent feels “in general”. In the Trait Anxiety subscale, individuals rate the frequency of their feelings. Answers include “almost never, sometimes, often and almost always”. Scores for each subscale can vary from a minimum of 20 to a maximum of 80. Higher scores indicate more anxiety . The scap < 0.05 (two-tailed) and analyses were performed using IBM SPSS Statistics 23 . Mediation and moderation analyses were performed using the Hayes SPSS Process Macro Models 4 and 5.All variables were evaluated using descriptive statistics, and values were expressed as means and standard deviations for continuous variables. The prevalence of fatigue, anxiety and depression was determined as a percentage. Independent t-tests were conducted to assess continuous variables according to gender. Pearson’s correlation was performed to determine the strength and direction of the relationship between variables. Linear regression models were constructed to investigate whether the associated variables were significant predictors of the independent variable. The linear regression hypotheses  were assessed by visual inspection of the variables, residual plots and quantile–quantile (QQ) plots. Statistical significance was set at 2), years of work and age (sample t-test), the sample showed no statistically significant difference (p > 0.05) compared to representative samples of the country’s nursing workforce from other studies  ,  < 0.05] . The medp < 0.05] ,  < 0.05] . The medFinally, we examined the moderating role of both the Spielberger State Anxiety and depression in the Spielberger Trait Anxiety–fatigue relationship. Spielberger State Anxiety did not show a moderating role.p < 0.01, In contrast, depression emerged as a positive moderator. Specifically, moderation analysis was performed using the PROCESS method model 5 . Depression showed a statistically significant moderating role in the Spielberger Trait Anxiety Inventory and Fatigue Assessment Scale relationship (p < 0.05]. At medium moderation (BDI = 8) the conditional effect was 0.1939 . At high moderation (BDI = 16) the conditional effect was 0.1381  (At low moderation (BDI = 1) the conditional effect was 0.2428  .Alongside the COVID-19 pandemic, an emerging health problem is very likely to co-exist. This problem is pandemic fatigue (PF), which, according to the World Health Organization (WHO), is defined as the physical and mental fatigue that can occur during a pandemic as a consequence of changes in a person’s usual activities due to the various measures implemented to reduce the transmission of the virus .Nurses are particularly vulnerable to developing mental and psychological problems, such as higher rates of anxiety, depression, fatigue, mental distress, emotional exhaustion and post-traumatic stress disorder during the peak of the pandemic, potentially increasing the risk of developing PF .Consistent with the above, the results of the present study showed a high prevalence of fatigue, situational and structural anxiety and depression . Our results also showed that Greek nurses had among the highest rates of fatigue ,39, anxiThese findings are probably due, among other reasons, to the fact that Greece, during the period of this study, was experiencing the worst phase of the pandemic  in termsIt is known that the prevalence of anxiety and depression is almost twice as high in women as in men ,43,44,45Statistically significant correlations were found among all the scales considered. Anxiety (state–trait), depression and chronic fatigue were positively correlated with each other. Numerous studies confirm the association between anxiety, depression and fatigue in both nurses  and patiFurthermore, depressive symptomatology and state anxiety are aggravatingly mediated by depressive symptomatology. This dual mediation works in a parallel fashion, although the mediation effect of depression is twice that of state anxiety. Depressive symptoms are important in this population as they act as a moderator in the relationship between trait anxiety and fatigue. This effect was observed at high, medium and low levels of depression. According to a study by Polikandrioti et al., both anxiety and depression can affect fatigue levels in different ways . People Ultimately, the nature, as well as the direction, of causality between these variables remains uncertain. While depression appears to be the stronger mediator of the effect of trait anxiety on fatigue, the relationship between the two mediators remains unclear. In future research, it will be useful to use the four-way decomposition method for greater clarity. In addition, our study was synchronic and could not determine with certainty the cause-and-effect relationship beyond the creation of a model. Despite the recent increase in research interest in this area, more longitudinal and/or intervention studies that could further enrich our understanding of the anxiety–fatigue–depression relationship are desirable.The prevalence of anxiety, depression and fatigue seems to be very high among nurses in Greek hospitals. To reduce the psychological impact of the COVID-19 pandemic on nurses, a number of studies and meta-analyses highlight the positive role of organizational support , interveWe have to note that the role of night work was not examined. Nurses working in rotating shifts or at night are exposed to sleep disturbances due to abnormal melatonin secretion at night and circadian rhythm disturbance ,61. NursConsidering the higher prevalence of insomnia in female nurses compared to other health professionals ,65 and tFinally, it is important to mention the willingness of nurses to participate in this research. It is common for Greek nurses to show high rates of acceptance to participate in studies with questionnaires, even in studies conducted online . NeverthIn the second year of the pandemic, nursing staff continue to experience high rates of anxiety, depression and fatigue. These findings are probably due, among other reasons, to the fact that Greece, during the period of this study, was experiencing the worst phase of the pandemic. The variation in fatigue appears to be significantly dependent on trait anxiety. Depressive symptomatology and state anxiety exert parallel positive mediation on the trait anxiety and fatigue relationship. In this relationship, depression has a moderating role at low, medium and high values. Despite the recent increase in research interest in this area, more longitudinal and/or intervention studies that could further enrich our understanding of the anxiety–fatigue–depression relationship are desirable. Finally, it is proposed to strengthen health protection in this most vulnerable category through prevention and intervention programs oriented toward nurses’ psychosocial support.


An internal validation cohort (n = 64) was applied to validate the model.This study aimed to develop and validate a nomogram for predicting the risk of severe pain in patients with knee osteoarthritis. A total of 150 patients with knee osteoarthritis were enrolled from our hospital, and nomogram was established through a validation cohort (Eight important variables were identified using the Least absolute shrinkage and selection operator (LASSO) and then a nomogram was developed by Logistics regression analysis. The accuracy of the nomogram was determined based on the C-index, calibration plots, and Receiver Operating Characteristic (ROC) curves. Decision curves were plotted to assess the benefits of the nomogram in clinical decision-making. Several variables were employed to predict severe pain in knee osteoarthritis, including sex, age, height, body mass index (BMI), affected side, Kellgren—Lawrance (K–L) degree, pain during walking, pain going up and down stairs, pain sitting or lying down, pain standing, pain sleeping, cartilage score, Bone marrow lesion (BML) score, synovitis score, patellofemoral synovitis, bone wear score, patellofemoral bone wear, and bone wear scores. The LASSO regression results showed that BMI, affected side, duration of knee osteoarthritis, meniscus score, meniscus displacement, BML score, synovitis score, and bone wear score were the most significant risk factors predicting severe pain.Based on the eight factors, a nomogram model was developed. The C-index of the model was 0.892 (95% CI: 0.839–0.945), and the C-index of the internal validation was 0.822 (95% CI: 0.722–0.922). Analysis of the ROC curve of the nomogram showed that the nomogram had high accuracy in predicting the occurrence of severe pain [Area Under the Curve (AUC) = 0.892] in patients with knee osteoarthritis (KOA). The calibration curves showed that the prediction model was highly consistent. Decision curve analysis (DCA) showed a higher net benefit for decision-making using the developed nomogram, especially in the >0.1 and <0.86 threshold probability intervals. These findings demonstrate that the nomogram can predict patient prognosis and guide personalized treatment. Osteoarthritis (OA) is one of the most important causes of pain and disability in the elderly in recent years . It mainAccording to clinical guidelines, the focus of osteoarthritis of the knee treatments is to relieve pain . Severe There is a need to investigate the pathology of knee osteoarthritis in terms of pain development and the factors influencing it. It was generally believed that the onset of KOA pain was due to mechanical loading or aging injury , but recIdentification of factors associated with severe pain may promote timely detection and early intervention. This will reduce the pain and burden on the patient. Therefore, we aimed to develop a model for predicting the risk of severe pain.A total of 150 KOA patients treated at the Third Hospital of Shanxi Medical University from 2018 to 2020 were retrospectively enrolled in this study. An additional 64 internal validation patients were collected based on the following inclusion criteria.Inclusion criteria (1). Patients who underwent TKA at the Department of Orthopedics, Third Hospital of Shanxi Medical University; (2). Patients with complete medical records; (3). Underwent first unilateral total knee arthroplasty.Exclusion criteria (1). Patients with severe heart, liver, lung, and kidney organ dysfunction; (2). Patients with incomplete data; (3). Patients who were unable to cooperate, unwilling to participate, or lost to follow-up.The study of this columnar graph prediction model was reviewed and approved by the Ethics Committee of the Third Affiliated Hospital of Shanxi Medical University. This study was conducted following the Declaration of Helsinki.General information about the patient, clinical presentation, and, most importantly, some critical information about the patient′s MRI were collected and counted.The K–L grading scale which is extensively used in KOA studies as adopted to assess x-Ray results. We have standardized the method of x-ray examination of the patient to the frontal and lateral knee position, and the patient′s position during the examination to the standing position. The severity of bone wear in the knee joint in KOA was scored on x-ray as follows, Grade 0: Normal; Grade 1: Suspicious narrowing of the joint space with possible bone piles; Grade 2: Mild narrowing of the joint space with significant small bone piles; Grade 3. Significant narrowing of the joint space, as well as a moderate amount of bone stumps, mild sclerosis of the subchondral bone, and possible knee deformity; Grade 4: Severe narrowing of the joint space, extensive bone stump formation, as well as significant sclerosis of the subchondral bone and significant knee deformity.Patients received a Philips 3.0 T knee MRI scan of the affected knee. Image sequences included: (1) T1-weighted 3D fat-suppressed gradient echo sequence with 90° flip angle, TR: minimum500 ms, maximun 700 ms, FOV: 170 × 170 mm, TE: 20 ms, matrix: 380 × 305. Layer thickness: 4.0 mm, 19 layers scanned. (2) T2-weighted 3D fat-suppressed fast spin-echo sequence, flip angle 90°, FOV: 170 × 170 mm, TR: 500 ms, TE: 20 ms, matrix 340 × 265, layer thickness 4.0 mm, 19 layers scanned. The MRI images of the knee were evaluated observationally using the StartWebclient software.In 1957, Kellgren and Lawrence (KL) first established and used the imaging classification scheme for OA, the K–L grading scoring system that was later used with our present study . Whole-OSynovitis score rating is based on the maximum expansion of the synovial cavity, with grade 0 typical , grade 1 less than 33% of the total potential increase, grade 2 accounting for 33%–66% of the maximum possible expansion, and grade 3 more significant than 66% of the maximum potential growth.To record T1 image, measuring the distance between the plumb line of the largest section of the meniscus and the plumb line over the edge of the tibial plateau was recorded. Meniscus displacement was measured on T1 images in the coronal MRI position, with two vertical lines drawn in the image, one over the largest section of the medial or lateral meniscal volume and the other over the edge of the medial or lateral tibial plateau (excluding the osteophyte), and the distance between the two vertical lines was defined as a measure of Meniscus displacement, as shown in Bone marrow lesion (BML) was histologically defined as bone marrow necrosis, trabecular bone abnormalities, bone marrow fibrosis, edema, cellular infiltration, and vascular hyperplasia. Magnetic Resonance Imaging (MRI) presents as a T1-weighted image with low signal and a T2-weighted image with high signal short-time inversion recovery sequence (STIR) high signal images in a punctate, map-like, or diffuse irregular pattern. Bone marrow lesions (BML) are measured in T2 images on MRI and are graded as follows, grade 0: normal; grade 1:≤33% of the area; grade 2: 33%–66% of the area; grade 3:≥66% of the area.Observations and diagnostic scores were assigned by two attending physicians who do not know each other, and if the results deviated significantly from the values, further assessments were made by a more senior and highly qualified chief physician with many years of experience.Pain was expressed based on the McMaster Universities Osteoarthritis Index (WOMAC) pain score, using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the degree of pain in the patient′s knee was determined , 36. TheThe knee was divided into 15 observation areas according to the WORMS scale as shown in The remaining variables, except BMI, were converted to binary variables. Patients’ outcome times were divided into two groups: the severe pain group and the non-severe pain group. The score for pain was determined by averaging the scores of two senior doctors in our department. The imaging assessment was conducted jointly by two experienced senior physicians from our imaging department.http://www.r-project.org/). Firstly, Lasso regression was used to select significant variables, logistics regression analysis was used to display risk factors, and a nomogram chart was constructed according to the RMS package′s univariate and multivariate analysis results. The accuracy of the nomogram was tested using the modeling cohort and the internal validation cohort through identification and calibration. Finally, C-index, calibration curve, and ROC curve were constructed to evaluate the accuracy of the prediction model. The DCA curve was also employed to assess the effectiveness of the nomogram in clinical applications.Statistical analysis was performed by SPSS 25.0  and R for windows  had a BMI >24.0. Moreover, 35.3% (53) patients had severe pain. Other clinical data of patients are presented in Among the 14 characteristics screened, 8 were considered potential predictors in 150 patients (∼2:1 ratio) and had non-zero coefficients in the LASSO regression model. These factors included BMI, affected side, duration of knee osteoarthritis, meniscus score, meniscus displacement, BML score, synovitis score, and bone wear score. The specific content is shown in .Logistic univariate regression showed that BML score, synovitis score, bone wear score, and meniscus displacement were more predictive and were independent risk factors for severe pain in patients with KOA. The regression coefficients of 8 variables and other analysis results are shown in P-value for BMI was more than 0.05 in our logistic univariate and multivariate regressions, we concluded that the BMI was a clinically significant risk factor for pain in osteoarthritis of the knee. Therefore, we included the BMI in the nomogram.The LASSO regression analysis results revealed that the BMI was a significant variable. Although the A nomogram for predicting the risk of severe pain in patients with KOA was constructed using eight variables: BMI, affected side, duration of knee osteoarthritis, meniscal score, meniscal displacement, BML score, synovitis score, and bone wear score. See Analysis of the calibration curve of the nomogram showed good agreement in this cohort. The C-index of the cohort prediction nomogram was 0.892 (95% CI:0.839–0.945), and for the internal validation it was 0.822 (95%: CI 0.722–0.922), indicating good discriminatory performance of the model. The nomogram showed good predictive power in predicting the occurrence of severe pain in KOA patients. The specific data of patients are shown in .The area under the ROC curve (AUC) analysis was used to assess the accuracy of the model. The higher the AUC value, the better the model accuracy. The results showed that the model for predicting the risk rate of severe pain in KOA patients had better accuracy, as seen in the modeling cohort (AUC = 0.892). The final result are present in Decision curve analysis of a nomogram predicting the risk of severe pain in KOA patients. The decision curves showed that the nomogram could effectively predict the risk of developing severe pain in KOA patients if the threshold probabilities for patients and physicians were >0.1 and <0.86, respectively. In this range, it showed excellent clinical effect based on the predicted risk of developing severe pain in KOA patients. The details are presented in Due to the increasing prevalence of global obesity and the growing aging population, the number of KOA patients has increased tremendously worldwide. Pain is one of the most important clinical manifestations in patients with KOA and is often a key factor influencing surgical treatment of TKA patients. The mechanisms of pain associated with knee OA are complex, and local structural changes in the knee, such as synovitis, degree of bone marrow pathology, and deformity changes in the kneecap, are postulated to cause or induce different kinds of pain .To our knowledge, this is the first study to develop and validate a risk probability model for predicting the occurrence of severe pain in KOA patients. In both the training and validation cohorts, the nomogram showed satisfactory agreement, and DCA revealed that it had good clinical applicability. Nomograms are widely used for various diseases, primarily because of their ability to reduce statistical predictive models to a single numerical representation of the probability of an event  tailored to an individual patient′s profile. The user-friendly and easy-to-understand graphical interface used to generate these estimates allows the use of nomograms in clinical practice to inform clinical decision making . In our Research has revealed a strong link between BMI and KOA. It has been shown that obesity can increase the occurrence of KOA and the progression of pain , 41. HigOur study found that KOA patients with a longer duration of disease, meniscal damage or higher meniscal scores, high synovitis scores, and right-sided KOA had a higher probability of severe pain. In addition, the more influential the bone wear, the greater the relative likelihood of obtaining severe pain. In the constructed nomogram we developed, the severity of bone wear was one of the most important factors influencing the occurrence of severe pain in KOA patients, followed by the synovitis score and whether the meniscus was displaced. These factors can be used to predict the risk of severe pain in KOA patients.There are some limitations to our study. First, this was a retrospective study, and therefore, there is some inherent bias. Moreover, many factors such as MRI and x-ray imaging data, were not available. Therefore, further studies are needed to validate our findings through multicenter internal validation.In this study, higher BMI, synovitis score, BML score, bone wear score, meniscus score, in addition to right-sided KOA or presence of meniscal displacement and longer duration of KOA were found to be risk factors for the development of severe pain in patients with KOA. A nomogram comprising eight predictors showed good ability to predict the risk of severe pain in patients with KOA more accurately.


Gestational diabetes mellitus (GDM), which is defined as a state of hyperglycemia that is first recognized during pregnancy, is currently the most common medical complication in pregnancy. GDM affects approximately 15% of pregnancies worldwide, accounting for approximately 18 million births annually. Mothers with GDM are at risk of developing gestational hypertension, pre-eclampsia and termination of pregnancy via Caesarean section. In addition, GDM increases the risk of complications, including cardiovascular disease, obesity and impaired carbohydrate metabolism, leading to the development of type 2 diabetes (T2DM) in both the mother and infant. The increase in the incidence of GDM also leads to a significant economic burden and deserves greater attention and awareness. A deeper understanding of the risk factors and pathogenesis becomes a necessity, with particular emphasis on the influence of SARS-CoV-2 and diagnostics, as well as an effective treatment, which may reduce perinatal and metabolic complications. The primary treatments for GDM are diet and increased exercise. Insulin, glibenclamide and metformin can be used to intensify the treatment. This paper provides an overview of the latest reports on the epidemiology, pathogenesis, diagnosis and treatment of GDM based on the literature. Gestational diabetes mellitus (GDM) is a state of hyperglycemia  that is first diagnosed during pregnancy . MothersDespite numerous studies, the pathogenesis of GDM remains unclear, and the results obtained so far indicate a complex mechanism of interaction of many genetic, metabolic and environmental factors . The basA review of current literature reports on epidemiology, pathogenesis, diagnosis and treatment of GDM.The study presents an analysis of data that are currently available in the literature that concern the epidemiology, pathogenesis, diagnosis and treatment of GDM. The study was based on reviews, original articles and meta-analyses published in English in the last 10 years.A literature search was conducted from 1 January 2021 to 31 March 2022 using Web of Science, PubMed, EMBASE, Cochrane, Open Grey and Grey Literature Report. MeSH terms, including “gestational diabetes”, “pregnancy induced diabetes”, “hyperglycemia”, “glucose intolerance”, “insulin resistance”, ”prevalence”, “incidence”, “GDM treatment” and “behavioral treatment”, were used alone or in combination.The growing problem of overweight and obesity around the world significantly contributes to the steady increase in the incidence of diabetes, including GDM in the population of women of reproductive age . Accordi2, the GDM frequency is 12.3%, and in women with first-line relatives that have a history of GDM, it is 11.6%. The combination of these two factors increases the risk of GDM up to 61% of cases [The incidence of hyperglycemia in pregnancy increases with age. According to Mosses et al., GDM was diagnosed in 6.7% of pregnancies in general, but in 8.5% of women over 30 years of age . Lao et of cases ,18,19. Mof cases . Recent of cases ,22,23. Mof cases .The decades-long polemic about the diagnosis of GDM has covered two issues: whether to include all pregnant women or only those with risk factors, and whether to use one- or two-stage diagnostic procedures. A GDM diagnosis is only possible if a previous diagnosis of diabetes  had been excluded early in the pregnancy. Screening of only risk groups may result in GDM not being diagnosed in as many as 35–47% of pregnant women, which is certain to affect obstetric results . The resMany potential markers of GDM occurrence are being described more and more frequently. The greatest hopes are connected with afamine, adiponectin and 1,5-anhydroglucitol ,35. Due Several factors may be responsible for the occurrence of GDM, the most important of which are insulin resistance and beta cell dysfunction, as well as genetic, environmental and dietary factors.In the pathogenesis of GDM, as in type 2 diabetes, a key role is played by insulin resistance and decreased insulin secretion relative to the patient’s needs. We observe GDM in both obese and lean women . InsulinThe analysis of insulin secretion disorders in GDM gives inconclusive results. The mechanisms of β-cell hypertrophy and proliferation, resulting in a 300% increase in insulin secretion in the first two trimesters of physiological pregnancy, is insufficient to explain GDM ,39. In tp < 0.05) [p = 0.013) [p < 0.05) as compared with those with GDM but without LGA [p < 0.001) and lower values of adiponectin  and the adiponectin/TNF-α ratio  than normal pregnant women. The ratio of adiponectin/TNF-α, which decrease significantly in GDM compared with normal pregnancy, might be an informative biomarker for the assessment of pregnant women at high risk of insulin resistance and dyslipidemia and for the diagnosis and therapeutic monitoring aims regarding GDM [A study conducted in Spain showed that carriers of the gene rs7903146 T-allele who followed the Mediterranean diet in early pregnancy had a lower risk of developing GDM . A growi < 0.05) . Mothers= 0.013) . Additiohout LGA . In addiding GDM .p = 0.01), especially in women in the first trimester of pregnancy. Experiencing lockdown during the first trimester of gestation increased the risk of GDM in these women by a factor of 2.29 (p = 0.002) compared with women whose pregnancies occurred before and after lockdown [The second severe acute respiratory distress syndrome (SEA) coronavirus (SARS-CoV-2) causes an acute respiratory disease called coronavirus disease 2019 (COVID-19). There are limited data on the impact of SARS-CoV-2 infection on the onset and course of GDM. A living systematic review and meta-analysis of 435 studies reported the incidence of COVID-19 in pregnant women of approximately 10% (7–14%) . The COVlockdown . This islockdown . The “lolockdown ,70.Regarding women with GDM, due to the lack of randomized clinical trials, it is extremely difficult to propose an unambiguous and uniform model of management in order to achieve obstetric results similar to the population of healthy women. The treatment of GDM is based on consensus and expert opinion. Analyses of Cochrane Database Reviews showed the lack of unambiguous data on the correlation between the intensity of glycemic control and obstetric outcomes . Based oNutritional recommendations help women to achieve normoglycemia, optimal weight gain and proper development of the fetus, and the introduction of a pharmacological treatment does not release the mother from the obligation to follow the diet . In GDM,A weight gain of over 18 kg is associated with a twice higher risk of macrosomia ,85. ManyThe main quality-oriented recommendations include the need to limit or eliminate processed products with a high content of salt, sugar and fats; avoiding unpasteurized milk, raw meat, alcohol and caffeine; and ensuring proper hydration of at least 2 L of water per day. In addition, the effect of the Dietary Approach to Stop Hypertension (DASH) diet on glycemic control was confirmed, and Sarathi et al. indicated that eating a high-protein diet based on soy products reduces insulin requirements in GDM patients ,93. Myoip = 0.01) [In women with GDM, the quantitative and qualitative recommendations for exercise are ambiguous in terms of improving glycemic control . Obstetr = 0.01) . A meta- = 0.01) .Patients who cannot achieve glycemic targets with a properly balanced diet and elimination of dietary errors should be treated pharmacologically . Most stGDM is one of the most common complications of pregnancy and confers lifelong risks to both women and their children. Observational data demonstrated a linear association between maternal glycemic parameters and risks for adverse pregnancy and offspring outcomes. SARS-CoV-2 infection will undoubtedly affect the risk of GDM. Many doubts regarding the diagnostic criteria and treatment of GDM are still under discussion. Treatment with insulin is effective, but costs and patient experiences limit its use in clinical practice. The use of metformin as a first-line agent for GDM remains controversial due to its transplacental passage and limited long-term follow-up data. Further clinical trials are necessary to use other oral hypoglycemic agents to treat GDM. It is very important for patients with GDM to receive behavioral therapy and to closely cooperate with the doctor. Future work in the field should include studies of both clinical and implementation outcomes, examining strategies to improve the quality of care delivered to women with GDM. The screening and treatment for GDM early in pregnancy are very controversial due to the lack of data from large randomized controlled trials. There is an urgent need for well-designed research that can inform decisions on the best practice regarding gestational diabetes mellitus screening and diagnosis.