Triglyceride-Glucose Index, HOMA Index and metabolic syndrome in a sample of adult men.

BACKGROUND: Metabolic syndrome (MetS) and its components are directly associated with cardiovascular risk. Insulin resistance (IR) is the most common pathophysiological feature of MetS. A novel index, the triglyceride-glucose index (TyG), is considered a surrogate marker of IR. Hence, we estimated the ability of TyG to predict the risk to develop MetS over a follow-up period of 8 years. In addition, we compared the predictive role of TyG and that of the HOmeostatis Model Assessment (HOMA) of IR index (a widely used tool to evaluate IR). METHODS: The analysis included 440 adult men (The Olivetti Heart Study) without MetS at baseline. The optimal cut-off point of the association of continuous TyG or HOMA-IR with MetS was identified by ROC analysis. RESULTS: During the follow-up period, 21.6% of participants developed MetS. Baseline TyG and HOMA-IR were both significantly greater in those who developed MetS than in those who did not. These results were confirmed upon adjustment for the main confounders. After stratification by the optimal cut-off point, TyG >4.78 was a significant predictor of MetS, also after adjustment for main confounders. Likewise, HOMA-IR >2.14 was associated with the risk of MetS development in multivariate models. CONCLUSIONS: The results of this prospective study indicate a significant predictive role of TyG on the risk of MetS, independently of the main confounders. They suggest that TyG may serve as a low-cost and simple non-invasive marker for cardio-metabolic risk stratification, with respect to more complex and expensive assays of IR requiring the insulin measurement.

Adherence to Mediterranean Diet, Dietary Salt Intake, and Susceptibility to Nephrolithiasis: A Case-Control Study.

Unhealthy dietary habits play a key role in the pathogenesis of nephrolithiasis (NL). The aims of this case-control study were to evaluate (i) the adherence to the Mediterranean Diet (MD) and the dietary salt intake in stone-forming patients (SF), (ii) the relationship occurring between MD adherence, salt intake and NL-related metabolic risk factors in SF, and (iii) the impact of combined high MD adherence and low salt intake on NL susceptibility. From 1 January 2018 to 31 December 2019, we recruited all SF consecutively referred to the Extracorporeal Shock Wave Lithotripsy (ESWL) center of Federico II University, and at least two control subjects without a personal history of NL, age-, sex-, and body mass index-matched to SF (NSF). All study participants were interviewed using the validated MEDI-LITE and MINISAL questionnaires. In an SF subgroup, the NL-related metabolic risk factors were also evaluated. SF showed a lower MD adherence and a higher salt intake compared with NSF. The NL susceptibility decreased by 36% [OR: 0.64 (0.59-0.70); p < 0.01] for each point of increase in MEDI-LITE score, while it increased by 13% [OR: 1.13 (1.03-1.25); p = 0.01] for each point of increase in MINISAL score. The SF prevalence was higher among subjects showing combined low MD adherence and high salt intake. In SF, the MEDI-LITE score directly correlated with 24 h-citraturia, whereas the MINISAL score directly correlated with urinary sodium and uric acid excretion. In conclusion, high MD adherence and low salt intake are associated with a reduced NL susceptibility, both separately and in combination.

Time to define food salt targets in Italy starting with cereal-based products: A safe and practical way to reduce the heavy burden of cardiovascular disease.

BACKGROUND AND AIMS: Excess salt intake is the leading dietary risk factor for cardiovascular disease in most countries, including Italy. While the cost-effectiveness of interventions aimed to reduce salt intake has been proved, the WHO recommendation to reduce salt intake by 30 % at the global level by 2025 is far from being reached. METHODS AND RESULTS: In Italy, two surveys of the general adult population have established that the average salt intake is still almost twice the WHO recommendation although it was reduced by 1.2 g/day between 2008-12 and 2018-19. Previous investigations had shown that non-discretionary salt added by the industry or by local craft producers represents at least 50 % of the total intake and indicated cereal-based products as the main source of non-discretionary salt. Two recent studies conducted by the Italian Society of Human Nutrition "Young Working Group" have provided updated information on the salt content of almost three thousand cereal-based products currently available on the Italian food market and shown that most of the items evaluated had a sodium content much higher than the sodium benchmarks recently proposed by WHO. CONCLUSIONS: Italy has built the foundations of an effective population strategy for salt intake reduction: it is time however to proceed with full commitment to food reformulation if any substantial further progress has to be made. Salt benchmarks for Italy need to be defined for the food categories most relevant to population salt intake and their implementation should ideally be mandatory after consultation with food producers.

Dietary Salt Restriction and Adherence to the Mediterranean Diet: A Single Way to Reduce Cardiovascular Risk?

The dietary restriction of salt intake and the adhesion to Mediterranean dietary patterns are among the most recommended lifestyle modifications for the prevention of cardiovascular diseases. A large amount of evidence supports these recommendations; indeed, several studies show that a higher adherence to Mediterranean dietary patterns is associated with a reduced risk of cardiovascular disease. Likewise, findings from observational and clinical studies suggest a causal role of excess salt intake in blood pressure increase, cardiovascular organ damage, and the incidence of cardiovascular diseases. In this context, it is also conceivable that the beneficial effects of these two dietary patterns overlap because Mediterranean dietary patterns are typically characterized by a large consumption of plant-based foods with low sodium content. However, there is little data on this issue, and heterogeneous results are available on the relationship between adherence to salt restriction and to Mediterranean dietary patterns. Thus, this short review focuses on the epidemiological and clinical evidence of the relationship between the adherence to Mediterranean dietary patterns and dietary salt restriction in the context of cardiovascular risk.

Relationship between leptin and white blood cells: a potential role in infection susceptibility and severity-the Olivetti Heart Study.

A number of evidence showed an emerging role of leptin on immune system, involving inflammation, and innate and adaptive immunity. Few observational studies have evaluated the relationship between leptin and immunity, albeit with low statistical power and methodological differences. Therefore, the aim of this study was to evaluate the potential role of leptin on the immunity, expressed as white blood cells (WBC)-and its subpopulations, by comprehensive multivariate models in a sample of adult men. A cross-sectional evaluation of a general population comprised 939 subjects participating in the Olivetti Heart Study, with available leptin levels and WBC-and its subpopulations. WBC were significantly and positively associated with leptin, C-reactive protein and HOMA index (p < 0.05), but not with age and anthropometric indices (p > 0.05). The multivariate analysis confirmed the association between leptin and WBC, after accounting for main confounders (p < 0.05). Additional analysis on WBC subpopulations showed a positive and significant correlation between leptin and lymphocytes, monocytes and eosinophils (p < 0.05), but not with neutrophils and basophils (p > 0.05). After stratification by body weight, the positive and significant association between leptin and WBC-and its subpopulations-was found in excess body weight participants. The results of this study indicate a direct relationship between leptin levels and WBC-and its subpopulations-in excess body weight participants. These results support the hypothesis that leptin has modulatory functions on immunity and role in the pathophysiology of immune-related diseases, in particular in those associated with excess body weight.

25-Hydroxy-Vitamin D and Risk of Recurrent Stroke: A Dose Response Meta-Analysis.

Stroke recurrence significantly improves the prognosis quoad vitam et valetudinem of patients with a first ischemic or haemorrhagic stroke. Other than in bone and skeletal metabolism, vitamin D is involved in the pathogenesis of cardiovascular disorders. This meta-analysis was performed to evaluate the relationship between 25OH-vitamin D [25(OH)D] levels at the first stroke and the stroke recurrence. To 31 July 2022, four prospective studies were identified. The potential non-linear relationship was evaluated by modelling 25(OH)D, using restricted cubic splines of 25(OH)D distribution. The pooled estimated risk (and 95% CI) of the recurrence of stroke, comparing the highest and the lowest levels, was assessed using a random-effect model. A non-linear association was found by dose-response analysis. This study found that 25(OH)D levels at the first stroke ≥9.3 ng/mL were associated with a lower risk of stroke recurrence, compared with 25(OH)D levels ≤8.5 ng/mL. In the pooled analysis, higher 25(OH)D levels at the first stroke significantly reduce the risk of stroke recurrence, with a significant heterogeneity among studies. In conclusion, 25(OH)D levels ≤8.5 ng/mL at the first stroke are significantly associated with a higher risk of recurrent stroke.

Hypertension and mortality in SARS-COV-2 infection: A meta-analysis of observational studies after 2 years of pandemic.

BACKGROUND: The worldwide pandemic SARS-CoV-2 infection is associated with clinical course including a very broad spectrum of clinical manifestations, including death. Several studies and meta-analyses have evaluated the role of hypertension on prognosis, but with important limitations and conflicting results. Therefore, we decided to perform a new meta-analysis of the observational studies that explored the relationship between pre-existing hypertension and mortality risk in patients with SARS-CoV-2 infection, using more stringent inclusion criteria to overcome the limitations inherent previous meta-analyses. METHODS: A systematic search of the on-line databases available up to 31 March 2022 was conducted, including peer-reviewed original articles, involving the adult population, where the role of hypertension on mortality due to SARS-CoV-2 infection was determined by Cox-proportional hazard models. Pooled hazard ratio (HR) was calculated by a random effect model. Sensitivity, heterogeneity, publication bias, subgroup and meta-regression analyses were performed. RESULTS: Twenty-six studies (222,083 participants) met the pre-defined inclusion criteria. In the pooled analysis, pre-existing hypertension was significantly associated with mortality due to SARS-CoV-2 infection, both in unadjusted and adjusted models (HR: 1.55; 95% CI: 1.22 to 1.97). However, in separate analyses including results adjusted for crucial and strong predictors of mortality during SARS-CoV-2 infection (e.g. body weight), the association disappeared. CONCLUSIONS: The results of this meta-analysis indicate that pre-existing hypertension is not an independent predictor of mortality during SARS-CoV-2 infection. Further studies should nevertheless be carried out worldwide to evaluate this role, independent of, or in interaction with, other confounders that may affect the mortality risk.

Dietary Potassium Intake and Risk of Diabetes: A Systematic Review and Meta-Analysis of Prospective Studies.

(1) Background: Dietary potassium intake is positively associated with reduction of cardiovascular risk. Several data are available on the relationship between dietary potassium intake, diabetes risk and glucose metabolism, but with inconsistent results. Therefore, we performed a meta-analysis of the prospective studies that explored the effect of dietary potassium intake on the risk of diabetes to overcome these limitations. (2) Methods: A random-effects dose-response meta-analysis was carried out for prospective studies. A potential non-linear relation was investigated using restricted cubic splines. (3) Results: A total of seven prospective studies met the inclusion criteria. Dose-response analysis detected a non-linear relationship between dietary potassium intake and diabetes risk, with significant inverse association starting from 2900 mg/day by questionnaire and between 2000 and 5000 mg/day by urinary excretion. There was high heterogeneity among studies, but no evidence of publication bias was found. (4) Conclusions: The results of this meta-analysis indicate that habitual dietary potassium consumption is associated with risk of diabetes by a non-linear dose-response relationship. The beneficial threshold found supports the campaigns in favour of an increase in dietary potassium intake to reduce the risk of morbidity and mortality. Further studies should be carried out to explore this topic.

Sodium Content in Cereal-Based Products Sold in Italy: How Far Are We from the Global Benchmarks?

Reformulation of food products is one of the measures needed for reducing salt consumption. Accordingly, the World Health Organization (WHO) recently proposed global sodium benchmarks for different food categories to be used for setting national policies. Therefore, the sodium content of cereal-based products currently sold in Italy was compared with the WHO benchmarks, highlighting those categories primarily needing a reformulation. To this aim, the sodium content and several declarations (i.e., nutrition and health claims, organic or gluten free declaration) were retrieved from 2917 cereal-based products sold on the Italian market. All "minimally processed breakfast cereals" had a sodium content below the benchmark, while "flatbreads" and "leavened bread" had the highest percentage of items above the respective sodium benchmarks. Flatbreads and "crackers/savory biscuits" showed the highest median delta values from the respective benchmarks of 360 and 278 mg/100 g, respectively. Large variability in terms of percentage of products with sodium content above the benchmark was observed within the same categories, as well as among products with different declarations. A large number of food products currently sold on the Italian market have a sodium content above the benchmark. This result suggests the need to reformulate many food products currently on the market to achieve the WHO/United Nations (UN) objective of 30% global reduction in sodium intake by 2025.

Evaluation of the Nutritional Status of Gaucher Disease Type I Patients under Enzyme Replacement Treatment.

(1) Background: Gaucher disease (GD) is a rare lysosomal storage disease. The few studies analyzing Resting Energy Expenditure (REE) in GD involved mainly untreated patients and supported a hypermetabolic condition possibly due to the associated inflammatory state. Definitive conclusions could not be drawn also because of the heterogeneity and the small size of the samples investigated. In order to expand current knowledge concerning, in particular the condition of patients under Enzyme Replacement Therapy (ERT), we evaluated the nutritional status of a relatively large sample of GD patients followed at Federico II University Hospital in Naples, Italy. (2) Methods: The study, having a cross-sectional design and involving 26 patients on ERT, included routine biochemical analyses, bioelectrical impedance analysis, indirect calorimetry, and administration of food frequency and physical activity questionnaires. The results in GD patients were compared with those from an appropriate control group. (3) Results: GD patients had normal biochemical parameters in 80% of cases, except for HDL-cholesterol, consumed a hyper-lipidic diet, and had a 60% prevalence of overweight/obesity. Body composition did not differ between patients and controls; however, measured REE was significantly lower than predicted and was reduced in comparison with the healthy controls. (4) Conclusions: This study provided novel elements to the present knowledge about REE and the nutritional status of GD patients under ERT. Its results warrant confirmation in even larger GD population samples and a more in-depth investigation of the long-term effects of treatment superimposed on the basic pathophysiological disease condition.

Vitamin D Status, Cardiovascular Risk Profile, and miRNA-21 Levels in Hypertensive Patients: Results of the HYPODD Study.

The vitamin D and microRNA (miR) systems may play a role in the pathogenesis of cardiometabolic disorders, including hypertension. The HYPODD study was a double-blind placebo-controlled trial aiming to assess the effects of cholecalciferol treatment in patients with well-controlled hypertension and hypovitaminosis D (25OHD levels < 50 nmol/L). In addition to this clinical trial, we also evaluated the effects of cholecalciferol and calcitriol treatment on miR-21 expression in vivo and in vitro, respectively. Changes in the cardiovascular risk profiles were evaluated in HYPODD patients treated with cholecalciferol (C-cohort) or with placebo (P-cohort). The miR-21circulating levels were measured in four C-cohort patients and five P-cohort patients. In vitro, the miR-21 levels were measured in HEK-293 cells treated with calcitriol or with ethanol vehicle control. Cholecalciferol treatment increased 25OHD levels and reduced parathormone, total cholesterol, and low-density lipoprotein cholesterol levels in C-cohort patients, whereas no significant changes in these parameters were observed in P-cohort patients. The miR-21 circulating levels did not change in the C- or the P-cohort patients upon treatment. Calcitriol treatment did not affect miR-21 levels in HEK-293 cells. In conclusion, hypovitaminosis D correction ameliorated the cardiovascular risk profiles in hypertensive patients treated with cholecalciferol but did not influence the miR-21 expression.

Validation of salt intake measurements: comparisons of a food record checklist and spot-urine collection to 24-h urine collection.

OBJECTIVE: Monitoring population salt intake is operationally and economically challenging. We explored whether a questionnaire assessment and a prediction of Na intake from spot-urine could replace or complement the recommended measurement of Na in 24-h urine (24-h U). DESIGN: Compare the agreement of a Na-specific food record checklist (FRCL) and a late-afternoon spot-urine measurement (PM-spot) with 24-h U measurement in estimating Na intake at group level. Each participant's use of these methods extended over 3 d. Agreement was assessed using mean (95 % CI) differences, linear regression models and Bland-Altman plots. SETTING: The validation study was part of a 1-year workplace intervention trial to lower salt intake in Switzerland. PARTICIPANTS: Seventy women and 71 men, aged 21-61 years, completed three FRCL, and acceptable PM-spot and 24-h U samples at baseline (April-October 2015). RESULTS: Mean Na intake estimates varied slightly across methods (3·5-3·9 g/d). Mean Na intake differences from 24-h U were 0·2 (95 % CI (0, 0·5)) g/d for FRCL and 0·4 (95 % CI (0·2, 0·6)) g/d for PM-spot. Linear regression models and Bland-Altmann plots more clearly depicted differences by sex and discretionary salt use. CONCLUSIONS: Although 24-h U remains the best reference method for monitoring Na intake at the population level, PM-spot and FRCL might be more practical instruments for frequent, periodic Na intake assessments. Population-specific prediction models to estimate 24-h U could be developed and evaluated.

Tumor-induced Osteomalacia: A Systematic Review and Individual Patient's Data Analysis.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, usually caused by small, benign, and slow-growing phosphaturic mesenchymal tumors. Clinically, TIO is characterized by renal phosphate leak, causing hypophosphatemia and osteomalacia. This review was performed to assess the clinical characteristics of TIO patients described worldwide so far. EVIDENCE ACQUISITION: On June 26, 2021, a systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library using the terms: "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia." There were no language restrictions. This review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. EVIDENCE RESULTS: Overall, 1725 TIO cases were collected. TIO was more frequent in adult men, who showed a higher incidence of fractures compared with TIO women. The TIO-causing neoplasms were identified in 1493 patients. The somatostatin receptor-based imaging modalities have the highest sensitivity for the identification of TIO-causing neoplasms. TIO-causing neoplasms were equally located in bone and soft tissues; the latter showed a higher prevalence of fractures and deformities. The surgery is the preferred TIO definitive treatment (successful in > 90% of patients). Promising nonsurgical therapies are treatments with burosumab in TIO patients with elevated fibroblast growth factor-23 levels, and with radiolabeled somatostatin analogs in patients with TIO-causing neoplasm identified by somatostatin receptor-based imaging techniques. CONCLUSION: TIO occurs preferentially in adult men. The TIO clinical expressiveness is more severe in men as well as in patients with TIO-causing neoplasms located in soft tissues. Treatments with burosumab and with radiolabeled somatostatin analogs are the most promising nonsurgical therapies.

Sodium and Health: Old Myths and a Controversy Based on Denial.

PURPOSE OF REVIEW: The scientific consensus on which global health organizations base public health policies is that high sodium intake increases blood pressure (BP) in a linear fashion contributing to cardiovascular disease (CVD). A moderate reduction in sodium intake to 2000 mg per day helps ensure that BP remains at a healthy level to reduce the burden of CVD. RECENT FINDINGS: Yet, since as long ago as 1988, and more recently in eight articles published in the European Heart Journal in 2020 and 2021, some researchers have propagated a myth that reducing sodium does not consistently reduce CVD but rather that lower sodium might increase the risk of CVD. These claims are not well-founded and support some food and beverage industry's vested interests in the use of excessive amounts of salt to preserve food, enhance taste, and increase thirst. Nevertheless, some researchers, often with funding from the food industry, continue to publish such claims without addressing the numerous objections. This article analyzes the eight articles as a case study, summarizes misleading claims, their objections, and it offers possible reasons for such claims. Our study calls upon journal editors to ensure that unfounded claims about sodium intake be rigorously challenged by independent reviewers before publication; to avoid editorial writers who have been co-authors with the subject paper's authors; to require statements of conflict of interest; and to ensure that their pages are used only by those who seek to advance knowledge by engaging in the scientific method and its collegial pursuit. The public interest in the prevention and treatment of disease requires no less.

Metabolic syndrome and its components predict the development of arterial stiffening in a sample of adult men.

BACKGROUND AND OBJECTIVE: Metabolic syndrome (MS) and its components are associated with greater cardiovascular risk. A number of studies found a positive association between MS and vascular damage, but few observational studies evaluated the predictive role of MS on arterial stiffening (AS). Therefore, the aim of this study was to estimate the ability of MS and its components to predict the risk of AS in an 8-year follow-up of a sample of adult men (Olivetti Heart Study). METHODS: The analysis included 778 men without AS (pulse pressure >60 mmHg) at baseline. A positive diagnosis of MS was made by recognized criteria, if at least three components were present. RESULTS: At the end of the follow-up period, there was an incidence of 11% in AS. The percentage of participants that developed AS was greater in the MS group than those without MS, also after adjustment for main confounders (odds ratio: 2.5, 95% confidence interval: 1.3-4.9). The risk of AS also increased with increase in the numbers of MS elements (p for trend <.01). In addition, the analysis of the predictive role of the single MS component showed that high blood pressure (HBP) was the strongest predictor. CONCLUSIONS: The results of this prospective study indicate a predictive role of MS on AS, independently of main confounders. In addition, HBP seems the strongest predictor of AS among MS components.

Isolated systolic hypertension of the young and sodium intake.

Isolated systolic hypertension is associated with higher risk of cardiovascular disease and all-cause mortality. Despite being the most common form of hypertension in the elderly, it is also detectable among young and middle-aged subjects. Dietary salt (sodium chloride) intake is an important determinant of blood pressure, and high salt intake is associated with greater risk of hypertension and cardiovascular events. In most countries, habitual salt intake at all age categories largely exceeds the international recommendations. Excess salt intake, often interacting with overweight and insulin resistance, may contribute to the development and maintenance of isolated systolic hypertension in young individuals by causing endothelial dysfunction and promoting arterial stiffness through a number of mechanisms, namely increase in the renin-angiotensin-aldosterone system activity, sympathetic tone and salt-sensitivity. This short review focused on the epidemiological and clinical evidence, the mechanistic pathways and the cluster of pathophysiological factors whereby excess salt intake may favor the development and maintenance of isolated systolic hypertension in young people.

Iodine Intake from Food and Iodized Salt as Related to Dietary Salt Consumption in the Italian Adult General Population.

Since the Italian iodoprophylaxis strategy is based on the use of iodized salt, we assessed the relationship between dietary salt consumption and iodine intake in the Italian adult population. We estimated the relative contribution given by the use of iodized salt and by the iodine introduced by foods to the total iodine intake. The study population included 2219 adults aged 25-79 years (1138 men and 1081 women) from all Italian regions, participating to the Osservatorio Epidemiologico Cardiovascolare/Health Examination Survey 2008-2012 (OEC/HES), and examined for sodium and iodine intake in the framework of the MINISAL-GIRCSI Programme. Dietary sodium and total iodine intake were assessed by the measurement of 24 h urinary excretion, while the EPIC questionnaire was used to evaluate the iodine intake from food. Sodium and iodine intake were significantly and directly associated, upon accounting for age, sex, and BMI (Spearman rho = 0.298; p < 0.001). The iodine intake increased gradually across quintiles of salt consumption in both men and women (p < 0.001). The European Food Safety Authority (EFSA) adequacy level for iodine intake was met by men, but not women, only in the highest quintile of salt consumption. We estimated that approximately 57% of the iodine intake is derived from food and 43% from salt. Iodized salt contributed 24% of the total salt intake, including both discretionary and non-discretionary salt consumption. In conclusion, in this random sample of the Italian general adult population examined in 2008-2012, the total iodine intake secured by iodized salt and the iodine provision by food was insufficient to meet the EFSA adequate iodine intake.

Serum leptin is associated with increased pulse pressure and the development of arterial stiffening in adult men: results of an eight-year follow-up study.

High leptin levels are associated with an unfavorable cardiometabolic risk profile. A number of studies found a positive association between leptin and vascular damage, but to date, no observational study has evaluated a potential predictive role of leptin for arterial stiffening. Therefore, the aim of this study was to estimate the role of leptin in the incidence of arterial stiffening (pulse pressure >60 mmHg) and changes in pulse pressure in an 8-year follow-up of a sample of adult men (The Olivetti Heart Study). The analysis included 460 men without baseline arterial stiffening and antihypertensive treatment at baseline and at follow-up (age: 50.0 years, BMI: 26.5 kg/m2). At the end of the follow-up period, the incidence of arterial stiffening was 8%. Baseline leptin was significantly greater in the group that developed arterial stiffening and was significantly correlated with pulse pressure changes over time (p < 0.05). According to the median plasma leptin distribution of the whole population, the sample was stratified into two groups: one with leptin levels above the median and the other with leptin levels below the median. Those who had baseline leptin levels above the median had a greater risk of developing arterial stiffening (odds ratio: 2.5, p < 0.05) and a greater increase in pulse pressure over time (beta: 2.1, p < 0.05), also after adjustment for confounders. The results of this prospective study indicate a predictive role of circulating leptin levels for vascular damage, independent of body weight and blood pressure.

Sodium Intake and Related Diseases.

Moderation in the use of salt (sodium chloride) in food and food preparations prevents the tendency of blood pressure to increase with age, and this is documented by many studies in current literature [...].