Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1–2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE. Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is associated with an increased global burden and represents the third most common cause of death worldwide .The incidence rate for VTE in a previous study on the general population in Norway was estimated at 1.43 per 1000 person-years, while that for DVT was 0.93 per 1000 person-years and that for PE was 0.50 per 1000 person-years . The estHowever, during the last decades, several improvements in diagnostic and therapeutic management yielded a linear decrease in VTE-related incidence and deaths from 12.8 to 6.5 per 100,000 persons, without substantial sex-specific differences .The healthcare costs attributable to VTE are estimated at EUR 1.5–2.2 billion regarding annual hospitalisations in Europe  and USD As VTE is a preventable disease in many cases, an early risk stratification of patients with the identification of high-risk patients may lead to more effective therapeutic strategies, with an estimated saving of EUR 0.5–1.1 billion/year ,15.Indeed, despite some VTE events occurring without any apparent major reason , most VTEs share one or more identifiable risk factors that may cause or facilitate the occurrence of VTE. These may be related to patients’ characteristics, usually permanent, as well as to acute clinical conditions, usually transient . FurtherCompared to previous works on this topic , the aimVTE is characterized by the development of thrombi in virtually all venous districts. Venous thrombi are more frequently found in valve pockets and dilated sinuses of the lower limbs, and they have a laminar structure enriched with platelets, red blood cells, leukocytes and fibrin . In the Virchow’s triad has historically represented a simple method to summarize the pathophysiology of VTE, including blood flow stasis, hypercoagulability, endothelial dysfunction and injury . This scThe pathogenesis of VTE is, however, complex, and other mechanisms, including endothelial damage, macrophages, red blood cells and platelets (PLTs), have been investigated .The first hit in the development of VTE is related to an injury of the venous endothelium due to local/systemic inflammation and blood hypoxemia. Indeed, an unharmed and intact vein vessel expresses thrombomodulin, endothelial protein C receptor, tissue factor (TF) pathway inhibitor and heparin-like proteoglycans that explicate an anticoagulant effect ,27 and eAfterwards, PLTs and white blood cells (WBCs) bind vWF and P- and E- selectin, and WBCs start expressing TF, triggering coagulation cascade activation ,22. In aSeveral factors modulate PLT activation, such as injury and inflammation ; indeed,Therefore, the binding of platelets to vWF and WBCs to P-selectin and E-selectin lead, on the one hand, to platelet activation and aggregation and, on the other, to the release of TF. In particular, the increased production of TF leads to the activation of the extrinsic pathway of coagulation, with final formation of fibrin and entrapment of red blood cells and PLTs, resulting in a red-blood-cells-rich thrombus formation ,27.p < 0.001) [p = 0.027) [Growing evidence suggests that male sex represents a risk factor for VTE. In a work performed by Baglin et al., VTE recurrence after a first unprovoked event was 25.7% in men and 11.7% in women after 2 years follow-up . A simil< 0.001) . Data fr= 0.027) .A patient-level meta-analysis of 7 prospective studies with 2554 patients with a first VTE showed that recurrent VTE at 1 year was higher in men than women, both at 1 year (9.5% vs. 5.3%) and at 3 years (11.3% vs. 7.3%) . The risAn analysis of 4 European cohorts , including 2185 patients with a first VTE (1043 men and 1142 women) showed that men had a 2.8-fold higher risk of recurrent VTE than women [However, the factors behind these divergent results are still unclear. Olié et al. found that risk factors for VTE recurrence may differ between male and female: Factor V Leiden mutation was a risk factor for recurrent VTE in male patients , while in women, the VTE recurrence rate seems to be more related to age at first event  and obesity  . A risk A recent study including 13,932 men with VTE, those aged <50 and ≥50 years without risk factors, had a recurrence risk of 10% at 2 years . For menMost epidemiological studies demonstrate an increased risk of VTE among diabetic patients. A metanalysis with 803,627,121 participants and 10,429,227 VTE patients showed that diabetes was associated with a higher risk of VTE  . FurtherDespite this convincing evidence, it is still unclear if poor glycaemic control may have a role in increasing the risk of VTE. In a case control study performed on 188 patients with VTE and 370 controls, increased glucose levels measured at presentation were associated with VTE . Thus, cData from the “Atherosclerosis Risk in Communities” (ARIC) study performed on 12,298 patients showed that haemoglobin A1c levels were not associated with VTE . SimilarOn the other hand, a case-control study performed on 2653 VTE patients and 10,612 controls showed that female patients with diabetes and HbA1c levels >7% may have a slightly higher risk for VTE than those with HbA1c 6.5–7.0% .It has been, therefore, questioned whether the increased risk of VTE associated with diabetes may result from the presence of confounders, such as concomitant comorbidities, rather than to diabetes itself . Indeed,Smoking is a well-proved risk factor for atherosclerotic disease, but its association with VTE is less established. A metanalysis that included participants without cardiovascular disease or VTE at baseline showed that current smoking was associated with an increased VTE risk . The HR remained similar after excluding patients diagnosed with cancer , that isThe association between smoking and VTE risk seems to be dose-dependent. A large metanalysis showed that compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95%CI 1.09–1.25) for ever smokers, 1.23 (95%CI 1.14–1.33) for current smokers and 1.10 (95%CI 1.03–1.17) for former smokers . The risNicotine and other addictive substances in cigarettes have been shown to increase the percentage of ROS, determining reduced nitric oxide (NO) availability and generating an inflammatory and prothrombotic microenvironment . The losObesity is a well-known risk factor for cardiovascular disease, but it is considered a weak risk factor for VTE . In the In an analysis from the Framingham heart study, obesity as defined by body mass index (BMI) ≥ 30 was associated with incident “unprovoked” VTE  .Gregson et al. analysed the relationship of different markers of adiposity  with VTE. The HR for “unprovoked” VTE were 1.40 (1.34–1.46) per 1-SD higher BMI, 1.58 (1.43–1.75) for waist–to–hip ratio and 1.67 (1.58–1.78) for waist circumference .Obesity may cause thrombosis due to the activity of adipocytokines, such as leptin and adiponectin, increasing coagulation activity and inflammation and decreasing the fibrinolytic cascade . Thus, lThere is also evidence for an increased release of IL-6 and leptin from adipose cells , which hAdiponectin is the most represented adipose-related cytokine, and its serum levels seem to be reduced in obese patients. Adiponectin had an anti-inflammatory, anti-atherosclerotic and antithrombotic effect by modulating endothelial function , smooth Under physiological conditions, factor V is a procoagulant protein that accelerates the conversion of prothrombin to thrombin and is inactivated by activated protein C. Factor V Leiden (FVL) is a gain-of-function mutation causing resistance to activated protein C, which determines the hypercoagulable state and an increased risk of VTE . FVL is FVL mutation is associated with an increased risk of VTE. The strength of this risk factor is different depending on it being inherited in homozygous or heterozygous form. The risk of a first episode of VTE in a heterozygous FVL is about 3 times higher than in patients without  , while tProthrombin G20210A Gene Mutation (PGM) is estimated to be the second most commonly inherited thrombophilia after FVL and was first described in 1996 by Poort and colleagues . The G20The prevalence of PGM is 2.0% in the general population  and rangThe risk of developing a first episode of VTE in PGM carriers is increased by nearly 3-fold  , while tWhile the prevalence of PGM in patients who develop a recurrence in VTE is estimated to be 6% , PGM carPAI-1 is a serine protease that plays a key role in the fibrinolytic system by inhibiting fibrinolytic activators tPA and uPa. Through this mechanism, PAI-1 compromises the conversion of plasminogen to plasmin, which dissolves fibrin blood clots . The 4G/In a study by Folsom et al., the prevalence of this mutation, in its homozygous form, is estimated to be 7.2% in patients presenting with an episode of VTE and 3.4% in healthy controls .PAI-1 mutation is associated with an increased susceptibility to VTE  when considered in its homozygous form 4G/4G versus the wild type 5G/5G, and with an OR of 1.38  when considering overall the carriage of a mutated allele versus the wild type . Data onCombined oral contraceptives and hormonal replacement therapy are established risk factors for thrombosis, both arterial and venous, with a higher incidence for the latter. Millions of women worldwide are estimated to be under this treatment, and this therapy is generally preceded by an evaluation of the patient’s thrombotic risk . HormonaThe use of combined oral contraceptives carries an increased risk of a first VTE episode, with a RR of 3.5 , although the risk may increase with higher oestrogen doses (>30 mcg of ethinyl oestradiol) and non-levonorgestrel progestin . HormonaA metanalysis also showed an association between hormonal contraceptive therapy and an increased risk of CVT, with an OR of 7.95  compared to untreated women .Being a moderate intensity risk factor, compared with non-users, the OR for recurrence among estrogen-containing-contraceptive users was 0.4 , indicating a very safe profile in terms of recurrence .As mentioned, hormonal therapy is linked to thrombotic risk mainly by oestrogens dose and oral administration, although the mechanisms are not fully understood . This kiCancer represents a strong risk factor for the development of cancer-associated thrombosis (CAT), with an estimated increased risk of VTE 4 to 6.5 times higher than in people without cancer .The prevalence of CAT is growing due to the longer patient survival; to a wider cancer surveillance, which increases the early and major detection of silent thrombosis; and to the major use of central venous catheters (CVC). Indeed, CAT represents almost 20% of the overall incidence of total VTE ,97. In tThe risk of VTE is highest in the first 3 months after cancer diagnosis  , probablOn top of that, CAT plays an important role in defining the mortality and morbidity of these patients; it represents the second leading cause of death after disease progression .The risk of CAT varies according to tumour-related factors, such as cancer site and stage, malignancy treatment, patient related factors and biomarkers. A metanalysis including 57,591 patients, representative of 8 types of cancer, showed an overall risk of VTE of 13 per 1000 person-years, increasing to 68 per 1000 person-years in patients with metastatic disease . The higIn addition, cancer treatments may favour CAT onset . The usep < 0.001) [In the Computerized Registry of Patients with Venous Thromboembolism (RIETE) study, recurrent CAT at 3 months occurred in 11.4% of patients with cancer vs. 2.1% in those without (< 0.001) .In a prospective study, the 1-year rate of CAT was high in gastrointestinal (HR 5.1 95%CI: 2.3–11.3) and lung cancer (HR 6.9 95%CI: 3–15.9) .The risk of CAT/VTE according to cancer type is reported in 9/L have a risk of CAT 3.5-fold higher than patients without malignancy [The association between cancer and VTE is based on complex mechanisms that result in a hypercoagulative state , determilignancy .Massive release of TF is another characteristic of many tumours; it is provoked by the presence of microparticles (MPs), cellular fragments of platelets or endothelial cells of 0.1–1 µm diameter, found in pancreatic, brain and lung cancer, especially in patients with high severity or metastatic disease. TF and MPs and P-selectin, which can be found on activated platelets or endothelial cells and whose levels above 75% percentile increase of 2.5-times the risk of VTE, are not only responsible for the activation of coagulation cascade, but also avoid immune detection of tumour cells and disease progression . ChemothThe risk of CAT may be increased by some specific patient’s characteristics, such as obesity, age (>65 years), medical comorbidities and ethnicity ,120. In The first cases of VTE associated with air travel were reported in 1954. Since them, other cases have been described, also regarding atypical thrombosis . The oveHowever, VTE risk associated with long-haul-flight increases with the presence of other VTE risk factors, such as a previous thrombosis history. In the above research from MacCallum et al., cases were 8-fold more likely to have a previous history of VTE than controls .The increased risk of VTE seems to be connected to two different factors, such as immobilization and hypobaric hypoxia. Immobilization and cramped seating during long-haul flights carry a major risk of VTE due to the compression of popliteal veins , with blAntiphospholipid syndrome (APS) is an immune-mediated disease characterized by thrombotic and/or obstetrical events . ThromboVTE in APS patients usually occurs as DVT of lower limbs , but venThe antiphospholipid antibodies’ profile shows a strong association with the risk of thrombosis. LA positivity carries the strongest association with both arterial and venous thrombosis . A positThe mechanisms through which aPLs induce thrombosis are unclear. First, there are the interactions with the coagulation and fibrinolytic systems, particularly inhibition of the protein C system, but also the interactions with antithrombin, TF and tissue-type plasminogen activator. In addition, there are other factors, such as vascular cells activation like endothelial cells, monocytes, neutrophils and platelet by aPL, particularly anti-β2GPI, complement activation and the destruction of annexin V and exposure of the procoagulant phosphatidylserine on the cellular surface ,141.An emerging risk factor for VTE recurrence is represented by residual venous thrombosis (RVT). According to a systematic review, RVT found within three months after acute event of thromboembolism appeared to be associated positively to a major risk of recurrence  .Another cohort study , which iIt was confirmed that ultrasound sonography allowed predicting recurrence in 75% of cases and suggested hypoechogenic thrombi  as a predictive marker of TVP recurrence .p = 0.004) for persistent residual thrombosis versus veins considered recanalized using ultrasound echography.As it that were enough, a review  that conAs a matter of fact, it has been supposed that the damaged endothelial wall and the blood stasis connected to the residual clot promote thrombotic recurrence , but it Since the start of the pandemic outbreak, an increased risk of VTE during SARS-CoV-2 infection has been reported in several studies of different design, size and quality, but there has been a high variability of reported rates. The large variability may be related to differences in diagnostic protocols or screening for VTE, such as outpatients vs. hospitalised and non-intensive care unit (ICU) or ICU setting or use of antithrombotic prophylaxis. Hospitalized patients with COVID-19 have many common risk factors for VTE as other inpatient, but severe SARS-CoV-2 results in an increased risk of thrombotic complications, occurring both in the venous and arterial system ,147.For example, a meta-analysis by Nopp et al. that involved 28,173 patients  reported an overall VTE prevalence of 14.1%, 40.3% with ultrasound screening and 9.5% without screening. Subgroup analysis revealed high heterogeneity, with a VTE prevalence of 7.9%  in non-ICU and 22.7%  in ICU patients . MoreoveAs a matter of fact, the occurrence of VTE increases the risk of death both in outpatients  and inpatients  .Moreover, many studies showed that the risk of hospital-associated VTE extends from the time of admission and within the first 90 days post hospital discharge also in COVID-19 patients ,151. TheA population study including 18,818 outpatients showed that VTE risk decreased from an HR 21.42 to 5.95 in the fully vaccinated participants who were then infected by SARS-CoV2 . A studyCOVID-19 is associated with coagulopathy favouring VTE through several mechanisms. First, SARS-CoV2 interacts with the angiotensin converting enzyme (ACE)-2 receptor on endothelial cells, which results in an increased release of the vasoconstrictor angiotensin-II and an endothelial dysfunction . In addiFractures are a strong provoking factor for VTE. In a study of 480 patients, the incidence of fractures in the 90 days before hospitalization for VTE was 11.8%, compared with incidence during the control period that was 3.6%, with an adjusted incidence rate ratio of 2.81  . ParticuInterestingly, a retrospective study reported that in patients with hip fractures 38.89% of all preoperative DVTs were on the uninjured site, suggesting that not the local fracture itself, but a post-injury hypercoagulation state may be the main contributing factor to this phenomenon .A particular setting is the risk of cerebral sinus-vein or jugular veins thrombosis after a cranial trauma. Among 90 patients with cerebral sinus-vein or jugular veins thrombosis, history of trauma appeared to be the main risk factor, with 14.4% of patients reporting a head trauma, with or without fracture, in the month preceding the DVT event .Fractures play a role in developing VTE because of the inflammatory storm consequent to the trauma and especially because of high levels of TF. As a matter of fact, trauma always represents a physical disruption of the endothelium, which leads to hypoxia and haemodynamic stress, involving in this phenomenon a large variety of cytokines , chemokines, antibodies and immunocomplexes . DamagedLower limb traumas other than fracture are not associated with VTE risk. In a case-crossover study on a cohort of 480 patients with VTE, the adjusted IRR for VTE for open wounds was 0.74 , for sprain 1.30  and for dislocation 1.33  . HoweverImmobilization by itself, complicated or not by trauma, has a direct effect on coagulative cascade because it determines blood stasis. To this, cellular margination and local hypoxia follow, and so endothelial activation, which is the beginning of the thrombotic process. By the way, data from animals have shown that blood stasis is not enough to activate coagulation ; TFs conMajor surgery. In 2020, a 3-round Delphi process consensus defined major surgery according to pre-existing comorbidity of the patients, extent and complexity of the procedure , its pathophysiological consequences  and consecutive clinical outcomes (as systemic inflammatory response or need for intensive care) [ve care) . Therefove care) . Surgicave care) . In non-ve care) . VTE risve care) . In addiMinor surgery. VTE events appear to be significantly lower in laparoscopic surgery when compared with open surgery. In a retrospective study that analysed data of 138,595 patients obtained from the University HealthSystem Consortium Clinical Database, the incidence of VTE among patients who underwent laparoscopic surgery was 0.28% versus 0.59% in patients who underwent open surgery  [ < 0.01) . Another < 0.01) .Even other retrospective studies found a relationship between time of surgery with general anaesthesia and VTE risk ,184,185.Surgery is a transient condition associated with an increased risk of VTE. Different mechanisms are involved, but venous stasis, endothelial activation and local accumulation of TF are the main ones responsible for the development of VTE .Venous stasis occurs both during and after surgery, especially in major orthopaedic surgery , and it Pregnancy is considered a transient risk factor for VTE. A Dutch registry including 1,919,918 women showed an incidence rate of VTE of 2.3 per 10,000 person-years . The ratp < 0.01) [A recent Korean study showed an incidence of pregnancy-related VTE of 2.62/10,000 deliveries, this risk increasing from 1.80 for women aged 20 years to 5.46 for women in their 40s  . Women u < 0.01) .Some factors, such as hypertension occurring during the pregnancy, seem to be implicated in VTE risk. Indeed, VTE risk is higher in women with hypertension , and highest among women with preeclampsia  compared to those without .The mechanism underlying the risk of VTE during pregnancy may rely on the physiological reduction of some natural anticoagulant proteins, such as protein S, that may be reduced by 40–50% of normal levels. However, it remains to be established whether this reduction leads to an increased risk of VTE . SimilarThe incidence of VTE is variable across countries and seems to be lower in Eastern Countries. Intrinsic and environmental risk factors may lead to VTE through several different mechanisms that are frequently overlapping . The exa


Background: Therapeutic exercise has an important role to manage chemotherapy-induced peripheral neuropathy symptoms. However, there is little evidence of its effectiveness. Objective: To synthesize the evidence regarding therapeutic exercise during chemotherapy to improve peripheral neuropathy symptoms. Databases: PubMed, CINAHL, Cochrane Library, PEDro, ScienceDirect, Scopus, Web of Science and BIREME. Methodology: Randomized clinical trials were included. GRADE was used to synthesize evidence and an inverse variance model for meta-analysis. Results: Up to May 2022, 2172 references were analyzed and 14 studies that evaluated 1094 participants were included. The exercises were highly effective in improving pain threshold and moderately effective in improving peripheral neuropathy symptoms at the 8-week follow-up and the 4–24 weeks. Furthermore, the evidence was low in improving thermal threshold, tactile and vibratory sensitivity. Conclusion: Therapeutic exercise generates a significant reduction in peripheral neuropathy symptoms in patients in short- and long-term follow-up with a moderate level of evidence quality. Cancer is a global health issue with an increasing incidence and mortality. It is estimated that there will be 18.1 million new cases worldwide and 9.6 million deaths due to this disease ) OR cancer AND (exercise) OR “Resistance Training” [Mesh] AND chemotherapy AND .The Start program  of the Federal University of São Carlos, Brazil) was used, which was held in the selection of titles, abstracts and full text, considering the analysis between evaluators and consensus criteria. Two independent reviewers (V.T. and D.O.) performed the selection process and two (C.S. and I.L.) participated in the consensus.This systematic review included only randomized clinical trials that included therapeutic exercise with a variable related to symptoms of peripheral neuropathy in patients who underwent chemotherapy. The language of the publications was unlimited and should contain a pre-post comparison exercise and that the beginning of the training program was during chemotherapy.www.pedro.org.au, accessed on 1 May 2022) scale was used to assess the methodological quality of the studies based on the Delphi list [To Physiotherapy Evidence Database, a PEDro  [The synthesis of evidence for each intervention was calculated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) that considers high, moderate, low or very low evidence level based on the following factors: limitations, indirectness, inconsistency, imprecision and lastly bias risk. In this review, the GRADEpro software (ay 2022)  was used2. The p values were calculated and statistical significance was set at <0.05. Statistical analysis was performed using the RevMan five-revision management software .A meta-analysis was performed using means and standard deviations from each selected clinical trial. The difference of standardized means and the 95% confidence interval were calculated using an inverse variance model of random effects for the meta-analysis, considering the data after the intervention. Data heterogeneity between studies were assessed using the I statisiticThe studies obtained based on the search with the keywords totaled 2.172 articles, which were examined by title and abstracts; after reading the full text of 42 studies, 14 articles were selected that met the inclusion criteria. The flow diagram used is presented in Of the 14 studies collected, 13 were indexed in the PEDro scale ,24,25,26Eight of the studies obtained a score equal to or greater than six; therefore, they were classified as having high methodological quality ,26,27,28The training frequency ranged from 2 to 7 days a week with a duration of 5 to 60 min depending on the exercise performed, a moderate intensity depending on the chemotherapy cycle in which the patients were, and the duration of the protocol varied between 4 and 56 weeks. A physiotherapist supervised 23% of the programs, while the others were supervised by a professional trained to carry out this work. The main variables analyzed were peripheral neuropathy perception, pressure pain threshold and thermal, tactile and vibratory sensitivity. The follow-up was carried out in a period where the minimum range was 4 weeks and the maximum was approximately 36 weeks. The effect size range varied from 0.05 to 0.93 for peripheral neuropathy perception; as for pressure pain threshold, it ranged from 0.44 to 0.57, thermal threshold was 0.06 to 0.28, tactile sensitivity presented a value of 0.01 and vibratory sensitivity presented a value of 0.15.The evidence regarding therapeutic exercises to improve symptoms of peripheral neuropathy, pressure pain threshold, thermal threshold, and tactile and vibratory sensitivity was synthesized according to GRADE with follow-up times of 8 weeks  and betwEight studies ,26,27,28Seven studies ,22,26,27The inconsistency was serious since three studies were classified as serious, one study was classified as very serious and two studies as not serious. Eight weeks of therapeutic exercises to strengthen the upper and lower limbs, equilibrium, aerobics and balance, presented moderate evidence to improve the symptoms of peripheral neuropathy during chemotherapy for cancer treatment.Two studies ,19 with Two studies ,20 with Along with the above, a follow-up of 6–19 weeks with therapeutic exercises on a vibration platform for the whole body, aerobics and strengthening exercises in the upper and lower limbs presented low evidence to improve the thermal threshold in the lower limb area.Two studies ,20 with Five studies ,22,24,25p = 0.04) .Ten of the fourteen selected studies presented the mean and standard deviation to calculate the effect size (TE) of the intervention ,26,27,28 = 0.04) , with si2 = 45%; p = 0.09).The sensitivity analysis revealed that heterogeneity was influenced by the studies by Bland et al. 2019  and MijwWith respect to the quantitative analysis of this systematic review, the findings of the meta-analysis show that a therapeutic exercise program of 4 to 56 weeks generates significant changes, reducing the symptoms of peripheral neuropathy in subjects with cancer compared to the control group with short-term and long-term follow-up. However, given the significant heterogeneity presented, these results should be viewed with caution.Of the main studies selected, two of them reported improvement of pressure pain threshold after a therapeutic exercise program ,19. The Regarding the evaluation of neuropathy symptoms through questionnaires, six studies ,26,27,28In regard to the studies that evaluated tactile sensitivity ,20 and tThe findings reported in this review are similar to the study by Dobson et al., 2014  that evaThe present systematic review determines that strengthening, aerobic and motor sensory exercises for a total average time of 14 weeks (considering a standard deviation of 9 weeks) 2 to 5 days per week and with low to moderate intensities present a moderate level of evidence for the improvement of neuropathy symptoms. These facts coincide with the results of the study by Kneis et al., 2019  that repAccording to the above and considering that there is still controversy regarding the effectiveness of drugs in the management of peripheral neuropathy , multimo2 = 86%) which is due to the different types of exercises between studies and different evaluation tools used, providing variability; (4) the selected studies used distant tools to evaluate peripheral neuropathy; (5) two studies [Some limitations of the present study should be considered: (1) three studies showed poor methodological quality ,15,18; ( studies ,20 used  studies ,27, on t studies , before  studies , during  studies ,25 or on studies . In addi studies ,26 did n studies ,24 did nIn general, this systematic review and meta-analysis suggest that therapeutic exercise generates a significant reduction in peripheral neuropathy symptoms in patients in short and long-term follow-up with a moderate level of evidence quality. However, these results must be viewed with caution due to the significant heterogeneity of the studies analyzed. The available studies are diverse in terms of methodology, exercise dosage, and tools to assess peripheral neuropathy; therefore, further research is warranted. Future clinical trials must present adequate methodological quality and use valid and reliable evaluation methods.


Foxtail millet has been traditionally considered to possess gastroprotective effects, but studies evaluating its use as a treatment for gastric ulcers are lacking. Here, we assessed the antiulcer effects of foxtail millet protein hydrolysate (FPH) and explored its mechanism by using blocking agents. In a mouse model of ethanol-induced gastric ulcers, pretreatment with FPH reduced the ulcerative lesion index, downregulated the expression of inflammatory cytokines in the gastric tissue, increased the activity of antioxidant enzymes, and improved the oxidative status. FPH increased constitutive the activity of nitric oxide synthase (cNOS), NO levels, and mucin expression in gastric mucosa, and inhibited the activation of the ET-1/PI3K/Akt pathway. In a mouse model of pyloric ligation-induced gastric ulcers, FPH inhibited gastric acid secretion and decreased the activity of gastric protease. Pretreatment of mice with the sulfhydryl blocker NEM and the NO synthesis inhibitor L-NAME abolished the gastroprotective effect of FPH, but not the KATP channel blocker glibenclamide and the PGE2 synthesis blocker indomethacin. Among the peptides identified in FPH, 10 peptides were predicted to have regulatory effects on the gastric mucosa, and the key sequences were GP and PG. The results confirmed the gastroprotective effect of FPH and revealed that its mechanism was through the regulation of gastric mucosal mucus and NO synthesis. This study supports the health effects of a millet-enriched diet and provides a basis for millet protein as a functional food to improve gastric ulcers and its related oxidative stress. Helicobacter pylori infection, alcohol abuse, stress, and hypersecretion of gastric acid. Dysregulation of ATP-sensitive K+ (KATP) channels and endogenous protective agents such as mucus, nitric oxide, prostaglandins, and growth factors are also important causes [Gastric ulcers are a digestive system disease with high rates of recurrence. The lifetime prevalence of gastric ulcers is approximately 5–10%, and the annual incidence rate is 0.1–0.3% . The patAt present, the main clinical treatment for gastric ulcers is drug therapy. The available treatment options for active gastric ulcers include antacids, cytoprotective agents, proton pump inhibitors, H2 histamine receptor antagonists, and a combination of antibacterial drugs . HoweverSetaria italica) is widely grown in Asia and Africa, and is the most widely consumed coarse grain in China. The protein content of millet is about 11–18% [Foxtail millet  on ethanol- and ligation-induced gastric ulcers in mice, and to investigate the underlying mechanisms by using blocking agents.Antibodies for Western blotting were purchased from Cell Signaling Technology . Gastrin (Gastrin), malondialdehyde (MDA), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), catalase (CAT), nitric oxide (NO), prostaglandin E2, myeloperoxidase (MPO), α-amylase, α-glucosidase, trypsin, a chymotrypsin kit, and an ELISA kit for interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were purchased from Nanjing Jiancheng Bioengineering Institute . w/v) was added to the pellet, and it was hydrolyzed with pepsin for 2 h . Next, trypsin was added and hydrolyzed for 2 h . The reactions were terminated by boiling and centrifuged at 9000× g for 15 min.The preparation of foxtail millet protein hydrolysate (FPH) was performed according to our previously published methods . BrieflyCompositional analysis of the FPH was performed according to previously reported methods and our previous study. Briefly, the protein content of FPH was determined by the Folin reagent method . The degAccording to the method of the Chinese national standards (GB5009.124-2016), the composition of amino acids in FPH was determined using an amino acid analyzer .Male ICR mice were purchased from Weitong Lihua  Laboratory Animal Technology Co., Ltd. Mice were raised in the Experimental Animal Center of Nankai University and maintained under standard laboratory conditions: 25 °C ± 2 °C and a 12 h light cycle. The experimental operation complied with the ethical requirements of animal experiments of Nankai University (permission number: SYKX 2019-0001).The gastroprotective effect of FPH was evaluated using the ethanol-induced gastric ulcer model recommended by China’s Food and Drug Administration . The mice were randomly divided into four groups, namely the normal group (NM), the model group (MD), the low-dose FPH group (LFPH), and the high-dose FPH group (HFPH), with 10 mice in each group and 3–4 mice per cage. Mice in the LFPH and HFPH groups were given 100 and 400 mg/kg·day of the FPH solution, respectively, while mice in the NM and MD groups were given an equal volume of saline for 14 days A. The don = 10). After 14 days of FPH gavage, the mice were fasted for 24 h and anesthetized by an intraperitoneal injection of a pentobarbital sodium solution . An abdominal incision was made and the pylorus was ligated according to previously reported methods [To determine the gastric juice’s parameters, a mouse model of pyloric ligation-induced gastric ulcers was used . Similarn = 10), and the mice were gavaged with 400 mg/kg FPH or the vehicle for 14 days (5 groups in each). Next, the abovementioned ethanol-induced gastric ulcer mouse model was established. Mice were pretreated with the blocking agents N-nitro-L-arginine methyl ester (L-NAME), N-ethylmaleimide (NEM), glibenclamide, and indomethacin before the ethanol gavage [One hundred mice were randomly divided into 10 groups  30 min before ethanol-induced gastric ulceration. To investigate the role of endogenous NO in the gastric protection of FPH, the mice were pretreated with L-NAME . To investigate the role of endogenous sulfhydryls (SHs) in the gastric protection of FPH, mice were pretreated with NEM . To investigate the involvement of KATP channels in the gastroprotection of FPH, mice were pretreated with glibenclamide  [To investigate the role of endogenous prostaglandins (PGs) in the antiulcer effects of FPH, the mice were pretreated with indomethacin  ,26.ULI1 represents the ULI of the MD mice and ULI2 represents the ULI of the FPH-treated mice.The gastric tissue was incised along the greater curvature and rinsed with pre-cooled saline. Gastric mucosal ulcers were observed, and their length and width were measured. The values of the ulcerative lesion index (ULI) and the ULI inhibition rate were calculated according to Formulas (1) and (2), respectively .ULI = 1After fixation with formalin, paraffin tissue sections (4 μm) were prepared and stained with hematoxylin–eosin (HE). Stained sections of the gastric mucosa were observed under a microscope and photographs were taken at 100× magnification.g for 10 min to obtain the gastric supernatant. The volume of gastric juice and the pH values were measured. Free acid and total acidity were determined by sodium hydroxide titration with methyl orange and phenolphthalein as the indicators [After pyloric ligation, the gastric juice was collected and centrifuged at 8000× dicators . Total aThe activity of pepsin in the gastric juice was determined according to the kit’s instructions.2 solution. Next, an equal volume of ether was added. After thorough mixing, the supernatant was removed by centrifugation at 3500× g for 20 min. The absorbance of the obtained emulsion was measured at 598 nm. The content of mucus was calculated with Alcian blue as a standard.The concentration of gastric mucus was determined according to a previously published method . Brieflyw/v) [w/v) was centrifuged at 2500× g for 10 min to obtain the supernatant. The activity of MPO, CAT, GSH-PX, and SOD in the supernatant was determined according to the kit’s instructions. The levels of MDA, PGE2, and NO were determined following the manufacturer’s instructions. Another part of the gastric tissue homogenate was centrifuged at 5000× g for 15 min to determine the levels of inflammatory cytokines  using specific ELISA kits. The protein concentrations in the supernatant were measured by the BCA method.Gastric tissues were homogenized in cold phosphate buffered saline  . A portiw/v) [g, the supernatant was collected and used as the enzyme solution. The activities of α-amylase, α-glucosidase, trypsin, and chymotrypsin in the duodenal supernatant from the mice were determined following the kit’s instructions.The duodenal contents of pylorus-ligated mice were collected and homogenized in cold phosphate buffered saline  . After cWestern blotting and qRT-PCR were performed according to our previously described methods . The prip < 0.05 indicating a significant difference.All experimental results were expressed as the mean ± standard error, and statistical analysis was performed using Graph Pad Prism software. One-way ANOVA followed by Tukey’s multiple comparison tests and two-way ANOVA followed by Bonferroni’s post-hoc test were used to compare the differences among groups, with First, the gastroprotective effect of FPH was evaluated by using an ethanol-induced gastric ulcer model. The gastric mucosa of mice in the MD group was severely damaged, with obvious hemorrhage and linear blood spots B. FPH efMPO activity can reflect neutrophil infiltration and is a biomarker of mucosal injury and an inflammatory response. Ethanol induction significantly increased the activity of MPO and the expression levels of IL-1β, TNF-α, and IL-6 in the gastric tissue of mice C,D. The Gastric tissue sections of the ethanol-induced gastric ulcers of mice were analyzed by HE staining. The mucosal layer, glandular layer, and submucosa of the NM group were intact A. HowevePGE2 inhibits the secretion of gastric acid and has immunosuppressive and anti-inflammatory effects. NO plays a crucial role not only in the regulation of gastrointestinal secretion and gastrointestinal motility but also in the inflammatory response as an immunoregulatory factor. Compared with the NM mice, the contents of PGE2 and NO in the gastric tissue of the MD mice were significantly reduced B. TreatmThe gastric mucus contains mucin, bicarbonate, and other components, which can adhere to the surface of the mucous epithelium and isolate gastric acid. Compared with the NM mice, the gastric mucus content of the MD mice was significantly reduced B. The FPCAT is an endogenous reactive oxygen species-scavenging enzyme. SOD is an antioxidant metalloenzyme that catalyzes the radical transfer disproportionation reaction of superoxide anions. MDA is produced by lipid peroxidation and is one of the indicators commonly used to measure the degree of oxidative stress.Ethanol treatment significantly decreased the activities of SOD, CAT, and GSH-PX, and increased the content of MDA in the gastric tissue of mice C. The acGastric acid is one of the main components of gastric juice, which is secreted by the parietal cells of the stomach. Pepsin is converted from pepsinogen under the action of gastric acid. An increase in the activity of pepsin indicates that excessive gastric acid secretion will damage the protective barrier of gastric mucosa, which may easily lead to chronic atrophic gastritis, gastric ulcers, and other diseases.In the pylorus-ligated gastric ulcer model, the treatment with 400 mg/kg FPH significantly decreased the ULI value of the MD group and increased the ULI inhibition rate . In addiPyloric ligation may lead to duodenal ulcers. Thus, we further determined the activity of digestive enzymes in the duodenal contents. Following pyloric ligation, the activity of trypsin was significantly increased in the duodenal contents of mice, but the activities of α-amylase, α-glucosidase, and chymotrypsin did not change significantly D. The FPTo explore the mechanism of the gastroprotective effect of FPH, we evaluated the effects of NO synthesis, SH compounds, PGE2, and KATP blocker pretreatments on the gastric prevention of FPH. FPH at 400 mg/kg had a protective effect on ethanol-induced gastric ulcers in the control mice that were not treated with the blocker B.For SH compounds, the protective effect of FPH on gastric ulcers was ineffective after pretreatment with the blocking agent NEM. The value ULI was similar to that of the MD mice, and the level of ULI inhibition was significantly lower than that of the control group mice fed with FPH B. For NOFurthermore, FPH increased the mucin content in the gastric tissues of the control mice, but this effect was abolished by the NEM treatment D. SimilaWe further investigated the upstream and downstream mechanisms related to NO synthesis. NO is produced by three isoenzymes, including endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). The first two isoforms are called constitutive NOS (cNOS), which produce the endogenous NO that maintains the integrity of the gastric mucosa and promotes wound healing . EthanolEndogenous NO can inhibit the expression of endothelin-1 (ET-1) , which iMUC1, MUC5AC, and MUC6 are the major mucins expressed in the gastric mucosa . AccordiThe amino acid composition and molecular weight distribution play key roles in the biological activity of peptides . TherefoThe protein content in FPH was 91.8% ± 5.95%, and the degree of hydrolysis was 32.6% ± 2.7%. Peptides with a molecular weight of <10 kDa accounted for 98.8% of the total content. Among them, peptides with molecular weights of 1–3 kDa had the highest content, accounting for 59.7%, and peptides with molecular weights of 3–5 kDa and 5–10 kDa accounted for 20.4% and 18.7%, respectively. Hydrophobic amino acids including Leu, Ala, Pro, Phe, Val, Ile, Tyr, and Met accounted for 50.2% of the total amino acids .In total, 2620 peptide sequences were identified in FPH based on the results of UPLC-MS/MS in our previously published study , and theIn this study, key peptides in FPH were predicted using the BIOPEP protein database and the PeptideRanker score based on our previous LC-MS/MS data . A PeptiFoxtail millet is widely cultivated in Asia and Africa, and is the most widely consumed coarse cereal in North China . It has Ethanol induction and pyloric ligation are common models for studying gastric ulcers. Ethanol-induced gastric injury can cause mucosal ulcers, luminal hemorrhage, lipid peroxidative damage, and inflammatory activation . The infFurthermore, the molecular mechanisms involving NO, mucus, KATP channels, and prostaglandins were analyzed by using blocking agents. Nitric oxide synthase (NOS) consists of eNOS, nNOS, and iNOS . The firIn addition, endogenous NO can inhibit the expression of ET-1 ,46, whicThe mucus–bicarbonate barrier is the main defense system of the gastric mucosa. Mucus protects the viscosity of the gastric mucosa from irritating substances, invading pathogens, or mechanical damage. Due to its alkalinity, it prevents proteolysis by pepsin . The sec+) to pass through the plasma membrane [Endogenous prostaglandins such as PGE2 prevent the formation of gastric mucosal lesions by stimulating mucus secretion, increasing mucosal blood flow, and inhibiting gastric acid secretion . PGE2 ismembrane . It is imembrane . In the Similarly, FPH still exhibited antiulcer activity after pretreatment with the KATP channel inhibitor glibenclamide, suggesting that KATP channels are not the main driver of its gastroprotective effect.The distribution of MW and the amino acid composition are considered to be critical factors affecting the bioactivity of peptides. Peptides with a MW< 3 kDa and with greater hydrophobicity have been suggested to be the bioactive peptides with the most potential . In thisThere are several limitations to this study. First, considering that FPH is a bioactive dietary ingredient, the gastroprotective effects of FPH were investigated by a comparison with the MD group rather than a positive control. However, a comparison with antiulcer agents, such as ranitidine, omeprazole, or cimetidine, would be helpful for verifying the gastroprotective effects of FPH or the bioactive peptides. Second, the antioxidant defense system in the gastric mucosa is composed of both enzymatic and nonenzymatic systems . The forIn conclusion, we firstly demonstrated the protective effect of FPH against ulcerative colitis. FPH inhibited gastric mucosal lesions, decreased the expression of inflammatory cytokines, and improved the oxidative state of the gastric tissue. In addition, FPH increased the expression of mucins, the activity of cNOS, and NO levels, and inhibited the activation of the ET-1/PI3K/Akt pathway in the gastric tissues. Through pretreatment with blocking agents, we confirmed that the gastroprotective mechanism of FPH is the regulation of gastric mucosal mucus and NO synthesis. Our study provides strong evidence that millet protein, as a functional food, can improve gastric ulcers. Given that protein is a major component of millet, these findings support the health effects of a millet-enriched diet.


The number of older patients is constantly growing, and early hospital readmissions in this population represent a major problem from a health, social and economic point of view. Furthermore, the early readmission rate is often used as an indicator of the quality of care. We performed a systematic review of the literature to better understand the risk factors of early readmission (30 and 90 days) in the geriatric population and to update the existing evidence on this subject. The search was carried out on the MEDLINE, EMBASE and PsycINFO databases. Three independent reviewers assessed the potential inclusion of the studies, and then each study was independently assessed by two reviewers using Joanna Briggs Institute critical appraisal tools; any discrepancies were resolved by the third reviewer. Studies that included inpatients in surgical wards were excluded. Twenty-nine studies were included in the review. Risk factors of early readmission can be classified into socio-economic factors, factors relating to the patient’s health characteristics, factors related to the use of the healthcare system and clinical factors. Among these risk factors, those linked to patient frailty play an important role, in particular malnutrition, reduced mobility, risk of falls, fatigue and functional dependence. The early identification of patients at higher risk of early readmission may allow for targeted interventions in view of discharge. The older population is continuously growing increasing public health challenges. According to statistics from the Report on the State of World Population, in 2050, one out of six persons in the world (one out of four in Europe and North America) will be over 65 16%), compared to one in eleven in 2019 (9%). The number of adults aged 80 years or over is expected to triple, from 143 million in 2019 to 426 million in 2050  OR “Geriatrics” [Mesh]) AND “Patient Readmission” [Mesh] AND “Risk Factors” [Mesh] NOT “Surgery” [MeSH Terms]). The search strategy is publicly available at https://pubmed.ncbi.nlm.nih.gov/?term=%28%22Aged%22%5BMesh%5D+OR+%22Geriatrics%22%5BMesh%5D%29+AND+%22Patient+Readmission%22%5BMesh%5D+AND+%22Risk+Factors%22%5BMesh%5D+NOT+Surgery%5BMeSH+Terms%5D&filter=dates.2012%2F1%2F1-2022%2F1%2F31&filter=hum_ani.humans&filter=lang.english&filter=age.aged&size=200 (accessed on 1 February 2022) for PubMed, “(‘aged’/exp OR ‘geriatrics’/exp) AND ‘patient readmission’/exp AND ‘risk factors’/exp NOT ‘surgery’/exp AND [01-01-2012]/sd NOT [01-02-2022]/sd AND [english]/lim” for EMBASE and “MeSH: geriatrics OR MeSH: old AND MeSH: patient readmission AND MeSH: risk factors NOT MeSH: surgery AND PsycInfo Classification: 2860 Gerontology for PsycINFO”.We carried out this systematic review in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis  was used to speed up the article selection process. All the papers retrieved by the search responding to inclusion/exclusion criteria were included; biases were evaluated for each article and noted in a dedicated database. In 17 studies [Two reviewers, working independently, screened the studies retrieved by the search according to the inclusion/exclusion criteria. Two reviewers independently evaluated the inclusion of each study; discrepancies between the two reviewers were solved by the third. The Rayyan studies ,34,35,36 studies ,30,31,33 studies ,32,34,35n = 193), wrong outcome (n = 121) or full paper non-available (n = 50). Twenty-nine articles were included in the Review  critical appraisal tools : JBI CriTwo reviewers independently evaluated the quality of each study; discrepancies between the two reviewers were solved by discussion and consensus among reviewers or by the third reviewer. The quality across studies was assessed using a graphic representation of the percentage of studies with a strong, moderate or weak rating for each section considered in the evaluation of the quality of individual studies.Twenty-nine studies published between 2012 and 2022 were included in the review ,47,48,49The study design of each study is detailed in The minimum age for patients’ inclusion differs amongst different studies; however, all the studies reported an average age of at least 65 years.Eleven studies ,45,47,48Nine studies ,42,46,49The incidence rates of readmission (both unplanned and for any cause) within 30 days ranged from 10.3% , while tHere, we take into account risk factors for readmission at 30 or 90 days according to the definition of early readmission in literature ,48,50,51The risk factors for readmission highlighted by the studies included in this review can be classified into four categories: socio-demographic and socio-economic factors, health factors, healthcare utilisation and clinical factors.Fifteen studies ,46,47,49The majority of the studies identified as risk factors for early readmission older age ,28,33,47Different risk factors of readmission are detailed in The results of the critical appraisal process are reported in D1–D11 are detailed in JBI Critical appraisal checklist  for cohoThe global quality assessment across the studies is presented in We highlight that the item “Outcome measured in a standard, valid and reliable way”  has a high risk of bias in the cohort studies  in the Cohort studies, a high risk of bias was attributed if the authors did not have information on non-readmitted patients . According to these criteria, only 45% of the cohort studies ,40,42,49In 20% ,34,45,49The aim of this review is to broadly evaluate the risk factors for early hospital readmission in geriatric patients; with this aim, we included very heterogeneous studies. The studies included widely differed in design, setting and data collection methods and were carried out in different countries with different cultures, health systems and economic situations.In addition, the definition of early readmission differs amongst the studies as readmission for any causes is included in 14 studies ,44,47,49Despite this heterogeneity, this review allows us to synthesise and update the knowledge on risk factors associated with early readmissions. According to the included studies, we classified risk factors for early readmission into four categories: socio-demographic and socio-economic factors, health factors, healthcare utilisation and clinical factors related to the index admission.The incidence rates of readmission (unplanned readmissions or any causes of readmissions) vary markedly between different studies ,21,23,47Regarding the socio-demographic and socio-economic factors, our review highlights contrasting results. Older age ,28,33,47Nevertheless, the majority of the studies did not find a significant association between gender and age and readmission rate ,44,45,48Regarding the health factors, factors associated with frailty syndrome  are associated with early readmission.Furthermore, the prescription of 15 or more drugs during the hospital stay , non-comFinally, Van Seben et al.  focused As pointed out above, the contrasting results could be explained by the differences between the different countries in which the studies were carried out and the differences in healthcare systems.Therefore, we compared the results of the different macro-areas .From this comparison, it can be inferred that some risk factors for early readmission are common to the different macro-areas  to assess the bias of the included papers allow us to standardise the evaluation and thus to draw objective conclusions even in the case of heterogeneous papers. However, due to the high heterogeneity of the different studies, the results are difficult to compare. Furthermore, all the included studies have biases according to the JBI tool.It is noteworthy to underline that about half of the studies included evaluated early readmission in a single ward or hospital; this probably leads to an underestimation of the total readmission rate. This bias is not negligible as, according to the literature , the ratAnother limit of this review is the type of readmission included in different studies, as about half of the studies ,44,47,49Due to these limitations, the authors believe that there is still room for further experimental studies with clear outcomes on early, unplanned hospital readmission in acute geriatric patients.The quality assessment carried out during the review will be particularly important for researchers wishing to carry out future work on the subject of readmissions, as it will enable them to have a more rigorous methodology with a lower risk of bias.Our review gives a broad overview of risk factors for early hospital readmission in geriatric patients. The early identification of the patients at higher risk of early readmission may allow for planning targeted interventions in view of hospital discharge.Amongst the risk factors highlighted by different studies, those associated with frailty syndrome play an important role, in particular malnutrition, reduced mobility, risk of falls, fatigue and functional dependence. This result is of paramount importance as these conditions are modifiable and must be taken into account in patients’ evaluation and treatment. Careful nutritional management and early mobilisation during hospitalisation are, therefore, low-cost measures that can lead to a reduction in the readmission rate ,23,38,41


As a result, several efforts have been made in recent decades to limit or eliminate the usage of Portland cement in concrete. Geopolymer has garnered a lot of attention among the numerous alternatives due to its early compressive strength, low permeability, high chemical resistance, and great fire-resistant behaviour. This study looks at the strength and microstructure of geopolymer based on fly ash and a combination of metakaolin and fly ash. Compressive strengths were measured at 7, 14, and 28 days, and microstructure was examined using SEM and XRD.The production of Portland cement is widely regarded as a major source of greenhouse gas emissions. This contributes to 6–7% of total CO Researchers have been examining the impact of greenhouse gases on global warming for the past three decades. Rising sea levels, changes in ocean water that threaten marine life, shifting weather patterns, and ecological degradation are all results of global warming . In the 2 emissions, according to the International Energy Agency (IEA) [A number of programmes and policies have been established in an attempt to minimise global carbon emissions and, as a result, global warming. The Kyoto Protocol  is an incy (IEA) . As a recy (IEA) ,17,18,19The interaction of aluminosilicate material with alkaline solutions produces geopolymers. As a result, the two main components of geopolymers are source materials and alkaline liquids. Natural minerals such as kaolinite, clays, micas, andalousite, spinel, and by-products such as fly ash, silica fume, slag, rice husk ash, red mud, and so on might be used as source materials ,21. Fly During both the preparation and development stages, the metakaolin (MK)-based geopolymer has the advantage of being able to be manufactured consistently and with predictable qualities.The plate-shaped particles, on the other hand, produce rheological challenges, increasing the processing complexity as well as the water need of the system. The geopolymer made from fly ash (FA) is often more durable and stronger . FA-base2 = 30.0%, Na2O = 11.5%, and water = 58.5%) for SiO2 to Na2O. In a fume cupboard, sodium hydroxide pellets were dissolved in deionized water to make an 8 M solution.Based on earlier research , the mixThe sodium silicate to sodium hydroxide ratios were varied between . The activator solution was held at a constant mass ratio of 0.4 with the binder. One mix was made entirely of fly ash, while the other was made with 70% fly ash and 30% metakaolin. Both fly ash and metakaolin were obtained from local sources in Western Australia. The properties of fly ash and metakaolin are summarised in The compressive strength tests were done in line with ASTM C109  StandardWhen compared to the FA-based geopolymer, the FA and MK-based geopolymer samples demonstrated a maximum gain in strength of 30% when an alkaline solution molar ratio of 1.0 was utilised. The strength of the FA and MK-based geopolymers improved the greatest after 28 days, with the FA-based geopolymers improving by 9.8%. In Mix 3, the strength of both geopolymers was equal. The compressive strength difference between each increment in the alkaline molar ratio is noteworthy in this study. This shows that FA-based geopolymers are more affected by the alkaline solution ratio. In contrast, the FA and MK-based geopolymer performed better in the early stages. The strength of the FA and MK-based geopolymers, for example, was 13% higher at 7 days than the FA-based geopolymer. Zhang et al. (2014)  discover2). Amorphous phases are also indicated by multiple tiny peaks between 20° and 40°. Mullite, Maghemite, Haematite, and Aluminum Silicon Oxide (Al2 SiO5) are among the other phases discovered. Despite the increase in compressive strength seen in The XRD patterns for FA and MK-based geopolymers are shown in 2SiO5) are among the other phases found. When XRD patterns of FA and MK-based geopolymers were compared to FA-based geopolymers (FA and MK-based geopolymers also appear to have a more consistent matrix or structure than FA-based geopolymers. Metakaolin’s chemical makeup aided in the dissolving of pozzolan, resulting in a more evenly dispersed structure. This was seen at a temperature of about 25°. Mullite, Maghemite, Haematite, and Aluminum Silicon Oxide (Alpolymers , the peaThe geopolymer made up of 70% fly ash and 30% metakaolin had a higher compressive strength than the geopolymer made up solely of fly ash.In comparison to geopolymers made entirely of fly ash, geopolymers made entirely of metakaolin appear to have a more homogeneous microstructure.When comparing geopolymer made up of 70% fly ash and 30% metakaolin to geopolymer made up of only fly ash, increasing the alkaline solution molar ratio resulted in a less porous structure with a lower number of unreacted fly ash and metakaolin particles.When compared to fly ash-based geopolymers, the geopolymer based on 70% fly ash and 30% metakaolin had a slightly higher peak/intensity for quartz.The following conclusions can be derived from the findings presented in this paper:


Membranous nephropathy (MN) is the main cause of adult nephrotic syndrome (NS). The pathogenesis of MN is complex and involves subepithelial immune complex deposition. Approximately one-third of patients with MN develop end-stage renal disease (ESRD). Timely diagnosis and reasonable intervention are the keys to improving prognosis. In recent years, with the development of high-throughput technologies, such as mass spectrometry (MS), microarray, and sequencing technologies, the discovery of biomarkers for MN has become an important area of research. In this review, we summarize the significant progress in biomarker identification. For example, a variety of podocyte target antigens and their autoantibodies have been reported. Phospholipase A2 receptor (PLA2R) is the most well-established target antigen in MN. PLA2R and its autoantibodies have clinical significance, with both diagnostic and therapeutic value for MN. In addition, a variety of new biomarkers, including proteins, metabolites, noncoding RNAs (ncRNAs), and immune cells, have recently been found. These MN-related biomarkers have great significance in the diagnosis, progression, prognosis, and treatment response of MN. Membranous nephropathy (MN) is the major cause of adult nephrotic syndrome(NS) and the second leading cause of primary glomerulonephritis and end-stage renal disease (ESRD). Approximately 80% of MN cases have no clear secondary causes, referred to as idiopathic membranous nephropathy (IMN) or primary membranous nephropathy (PMN), and approximately 20% of MN cases are secondary to autoimmune diseases, infections, malignancies, drug use, and heavy metal poisoning, referred to as secondary membranous nephropathy (SMN) . The patin situ immune complexes of circulating autoantibodies and their target antigens on glomerular podocytes are deposited under epithelial cells, resulting in complement activation, thereby destroying the podocyte structure and resulting in proteinuria –double-stranded DNA antibody (dsDNA Ab) complexes in patients with systemic lupus erythematosus, under the epithelium may also be involved in the pathogenesis of MN  in podocytes , and itsThere are different predominant IgG subtypes in different podocyte target antigen-associated MN Table 1.A large number of studies have proven that the above-mentioned MN-related podocyte antigens and autoantibodies can be used as biomarkers of MN and play auxiliary roles in the diagnosis, analyses of treatment responses, and prediction of prognosis. The clinical value of podocyte target antigen-based biomarkers (including autoantigens and their autoantibodies) of MN Table 1 Among the MN podocyte target antigen and autoantibody biomarkers found to date, PLA2R and anti- PLA2R antibody have better clinical diagnostic value for IMN than other biomarkers. A meta-analysis based on data from 10 studies involving 1,550 participants showed that in the active phase, the sensitivity and specificity of serum PLA2R antibody levels for the diagnosis of IMN are approximately 74.0% and 95.0%, respectively . Many stMany studies have shown that PLA2R is more common in IMN than in SMN –31, suggA number of studies have shown that PLA2R and its autoantibodies are closely related to the severity, treatment efficacy, and prognosis of MN. Levels of serum anti-PLA2R antibodies are related to serum albumin, serum creatinine, eGFR, and proteinuria. Compared with glomerular PLA2R deposition, serum anti-PLA2R antibody levels are more closely correlated with disease activity and renal function . Serum aAt present, there are insufficient data to support the application of anti-THSD7A antibodies as a diagnostic biomarker for MN instead of biopsy . AlthougSimilar to the anti-PLA2R antibody, the anti-THSD7A antibody is mostly detected in IMN; however, it cannot completely distinguish IMN from SMN. Maifata et al.  detectedThe etiology of SMN is mainly autoimmune diseases, and LN is the main cause of SMN caused by autoimmune diseases. Approximately 30%–40% of SMN are EXT1/EXT2-related MN, and nearly 35% of EXT1/EXT2-related SMN are membranous LN. Therefore, EXT1/EXT2 is considered the main subtype of SMN and can be used as a potential representative biomarker of SMN and LN . In addiNCAM-1 is another podocyte target antigen in LN. It is found in the tissues of patients with membranous LN, with no positive staining in normal kidney tissues. Studies have shown that approximately 6.6% of NCAM-1 associated renal disease is membranous LN and 2.0% is PMN. Circulating anti-NCAM1 antibodies have been confirmed to exist in a subset of lupus patients . Both NCIn NELL-1-, Sema-3B-, PCDH7-, and HTRA1-related MN, their respective autoantigens and circulating autoantibodies can be identified, which can be considered as potential biomarkers for MN diagnosis. In addition, NELL-1-, Sema-3B-, PCDH7-, and HTRA1-related MN also have their own clinical characteristics, which are helpful for accurate clinical diagnosis and treatment.One characteristic of NELL-1 associated MN is that malignant tumors may exist in it. The incidence of NELL-1-related MN malignant tumors ranges from 11.7% to 33% . MN may Sema-3B-associated MN occurs in children and young people. Sethi et al. showed that among 11 cases of Semaphorin 3B-associated MN, 8 were pediatric cases and 5 cases started at or below the age of 2 . In pediHTRA1 and PCDH7 are newly discovered MN podocyte target antigens based on MS , 17. It Exploring differentially expressed proteins and metabolites between patients with MN and healthy individuals is an important research goal, providing candidate biomarkers and improving our understanding of the underlying molecular mechanisms. Recently, various proteins and metabolic biomarkers have been detected by proteome and metabolome analysis based on MS technologies Table 2.Differences in the levels of various non-podocyte autoantigen or autoantibody proteins and metabolites have recently been reported between MN and healthy controls or patients with other glomerular diseases. These differential proteins and metabolomics are expected to become potential diagnostic biomarkers for MN. Using the iTRAQ (relative and absolute quantitative isobaric labeling) technique, Root et al.  found thTie et al.  used a nIn addition, Yu et al.  used nanA study of two groups of patients with different responses to immunosuppressive therapy (Ponticelli protocol) had kidney biopsies and performed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which revealed that the signal at m/z 1,303 showed the greatest discriminatory power, and the corresponding trypsin peptide was identified as a macrophage migration inhibitory factor (MIF). These results suggest that MIF may be a predictor of the response to immunosuppressive therapy in MN .Although these non-podocyte target antigens and autoantibody biomarkers have not been widely validated and little is known about correlations between these biomarkers and clinical manifestations and pathological features, the discovery of these biomarkers provides a basis and new directions for diagnosis, differential diagnosis, monitoring, and treatment of MN.Noncoding RNAs (ncRNAs) are a kind of RNA that do not encode proteins but have biological functions at the RNA level, including ribosomal RNAs, transport RNAs, small nucleolar RNAs, small nucleolar RNAs, long-chain noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and small interfering RNAs. With the development of gene sequencing technology and bioinformatics methods, the biological functions of ncRNAs have become a focus of recent research. Many studies have shown that imbalances in ncRNA expression are related to the occurrence and development of many diseases. Because ncRNAs stably exist in body fluids and can be detected noninvasively, they are a promising new biomarker type for disease prediction. Recent studies have shown that the expression levels of ncRNAs in the urine, blood, and kidneys of patients with MN differ from those in healthy individuals Table 3.MiRNAs are small noncoding RNAs containing approximately 22 nucleotides that are involved in posttranscriptional gene silencing. In recent years, some studies have shown that abnormal miRNAs play a significant role in the pathogenesis of many kidney diseases , 70. Howin vitro could inhibit the expression of the target gene TNFSF11 and protect podocytes. The downregulation of miR-217 expression can lead to increased levels of the target gene TNFSF11 and podocyte apoptosis, suggesting that miR-217 participates in podocyte apoptosis by negatively regulating the expression of the target gene TNFSF11. In addition, the area under the curve (AUC) for miR-217 for MN diagnosis was 0.941 , and the sensitivity and specificity were 88.9% and 75.9%, respectively. These results showed that miR-217 is involved in podocyte apoptosis and has potential diagnostic value in MN.Li et al.  found thPLA2R in the podocyte damage model stimulated by Ang II. All these findings indicated that the decrease in miR-130a-5p expression in MN patients may accelerate podocyte apoptosis by upregulating the expression of PLA2R, thereby promoting IMN development , are important biomarkers of poor renal survival in patients with IMN. The combined detection of miR-193a with PODXL and WT1 can be used as a strategy for diagnosing IMN (AUC = 0.994) and predicting renal survival status (AUC = 0.824). Although this study failed to figure out how miR-193a/WT1/PODXL axis functioned underlying the etiology of IMN, another study  and miRNA database GSE64306  datasets  and founIL-6 and MYC which have strong negative correlations with clinical parameters, such as proteinuria and total cholesterol. These data indicated that the 10 miRNAs and their downstream network could be considered as potential diagnostic biomarkers of MN and may be involved in MN pathogenesis.A recent study  confirmeSha et al.  showed tWu et al.  showed tvia various miRNAs, providing novel insights for targeted gene therapy.Previous studies have shown that the expression levels of circRNAs in the serum and urine exosomes, peripheral blood, and renal tissues differ between patients with IMN and healthy controls. Jin et al.  detectedA circRNA sequencing analysis of serum and urine exosomes from patients with IMN and healthy controls revealed 89 significantly differentially expressed circRNAs in the serum exosomes, of which 49 were upregulated and 40 were downregulated in IMN. There were 60 significantly differentially expressed circRNAs in the urine exosomes, of which 54 were upregulated and 6 were downregulated in IMN. These differentially expressed circRNAs may be involved in the pathogenesis of MN .via the circ_0000524/miR-500a-5p/CXCL16 pathway, which may play an important role in podocyte injury in MN.Recently, Sun et al.  found thHuang et al. found that lncRNA XIST is upregulated in renal tubular epithelial cells and glomerular cells of mice with MN, and its expression is positively correlated with the severity of MN. In addition, XIST levels are significantly elevated in the urine of MN mouse model and in patients with glomerulonephritis (including MN), and XIST concentrations in the urine are positively correlated with the severity of MN. Accordingly, urine XIST may be a potential noninvasive biomarker of MN . In addiMN is an autoimmune disease, and immune cells are involved in the occurrence and development of MN. Studies have shown increases in the CD4+/CD8+ T-cell ratio and Th2/Th1 cell ratio in the peripheral blood of patients with IMN . AlthougT cells participate in the activation and proliferation of B cells in the occurrence and development of MN, and B cells proliferate and differentiate into plasma cells for autoantibody production. Autoantibodies and complement activation can cause the infiltration of macrophages derived from peripheral blood monocytes. In recent years, some subsets of T cells and monocytes in the peripheral blood of patients with MN have been identified as candidate biomarkers to evaluate the curative effect and progression of MN. The candidate immune cell biomarkers and their potential clinical values in MN are described as follows:Treg cells are TCRαβ+Foxp3+CD4+ T cells that are endowed with suppressive activity, and the main role of Treg cells is to control the inflammatory and immune response to self-antigens, thereby preventing autoimmune disease; therefore, the lack of Treg cells may occur in many autoimmune conditions , 79. MotTfh cells are an independent CD4+ cell subgroup located in lymphatic follicles and are thought to be critical for the formation and function of germinal center in the generation of memory B cells and long-lived plasma cells. ICOS and PD-1 are the two main extracellular markers expressed by Tfh cells. IL-21, as a key effector of activated Tfh cells, induces B-cell proliferation, mediates the differentiation of activated B cells into plasma cells, and promotes IgM, IgG, and IgA production. Shi et al.  found thMonocytes, as progenitors of dendritic cells or macrophages in tissues, are important regulators of the immune response. Human PBMCs can be differentiated into M2 monocytes, which are characterized by CD14+ CD163+. After activation, the expression levels of CD206 and CD115 increase and anti-inflammatory mediators, such as interleukin IL-10, are secreted. Hou et al.  found thMN is one of the main pathological types of NS and the major cause of ESRD. At present, renal biopsy is the gold standard for MN diagnosis. Due to its invasive limitation, exploring new biomarkers in MN has become a research hotspot. In recent years, the discovery of MN biomarkers has advanced substantially since the development of high-throughput MS and gene sequencing technologies. Proteomic, metabolomic, and transcriptomic approaches have been used to evaluate the molecular basis of MN.A variety of MN podocyte target antigens and their autoantibodies have been discovered, among which the anti-PLA2R antibody provides a good theoretical basis for the diagnosis of clinical IMN. However, of the IMN cases, the percentage of PLA2R-positive MN is approximately 70%–80%, and there are still 10%–20% of IMN-related podocyte target antigens unknown that need to be discovered.Furthermore, various new biomarker types, such as proteins, metabolic markers, ncRNAs, and immune cells, have recently been shown to have diagnostic, monitoring, and prognostic significance in MN. Although these new markers have not been used in clinical settings and need to be verified, they may guide the development of diagnostic and therapeutic approaches for MN and improve our understanding of the pathogenic mechanism of MN.XQ and QL participated in the conceptual design and wrote the manuscript. QL, JL, BX, YZ, MM, and MY wrote the manuscript and created the figures and tables. XQ, QL and JL revised and edited the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by the National Key Research and Development Program of China (No. 2018YFE0207300). This work was also supported in part by the “345 Talent Project” of Shengjing Hospital of China Medical University (No. 50A) and Major Special Project of Construction Program of China Medical University in 2018 (No. 112/3110118034).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.


Between m6 and m9, a gain in fat mass was only observed in patients in the APA and ALs+APA groups. Conclusion: In our randomized controlled trial, arginine and leucine supplementation failed to improve MetS in patients with obesity, as did the supervised adapted physical activity program and the combination of both. Only the cardiorespiratory parameters were improved by exercise training.Background: In patients with obesity and metabolic syndrome (MetS), lifestyle interventions combining diet, in particular, and physical exercise are recommended as the first line treatment. Previous studies have suggested that leucine or arginine supplementation may have beneficial effects on the body composition or insulin sensitivity and endothelial function, respectively. We thus conducted a randomized controlled study to evaluate the effects of a supervised adapted physical activity program associated or not with oral supplementation with leucine and arginine in MetS-complicated patients with obesity. Methods: Seventy-nine patients with obesity and MetS were randomized in four groups: patients receiving arginine and leucine supplementation , patients on a supervised adapted physical activity program , patients combining ALs and APA , and a control group (n = 19). After the baseline evaluation (m0), patients received ALs and/or followed the APA program for 6 months (m6). Body composition, MetS parameters, lipid and glucose metabolism markers, inflammatory markers, and a cardiopulmonary exercise test (CPET) were assessed at m0, m6, and after a 3-month wash-out period (m9). Results: After 6 months of intervention, we did not observe variable changes in body weight, body composition, lipid and glucose metabolism markers, inflammatory parameters, or quality of life scores between the four groups. However, during the CPET, the maximal power (Pmax and Ppeak), power, and O Obesity, defined by the World Health Organization (WHO) as an increase in the adipose tissue with negative impacts on organisms, is a serious public health challenge, especially due to the huge growth of class II and III obesity. By 2050, obesity is expected to affect up to 20% of the world’s population ,2. ObesiLifestyle interventions combining, in particular, diet and physical exercise are recommended as the first line treatment. It is well established that aerobic physical training increases energy expenditure and activates lipolysis . A physiIt has been reported that leucine is able to stimulate and regulate protein synthesis in the body , especiaTherefore, we aimed to evaluate the effects of adapted physical activity associated or not with arginine and leucine supplementation in subjects with obesity and MetS in a randomized controlled clinical trial.The present study was an open randomized controlled study  supported by the French National Program for Clinical Research (PHRC n° 2008/066/HP), with an enrolment period spanning from 2011 to 2014. The study was approved by the ethics committee (CPP Sud Mediterranee). 2, and a MetS diagnosis according to the International Diabetes Federation. The exclusion criteria were: body weight greater than 135 kg for technical reasons (limits of the equipment), pulmonary disease, musculoskeletal abnormalities, tobacco consumption greater than or equal to eight cigarettes per day, treatment with beta-blockers, and pregnancy.The study was proposed to all patients with obesity and MetS reviewed at the Nutrition Department of the Rouen University Hospital according to the following inclusion/exclusion criteria. The inclusion criteria were: age from 18 to 55 years, a body mass index (BMI) greater than or equal to 30 kg/mAfter checking the inclusion and exclusion criteria, the clinical trial was explained to all participants, who gave written informed consent. Patients were randomly assigned in a 1:1:1:1 ratio to one of the four following groups: the control group, arginine- and leucine-supplemented group (ALs), adapted physical activity group (APA), or the group treated with both arginine and leucine supplementation and adapted physical activity (ALs+APA). A block randomization was used and performed by the hospital pharmacy. After randomization, all the patients were followed monthly during the 6-month treatment period (from 0 (m0) to 6 months (m6)) and then assessed at 9 months . Patients in the control group received routine clinical care with monthly visits to dietician. In the ALs group, from m0 to m6, patients received an oral supplementation with 9 g of arginine and 21 g of leucine per day. In the APA group, from m0 to m6, patients followed a program of physical activity 3 times per week. In the ALs+APA group, from m0 to m6, patients received 9 g arginine and 21 g leucine supplementation per day and followed the APA program 3 times per week. The collected and measured parameters are detailed in The arginine and leucine powders  were prepared by the pharmacy of Rouen University Hospital and supplied to the patients for 1 month. Patients were instructed to consume 21 g of leucine and 9 g of arginine per day in 3 meals. At each visit, patients received new bottles for the next month. The chosen doses of arginine and leucine were based on a compromise between previous studies ,25,26,27Patients from the APA and ALs+APA groups performed a 6-month structured adapted physical activity (APA) program under the supervision of sport science graduates at a rate of 3 days per week. Each session comprised of a warmup (10 min), endurance training (20–60 min), strength training (20 min), and a final stretching phase (10 min). The endurance training intensity was maintained at 60% of the heart rate reserve (HRR) ±10 beats/min, with the HRR estimated using the Karvonen equation (220–age–resting heart rate) . The str−2)After overnight fasting, anthropometric measures were performed, including body weight (kg), body height (cm), and the waist and hip circumferences (cm). The waist circumference was measured at the mid-point between the bottom of the rib cage and the iliac crest, and the hip circumference was measured at the widest point at the hip. Body mass index was calculated as body mass divided by the square body height  was performed in the supine position after 10 min of equilibration with Bodystat Quadscan 4000 equipement (BodyStat), as previously described . A manufAt m0, m6, and m9, patients filled in a quality-of-life questionnaire based on the Medical Outcome Study Short Form-36 (MOS SF-36) . This in2), and the carbon dioxide output (VCO2), as well as the heart rate by a 12-lead electrocardiogram . The ventilatory threshold (VT) was determined using the computerized V-slope method  for the quantitative variables and absolute numbers with their percentages for the categorical variables. To compare the patients’ characteristics at the baseline and changes between m0 and m6 or between m6 and m9, Kruskal–Wallis tests were performed followed by Dunn’s post tests for continued data if necessary. Chi squared tests or Fisher’s exact tests were used for the discontinued data. A p = 0.0325, Kruskal–Wallis test). The waist circumference seemed to be higher in the control group, but the Dunn post test was not significant. A trend of higher body weight and BMI was also observed, but difference did not reach significance . Concerning secondary the endpoints, we did not observe differences in body weight, BMI, waist circumference, or body composition parameters (p = 0.0819). By contrast, there was no variation in the SF36 component evaluating physical function between groups.After 6 months of treatment, the primary endpoint results were not significantly different between the different groups. Indeed, the fat mass changes measured by DXA were −2.10 , −2.22 , −2.60 , and −3.02 % in the control, ALs, APA and ALS+APA groups, respectively, . Similarly, Ppeak changes were also more pronounced in patients after they completed the APA program (p = 0.0006). The power at threshold (P(VT)) and O2 consumption were also affected. The forced vital capacity (FCV) or O2 consumption also seemed to increase more in patients from the APA and ALs+APA groups. However, we observed that the CPET exhibited modified results between the four groups . Indeed,p = 0.0151). Indeed, patients in the ALs+APA group seemed to gain more fat mass compared to the other groups (After 3 months of the wash-out period (m6 to m9), body weight and BMI changes were not different between the four groups . Howeverr groups . Patientr groups . In addir groups . In our randomized controlled study of patients with obesity, we failed to demonstrate beneficial effects of the 6-month program consisting of arginine and leucine supplementation in a supervised adapted physical activity program, neither in terms of body weight, body fat mass, nor the MetS parameters. However, we observed that exercise training was able to improve several cardiorespiratory variables, but it was also associated with an adiposity rebound 3 months after the end of the program. 2 at ventilatory threshold and forced vital capacity were improved after exercise training  in our population of subjects with class II and III MetS-complicated obesity. However, the VO2 max and expiratory volumes were not affected. Previous studies showed different levels of improvement in the VO2 max among women with obesity according to the duration and intensity of exercise, with values from 7.1% to 19% [In patients with obesity, respiratory impairment, such as the impairment of the forced vital capacity, forced expiratory volume in one second, or expiratory reserve volume, has been reported ,38. Weig% to 19% ,41,42. W% to 19% . All theIn our clinical trial, the improvements in the cardiorespiratory parameters after the 6-month activity program were not associated with modifications in body weight or body composition. In a recent systematic review, Zouhal et al.  showed tFinally, in our study, not only did the physical activity program fail to improve the body weight, body composition, and metabolic parameters, but the amino acids supplementation failed to do so as well. Previous studies suggested that branched amino acids are able to stimulate muscle protein synthesis and, thus, contribute to maintaining or increasing the lean mass . In dietOur study has some limitations. The numbers of analyzed data for each group were small. Indeed, 22 out of 79 patients discontinued their participation in the program during the 6-month intervention period, which limits the strength of our results and underlines the poor compliance of the patients. A better selection of patients would have enhanced the level of compliance; however, it would have be less relevant to clinical practice. Consequently, we performed a per-protocol analysis of the data that constitutes another limitation of the present study. In addition, we did not make adjustments based on body weight, age, or sex, for instance, because these parameters were not different between the groups at baseline and because our study failed to show changes by the primary endpoint at 6 month. Finally, to better understand the observed results, it would be interesting to assess the feeding behavior and food intake of the patients, as well as their levels of previous training. Unfortunately, we did not have these data in the present study. In our randomized clinical trial, a 6-month supervised adapted physical activity program was associated with improvements in the cardiorespiratory capacities of MetS-complicated patients with obesity but failed to improve their body weight and body composition. Arginine and leucine supplementation had no effect. Our study underlines the need for randomized clinical trials evaluating the effects of multidisciplinary ambulatory intervention programs combining adapted physical activity and nutritional interventions, as well as psychosocial approaches in order to improve the care of patients with obesity and MetS.