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Background Combined markers of renal dysfunction and inflammation, e.g., cystatin C, might assist with risk stratification and clinical decisions in patients with coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression of serum cystatin C in COVID-19. Methods We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum cystatin C concentrations, measures of clinical severity and survival outcomes in hospitalized COVID-19 patients (PROSPERO registration number: CRD42021245295). Results Thirteen studies in 2510 COVID-19 patients, 1972 with low severity or survivor status and 538 with high severity or non-survivor status during follow up, were included in the meta-analysis. The pooled results showed that serum cystatin C concentrations were higher in patients with high disease severity or non-survivor status (standard mean deviation, SMD, 1.71, 95% CI 0.95 to 2.46, p

BACKGROUND While a number of individual patient characteristics are associated with survival in idiopathic pulmonary fibrosis (IPF), their incorporation into combined indexes, such as the GAP index, has been shown to increase the predictive capacity. It is unknown whether the predictive capacity of GAP-derived indexes that also include anthropometric and exercise parameters is superior to the original instrument. METHODS We tested the four-year survival predictive capacity of a modified, adimensional and multiplicative GAP index (IC4) that included percent forced vital capacity (FVC%), diffusing capacity of the lung for carbon monoxide (DLCO%), body mass index (BMI), and six-minute walk distance (6MWD) in 90 IPF patients recruited from two centres in France and Italy. RESULTS In ROC comparisons, the AUC of the IC4 (0.859, 95% CI 0.770-0.924 p

Carotid artery disease is commonly encountered in clinical practice and accounts for approximately 30% of ischemic strokes in the general population. Numerous biomarkers have been investigated as predictors of the onset and progression of carotid disease, the occurrence of cerebrovascular complications, and overall prognosis. Among them, blood cell count (BCC) indexes of systemic inflammation might be particularly useful, from a pathophysiological and clinical point of view, given the inflammatory nature of the atherosclerotic process. The aim of this review is to discuss the available evidence regarding the role of common BCC indexes, such as the neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), mean platelet volume (MPV), platelet distribution width (PDW), and red cell distribution width (RDW), in the diagnosis and risk stratification of carotid artery disease, and their potential clinical applications.

Patients with rheumatoid arthritis (RA), a chronic and disabling autoimmune condition that is characterized by articular and extra-articular manifestations and a pro-inflammatory and pro-oxidant state, suffer from premature atherosclerosis and excessive cardiovascular disease burden. A key step in the pathogenesis of atherosclerosis is impaired synthesis of the endogenous messenger nitric oxide (NO) by endothelial cells which, in turn, alters local homeostatic mechanisms and favors vascular damage and plaque deposition. While the exact mechanisms of endothelial dysfunction in RA remain to be established, there is good evidence that RA patients have relatively high circulating concentrations of the methylated arginine asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of endothelial NO synthase (eNOS). This review discusses the biological and pathophysiological role of ADMA, the interplay between ADMA, inflammation and oxidative stress, and the available evidence on the adverse impact of ADMA on endothelial function and atherosclerosis and potential ADMA-lowering therapies in RA patients.

Purpose: To assess the role of complete blood cell count (CBC) dimensional indices and CBC-derived measures in non-arteritic anterior ischemic optic neuropathy (NA-AION). Methods: In this retrospective case-control survey, 37 newly diagnosed NA-AION patients and 37 sex- and age-matched cataract controls were enrolled in 2017-2018. On the same day of NA-AION diagnosis, a blood sample was collected and CBC was determined using an automatic blood counter. CBC dimensional indices, such as mean platelet volume (MPV) and red cell distribution width (RDW), and CBC-combined indices, including neutrophil/lymphocyte ratio (NLR), derived NLR [dNLR = neutrophils/(white blood cells - neutrophils)], and platelet/lymphocyte ratio (PLR), were evaluated. Erythrocyte sedimentation rate (ESR) was also measured. Results: Mean platelet count, median MPV, RDW, NLR, and dNLR were 221±48 x 109/L, 8.2 fL (IQR=7.6-8.9), 13% (IQR=12-14.5), 2.50 (IQR=1.77-3.06), and 1.73 (IQR=1.31-2.07) in NA-AION patients and 248±56 x 109/L, 7.60 fL (IQR=7.05-8.25), 12% (IQR=11.6-13), 1.95 (IQR=1.43-2.49) and 1.36 (IQR=1.07-1.69) in controls. NA-AION patients showed significantly lower platelet count (p=0.03) and significantly higher median values of MPV (p=0.01), RDW (p=0.015), NLR (p=0.03), and dNLR (p=0.01). Multivariate logistic regression models disclosed a significant correlation only between higher levels of RDW and NA-AION (p≤0.05). The attributable risk of the association between NA-AION and RDW was 33%. Conclusions: Results suggest that RDW may be somehow involved in the pathogenesis of NA-AION. However, high-quality cohort studies are warranted to confirm whether, or not, an altered RDW may be considered a potential biomarker of this vascular disorder affecting the optic nerve.

PURPOSE To investigate the role of complete blood cell count (CBC) measures in retinal artery occlusion (RAO). METHODS This was a case-control study, including 73 newly diagnosed RAO patients and 73 sex- and age-matched subjects without RAO. On the same day of RAO diagnosis, a blood sample was collected and CBC was determined using an automatic blood counter. Dimensional CBC indices, such as mean platelet volume (MPV) and red cell distribution width (RDW), and some CBC-combined indices, including neutrophil/lymphocyte ratio (NLR), derived NLR [dNLR = neutrophils/(white blood cells - neutrophils)] and platelet/lymphocyte ratio (PLR), were evaluated. Erythrocyte sedimentation rate (ESR) was also measured. RESULTS Median neutrophils, red cell distribution width (RDW), NLR and dNLR were 4.5x109 /L (IQR = 3.8-5.8), 13.4% (IQR = 12.7-14.75), 2.47 (IQR = 1.85-3.13) and 1.70 (IQR = 1.26-2.18) in RAO patients and 4x109 /L (IQR = 3.18-4.93), 12.9% (IQR = 12-14), 1.86 (IQR = 1.42-2.44) and 1.32 (IQR = 1.02-1.64) in controls. RAO patients had significantly higher values of neutrophils (p = 0.003), RDW (p = 0.0011), NLR (p = 0.0001) and dNLR (p = 0.0001). There were no significant differences between the values of white blood cells, lymphocytes, platelet count, MPV and PLR. Multivariate logistic regression models revealed a statistically significant correlation between RAO and increased RDW (OR = 1.36, 95% CI = 1.06-1.73, p = 0.015), NLR (OR = 2.02, 95% CI = 1.34-3.06, p = 0.0009) and dNLR (OR = 3.4, 95% CI = 1.71-6.75, p = 0.0005). CONCLUSION Results suggest that RDW, NLR and dNLR may be involved in the pathogenesis of RAO and predict its occurrence. However, high-quality epidemiologic studies, preferably of cohort design, are warranted to confirm whether, or not, an RDW, NLR and dNLR may be considered potential biomarkers of RAO.

Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.

Introduction. Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation that is not fully reversible after inhaled bronchodilator use associated with an abnormal inflammatory condition. The biggest risk factor for COPD is cigarette smoking. The exposure to noxious chemicals contained within tobacco smoke is known to cause airway epithelial injury through oxidative stress, which in turn has the ability to elicit an inflammatory response. In fact, the disruption of the delicate balance between oxidant and antioxidant defenses leads to an oxidative burden that has long been held responsible to play a pivotal role in the pathogenesis of COPD. There are currently several biomarkers of oxidative stress in COPD that have been evaluated in a variety of biological samples. The aim of this review is to identify the best studied molecules by summarizing the key literature findings, thus shedding some light on the subject.Methods. We searched for relevant case-control studies examining oxidative stress biomarkers in stable COPD, taking into account the analytical method of detection as an influence factor.Results. Many oxidative stress biomarkers have been evaluated in several biological matrices, mostly in the blood. Some of them consistently differ between the cases and controls even when allowing different analytical methods of detection.Conclusions. The present review provides an overview of the oxidative stress biomarkers that have been evaluated in patients with COPD, bringing focus on those molecules whose reliability has been confirmed by the use of different analytical methods.

Obstructive Sleep Apnoea (OSA) is characterized by a pro-oxidant state that results from the recurrent hypoxia-reoxygenation cycles. Superoxide dismutase (SOD), a key antioxidant enzyme involved in the detoxification of superoxide radicals, could represent a reliable marker to monitor the antioxidant defences in OSA. In order to capture and critically appraise the available evidence, we performed a systematic review and meta-analysis of studies reporting SOD concentrations in OSA patients and non-OSA controls in the electronic databases Pubmed, Web of Science, Scopus and Google Scholar. In total, 13 studies in 847 OSA patients and 438 non-OSA controls were included in the meta-analysis. Blood SOD concentrations were significantly lower in OSA patients (SMD = 0.87, p < 0.001). By contrast, serum/plasma SOD concentrations were not significantly different between the two groups. Although extreme between-study heterogeneity was observed, the SMD was not substantially modified when individual studies were sequentially removed. In conclusion, we observed that whole blood, but not serum/plasma, SOD concentrations were significantly lower in OSA patients compared with controls. Our meta-analysis suggests an impaired antioxidant defence in OSA that is more robustly assessed in the corpuscular biological matrix and provides useful background information for further studies investigating the association between SOD changes and clinical status in OSA.

Statins may exert protective effects against oxidative stress by upregulating specific antioxidant mechanisms. We conducted a systematic review and meta-analysis of the effect of statins on three key antioxidant enzymes: glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. The electronic databases PubMed, Web of Science, and Scopus were searched from inception to July 2021. The risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal Checklist and certainty of evidence was assessed using the GRADE framework. In 15 studies, reporting 17 treatment arms in 773 patients (mean age 53 years, 54% males), statins significantly increased the concentrations of both GPx (standardized mean difference, SMD = 0.80, 95% confidence interval, CI 0.13 to 1.46, p = 0.018; high certainty of evidence) and SOD (SMD = 1.54, 95% CI 0.71 to 2.36, p < 0.001; high certainty of evidence), but not catalase (SMD = −0.16, 95% CI −0.51 to 0.20, p = 0.394; very low certainty of evidence). The pooled SMD values were not altered in sensitivity analysis. There was no publication bias. In conclusion, statin treatment significantly increases the circulating concentrations of GPx and SOD, suggesting an antioxidant effect of these agents (PROSPERO registration number: CRD42021271589).

Chronic obstructive pulmonary disease (COPD) is a progressive disease that is characterized by a state of persistent inflammation and oxidative stress. The presence of oxidative stress in COPD is the result of an imbalance between pro-oxidant and antioxidant mechanisms. The aim of this review was to investigate a possible association between glutathione peroxidase (GPx), a key component of antioxidant defense mechanisms, and COPD. A systematic search for relevant studies was conducted in the electronic databases PubMed, Web of Science, Scopus, and Google Scholar, from inception to June 2021. Standardized mean differences (SMDs) were used to express the differences in GPx concentrations between COPD patients and non-COPD subjects. Twenty-four studies were identified. In 15 studies assessing whole blood/erythrocytes (GPx isoform 1), the pooled results showed that GPx concentrations were significantly lower in patients with COPD (SMD = −1.91, 95% CI −2.55 to −1.28, p < 0.001; moderate certainty of evidence). By contrast, in 10 studies assessing serum/plasma (GPx isoform 3), the pooled results showed that GPx concentrations were not significantly different between the two groups (very low certainty of evidence). The concentration of GPx-1, but not GPx-3, is significantly lower in COPD patients, suggesting an impairment of antioxidant defense mechanisms in this group.

BACKGROUND Increased oxidative stress potentially leads to accelerated atherosclerosis and, consequently, cardiovascular diseases, the main cause of death in systemic lupus erythematous (SLE). To gain insight into these mechanisms, we studied the association of uncoupling protein (UCP) 2 genetic variants, gene involved in the mitochondrial production of reactive oxygen species, and oxidative stress with SLE and the presence of atherosclerosis. METHODS Genetic analysis of the UCP2 -866G/A and UCP2 Ins/Del polymorphisms was performed in 45 SLE patients and 36 healthy controls by RFLP-PCR. Oxidation status was determined by measuring malondialdehyde (MDA) levels. Presence of subclinical atherosclerosis was investigated by evaluation of intima-media thickness using echo-color-Doppler carotid ultrasound examination. RESULTS Allelic and genotypic frequencies of the SNPs analysed were evaluated by gene count. Significant association was found between UCP2-866A allele and susceptibility for SLE (P=0.001). Higher levels of MDA were found significantly increased in SLE patients (MDA, 5.05±3.36 µmol/L) compared to normal controls (MDA, 2.79±0.89 µmol/L) (P

Variable patterns of disease progression are typically observed in patients with idiopathic pulmonary fibrosis (IPF). We sought to determine the prognostic capacity of blood cell count indexes, derived from routine complete blood cell (CBC) count, in a cohort of IPF patients. The neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) were calculated at baseline in a consecutive series of 82 IPF patients followed for four years. After adjusting for age, gender, body mass index, smoking status, and disease stage, only the AISI was significantly associated with mortality (HR 1.0013, 95% CI 1.0003–1.0023, p = 0.015). Patients with AISI &lt, 434 and ≥434 had a median survival from the diagnosis of 35.3 ± 15.2 and 26.6 ± 16.3 months (p = 0.015), and a four-year survival rate of 54% and 34%, respectively. The AISI, easily derivable from routine laboratory tests, is independently associated with mortality in patients with IPF. Prospective studies in larger cohorts are required to confirm this association.

Cystinuria, a rare inherited aminoaciduria condition, is characterized by the hyperexcretion of cystine, ornithine, lysine, and arginine. Its main clinical manifestation is cystine stone formation in the urinary tract, being responsible for 1–2% total and 6–8% pediatric lithiasis. Cystinuria patients suffer from recurrent lithiasic episodes that might end in surgical interventions, progressive renal functional deterioration, and kidney loss. Cystinuria is monitored for the presence of urinary cystine stones by crystalluria, imaging techniques or urinary cystine capacity; all with limited predicting capabilities. We analyzed blood and urine levels of the natural antioxidant L-ergothioneine in a Type B cystinuria mouse model, and urine levels of its metabolic product S-methyl-L-ergothioneine, in both male and female mice at two different ages and with different lithiasic phenotype. Urinary levels of S-methyl-L-ergothioneine showed differences related to age, gender and lithiasic phenotype. Once normalized by L-ergothioneine to account for interindividual differences, the S-methyl-L-ergothioneine to L-ergothioneine urinary ratio discriminated between cystine lithiasic phenotypes. Urine S-methyl-L-ergothioneine to L-ergothioneine ratio could be easily determined in urine and, as being capable of discriminating between cystine lithiasis phenotypes, it could be used as a lithiasis biomarker in cystinuria patient management., This work has been supported by the Spanish Health Institute Carlos III Grants FIS PI13/00121-R-FEDER, PI16/00267-R-FEDER and PI20/00200-R_FEDER (to VN), Generalitat de Catalunya Grant SGR2017-191 (to VN). VN acknowledge the support of the CERCA Program/Generalitat de Catalunya.

Lipid profile alterations have been observed in patients with coronavirus disease 2019 (COVID-19) in relation to disease severity and mortality. We conducted a systematic review and meta-analysis with meta-regression of studies reporting total, HDL, and LDL-cholesterol, and triglyceride concentrations in hospitalized patients with COVID-19. We searched PubMed, Web of Science and Scopus, between January 2020 and January 2021, for studies describing lipid concentrations, COVID-19 severity, and survival status (PROSPERO registration number: CRD42021253401). Twenty-two studies in 10,122 COVID-19 patients were included in the meta-analysis. Pooled results showed that hospitalized patients with severe disease or non-survivor status had significantly lower total cholesterol (standardized mean difference, SMD = −0.29, 95% CI −0.41 to −0.16, p < 0.001), LDL-cholesterol (SMD = −0.30, 95% CI −0.41 to −0.18, p < 0.001), and HDL-cholesterol (SMD = −0.44, 95% CI −0.62 to −0.26, p < 0.001), but not triglyceride (SMD = 0.04, 95% CI −0.10 to −0.19, p = 0.57), concentrations compared to patients with milder disease or survivor status during follow up. Between-study heterogeneity was large-to-extreme. In sensitivity analysis, the effect size of different lipid fractions was not affected when each study was in turn removed. The Begg's and Egger's t-tests did not show evidence of publication bias, except for studies investigating LDL-cholesterol. In meta-regression, significant associations were observed between the SMD of LDL-cholesterol and age and hypertension, and between the SMD of triglycerides and study endpoint and aspartate aminotransferase. In our systematic review and meta-analysis, lower total, HDL, and LDL-cholesterol, but not triglyceride, concentrations were significantly associated with COVID-19 severity and mortality. Cholesterol concentrations might be useful, in combination with other clinical and demographic variables, for risk stratification and monitoring in this group.Systematic Review Registration: PROSPERO registration number: CRD42021253401.

Alterations in cardiac and renal biomarkers have been reported in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis to investigate serum concentrations of hydroxybutyrate dehydrogenase (HBDH), a combined marker of myocardial and renal injury, in hospitalized COVID-19 patients with different disease severity and survival status. We searched PubMed, Web of Science and Scopus, between December 2019 and April 2021, for studies reporting HBDH in COVID-19. Risk of bias was assessed using the Newcastle-Ottawa scale, publication bias was assessed with the Begg's and Egger's tests, and certainty of evidence was assessed using GRADE. In 22 studies in 15,019 COVID-19 patients, serum HBDH concentrations on admission were significantly higher in patients with high disease severity or non-survivor status when compared to patients with low severity or survivor status (standardized mean difference, SMD = 0.90, 95% CI 0.74 to 1.07, p < 0.001; moderate certainty of evidence). Extreme between-study heterogeneity was observed (I2 = 93.5%, p < 0.001). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and the direction of the effect size were not substantially modified. A significant publication bias was observed. In meta-regression, the SMD of HBDH concentrations was significantly associated with markers of inflammation, sepsis, liver damage, non-specific tissue damage, myocardial injury, and renal function. Higher HBDH concentrations were significantly associated with higher COVID-19 severity and mortality. This biomarker of cardiac and renal injury might be useful for risk stratification in COVID-19. (PROSPERO registration number: CRD42021258123).

Endothelial cell injury is an early event in systemic sclerosis (SSc) pathogenesis and several studies indicate oxidative stress as the trigger of SSc-associated vasculopathy. Here, we show that circulating factors present in sera of SSc patients increased reactive oxygen species (ROS) production and collagen synthesis in human pulmonary microvascular endothelial cells (HPMECs). In addition, the possibility that iloprost, a drug commonly used in SSc therapy, might modulate the above-mentioned biological phenomena has been also investigated. In this regard, as compared to sera of SSc patients, sera of iloprost-treated SSc patients failed to increased ROS levels and collagen synthesis in HPMEC, suggesting a potential antioxidant mechanism of this drug.

BACKGROUND: The early detection of factors predicting hospital length of stay (LOS) in patients affected by severe acute respiratory syndrome in Coronavirus 2 (SARS-CoV-2) disease (COVID-19) might facilitate therapeutic decisions and patient flow management. METHODS: We collected routine clinical and laboratory parameters and derived inflammatory indexes on admission in 65 consecutive COVID-19 patients transferred to the Unit of Respiratory and Infectious Disease of the University Hospital of Sassari (North-Sardinia, Italy) who were alive on discharge. RESULTS: Patients with prolonged length of stay (LOS) (PLOS >= 26 days, N.=22) had significantly higher chest CT severity scores, neutrophils, neutrophil lymphocyte ratio (NLR), aggregate index of systemic inflammation, Systemic Inflammation Response Index, Systemic Inflammation Index (SII), aspartate aminotransferase, lactate dehydrogenase (LDH), and rates of obesity and respiratory support, than non-PLOS patients (N.=43). In univariate analysis, LOS was significantly and negatively correlated with lymphocytes and monocytes, and positively correlated with Body Mass Index (BMI), intensity of care, chest CT severity score, NLR, platelet lymphocyte ratio, SII and LDH. In multivariate regression analysis, only the SII was significantly associated with LOS (beta=0.506, P=0.002) after adjusting for BMI, intensity of care, chest CT severity score and LDH. CONCLUSIONS: SII values on admission were independently associated with LOS in COVID-19 patients. Prospective studies in larger cohorts are required to confirm our findings and to determine the role of the SII in clinical decision making.

Increasing age is a strong, independent risk factor for atherosclerosis and cardiovascular disease. Key abnormalities driving cardiovascular risk in old age include endothelial dysfunction, increased arterial stiffness, blood pressure, and the pro-atherosclerotic effects of chronic, low-grade, inflammation. The identification of novel therapies that comprehensively target these alterations might lead to a major breakthrough in cardiovascular risk management in the older population. Systematic reviews and meta-analyses of observational studies have shown that methotrexate, a first-line synthetic disease-modifying anti-rheumatic drug, significantly reduces cardiovascular morbidity and mortality in patients with rheumatoid arthritis, a human model of systemic inflammation, premature atherosclerosis, and vascular aging. We reviewed in vitro and in vivo studies investigating the effects of methotrexate on endothelial function, arterial stiffness, and blood pressure, and the potential mechanisms of action involved. The available evidence suggests that methotrexate might have beneficial effects on vascular homeostasis and blood pressure control by targeting specific inflammatory pathways, adenosine metabolism, and 5' adenosine monophosphate-activated protein kinase. Such effects might be biologically and clinically relevant not only in patients with rheumatoid arthritis but also in older adults with high cardiovascular risk. Therefore, methotrexate has the potential to be repurposed for cardiovascular risk management in old age because of its putative pharmacological effects on inflammation, vascular homeostasis, and blood pressure. However, further study and confirmation of these effects are essential in order to adequately design intervention studies of methotrexate in the older population.

To explore the significance of the association between treatment with methotrexate (MTX) and liver stiffness in rheumatoid arthritis (RA) patients.We enrolled 140 consecutive RA patients under MTX treatment (MTX-treated RA; mean treatment duration: 6.2 years; mean MTX cumulative dose: 4.67 g), 33 RA patients naive to MTX (MTX-naive RA) and 100 age and sex-matched healthy blood donors (HD). Liver stiffness was assessed by real time two-dimensional shear wave elastography, with values ≥7.1 Kilopascals (kPa) defining significant liver fibrosis.kPa values in HD (4.32 ± 0.7) were lower than that in MTX-naive RA (4.92 ± 0.8) and MTX-treated RA (4.85 ± 0.9, p .0005 for trend). On the contrary, the difference in kPa between MTX-naive and MTX-treated RA was not significant (p = .89). Similarly, liver stiffness was not significantly different across strata of cumulative MTX dose (4.95 ± 0.7 kPa in MTX1 g, 4.90 ± 1.1 kPa in MTX 1-3 g and 4.80 ± 0.9 in MTX3 g, p = .610). Significant liver fibrosis was diagnosed in 4 patients in the MTX-treated RA (highest kPa value = 7.6; no liver function test abnormalities or clinical signs of hepatic failure) and in none in both the MTX-naive RA and HD groups (p = .145).Liver stiffness values, although within the normal range, are significantly higher in RA patients vs. controls, irrespective of MTX treatment. RA patients taking MTX do not have a higher prevalence of significant liver fibrosis when compared to MTX naive RA patients and the general population.

Objective To evaluate the diagnostic accuracy of anticarbamylated protein antibodies (CarP), alone and in combination with traditional biomarkers (rheumatoid factor [RF] and anticitrullinated peptide antibodies [ACPA]), in established rheumatoid arthritis (RA). Methods A commercially available enzyme‐linked immunosorbent assay (ELISA) kit was used to assess CarP concentrations in serum samples of 200 established RA and 206 controls (115 healthy donors and 55 patients with other rheumatic diseases). Main outcome measures were sensitivity, specificity, and area under the curve (AUC; 95% confidence interval [CI]). Difference in accuracy was evaluated by comparison of the respective AUCs. Results A serum CarP cut‐off of 1.47 ng/ml or more differentiated patients with RA from controls with 30% sensitivity, 97.1% specificity, and good accuracy (AUC[95%CI] = 0.83[0.79‐0.86], P < 0.0001). However, it showed moderate diagnostic accuracy in seronegative RA patients: sensitivity 17.9%, specificity 96.9%, and AUC (95% CI) = 0.69 (0.63‐0.75). The diagnostic accuracy of CarP_ACPA and CarP_RF combinations was significantly superior to that of ACPA and RF alone (P < 0.0001 and P = 0.015, respectively), but not to that of ACPA_RF combination (P = 0.089) In addition, the CarP_ACPA_RF combination did not improve the diagnostic accuracy of the ACPA_RF combination (AUC mean difference [95% CI] = 0.006 [−0.001 to 0.015], P = 0.10). The number of positive autoantibodies (0, 1, 2, or 3) was not significantly associated with moderate‐severe disease (Disease Activity Score‐28 [DAS‐28] > 3.2) in adjusted multiple regression analysis. Conclusion CarP has good diagnostic accuracy in established RA but not in seronegative RA. The addition of CarP to ACPA and RF alone or in combination does not significantly enhance the diagnostic accuracy of ACPA_RF combination.

Raised circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), have been reported in several rheumatic diseases (RDs). However, the strength of this relationship is unclear. Therefore, the aim of this systematic review and meta-analysis was to evaluate the magnitude and the robustness of the association between ADMA concentrations and RDs. We calculated standardized mean differences (SMD, with 95% confidence intervals, CI). Study heterogeneity was evaluated by meta-regressions and sensitivity analyses according to type of RDs, conventional cardiovascular risk factors, inflammatory markers, and type of ADMA assessment methodology. Thirty-seven studies with a total of 2,982 subjects (1,860 RDs patients and 1,122 healthy controls) were included in our meta-analysis. Pooled results showed that ADMA concentrations were significantly higher in patients with RDs than in healthy controls (SMD = 1.27 µmol/L, 95% CI 0.94–1.60 µmol/L; p

Alterations in cardiac biomarkers have been reported in patients with coronavirus disease 2019 (COVID-19) in relation to disease severity and mortality. We conducted a systematic review and meta-analysis with meta-regression of studies reporting B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) plasma concentrations in COVID-19. We searched PubMed, Web of Science, and Scopus, between January 2020 and 2021, for studies reporting BNP/NT-proBNP concentrations, measures of COVID-19 severity, and survival status (PROSPERO registration number: CRD42021239190). Forty-four studies in 18,856 COVID-19 patients were included in the meta-analysis and meta-regression. In pooled results, BNP/NT-proBNP concentrations were significantly higher in patients with high severity or non-survivor status when compared to patients with low severity or survivor status during follow up (SMD = 1.07, 95% CI: 0.89–1.24, and p < 0.001). We observed extreme between-study heterogeneity (I2 = 93.9%, p < 0.001). In sensitivity analysis, the magnitude and the direction of the effect size were not substantially modified after sequentially removing individual studies and re-assessing the pooled estimates, (effect size range, 0.99 – 1.10). No publication bias was observed with the Begg's (p = 0.26) and Egger's (p = 0.40) t-tests. In meta-regression analysis, the SMD was significantly and positively associated with D-dimer (t = 2.22, p = 0.03), myoglobin (t = 2.40, p = 0.04), LDH (t = 2.38, p = 0.02), and procalcitonin (t = 2.56, p = 0.01) concentrations. Therefore, higher BNP/NT-proBNP plasma concentrations were significantly associated with severe disease and mortality in COVID-19 patients.

Activation of the complement system has been observed in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression to investigate possible differences in the serum concentrations of two routinely measured complement components, C3 and C4, in COVID-19 patients with different severity and survival status. We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum complement C3 and C4, measures of COVID-19 severity, and survival. Eligibility criteria were a) reporting continuous data on serum C3 and C4 concentrations in COVID-19 patients, -b) investigating COVID-19 patients with different disease severity and/or survival status, c) adult patients, d) English language, e) ≥10 patients, and f) full-text available. Using a random-effects model, standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated to evaluate differences in serum C3 and C4 concentrations between COVID-19 patients with low vs. high severity or survivor vs. non-survivor status. Risk of bias was assessed using the Newcastle-Ottawa scale whereas publication bias was assessed with the Begg’s and Egger’s tests. Certainty of evidence was assessed using GRADE. Nineteen studies in 3,764 COVID-19 patients were included in the meta-analysis. Both C3 and C4 concentrations were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status (C3 SMD=-0.40, 95% CI -0.60 to -0.21, p2 = 82.1%; C4, I2 = 84.4%). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. There was no publication bias. In meta-regression, the SMD of C3 was significantly associated with white blood cell count, C-reactive protein (CRP), and pro-thrombin time, whereas the SMD of C4 was significantly associated with CRP, pro-thrombin time, D-dimer, and albumin. In conclusion, lower concentrations of C3 and C4, indicating complement activation, were significantly associated with higher COVID-19 severity and mortality. C3 and C4 might be useful to predict adverse clinical consequences in these patients.Systematic Review Registration: PROSPERO, Registration number: CRD42021239634.

Platelets play an important role in the pathophysiology of chronic obstructive pulmonary disease (COPD) by mediating thrombotic, inflammatory, and immune processes in the lung. We conducted a systematic review and meta-analysis of studies investigating the platelet count and three platelet indices, mean platelet volume (MPV), platelet distribution width (PDW), and platelet to lymphocyte ratio (PLR) in stable COPD vs. non-COPD patients and in stable COPD vs. acute exacerbation of COPD (AECOPD) patients (PROSPERO registration number: CRD42021228263). PubMed, Web of Science, Scopus and Google Scholar were searched from inception to December 2020. Twenty-seven studies were included in the meta-analysis, 26 comparing 4,455 stable COPD patients with 7,128 non-COPD controls and 14 comparing 1,251 stable COPD with 904 AECOPD patients. Stable COPD patients had significantly higher platelet counts (weighted mean difference, WMD = 13.39 x10

OBJECTIVES: D-dimer elevations, suggesting a pro-thrombotic state and coagulopathy, predict adverse outcomes in coronavirus disease 2019 (COVID-19). However, the clinical significance of other coagulation markers, particularly the international normalized ratio (INR), is not well established. We conducted a systematic review and meta-analysis of the INR in COVID-19. METHODS: A literature search was conducted in PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting INR values, measures of COVID-19 severity, and mortality (PROSPERO registration number: CRD42021241468). RESULTS: Thirty-eight studies in 7440 COVID-19 patients with low disease severity or survivor status during follow up (50 ​% males, mean age 57 years) and 2331 with high severity or non-survivor status (60 ​% males, mean age 69 years) were identified. The INR was significantly prolonged in patients with severe disease or non-survivor status than in patients with mild disease or survivor status (standard mean difference, SMD, 0.60; 95 ​% confidence interval, CI 0.42 to 0.77; p ​

Introduction Cancer immunotherapy represents one of the most important innovations in modern medicine. Durvalumab is an anti-programmed cell death ligand 1 (PDL-1) agent which is currently under investigation in several studies in combination with the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drug tremelimumab. The aim of this review was to systematically identify and revise the current scientific literature investigating the combination of these two drugs in solid tumors. Methods A digital search on the Medline (PubMed interface) and Scopus databases for articles published from inception to 26 February 2021 was performed. The terms used for the search were durvalumab AND tremelimumab. Trials reported in English involving adult patients with solid cancers treated with the combination durvalumab plus tremelimumab were retrieved; the references of the articles were cross-checked to identify missing papers. Results The electronic search produced 267 results; after exclusion of duplicates, irrelevant articles, reviews, and papers not in English or missing data, 19 articles were included for revision. The total number of patients treated with the combination of durvalumab and tremelimumab in the studies retrieved was 2052. Conclusion The combination of durvalumab plus tremelimumab showed some oncological advantages in comparison with traditional chemotherapies in some subsets of tumors, but generally has not shown consistent advantages in comparison with the employment of durvalumab monotherapy. A number of the studies examined had intrinsic methodological limitations; therefore, future well-designed studies involving larger cohorts are warranted. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01796-6.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease characterized by a not fully reversible airflow limitation associated with an abnormal inflammatory response. Exacerbations of COPD are of major importance in the acceleration of disease progression, in healthcare costs, and negatively affect the patient’s quality of life. Exacerbations are characterized by a further increase in the airway inflammation likely driven by oxidative stress. In order to deepen the knowledge about this topic, several studies have focused on oxidative stress biomarkers levels. This review summarizes the literature findings about oxidative stress biomarkers in exacerbated COPD patients compared to ones in the stable state. Methods: a systematic search in electronic databases Pubmed, Web of Science, Scopus and Google Scholar from inception to January 2021, was conducted using the terms: “oxidative stress”, “chronic obstructive pulmonary disease” or “COPD”, “exacerbation”. Results: 23 studies were selected for the systematic review. They showed the presence of an imbalance between oxidant and antioxidant molecules in favor of the former in exacerbation of COPD. Conclusions: future studies using standardized methods in better characterized population are needed. However, this review suggests that targeting oxidative stress could be useful in monitoring the disease progression in COPD patients and especially in those more susceptible to exacerbations.

BACKGROUND AND OBJECTIVES: An excessive inflammatory response in patients with coronavirus disease 2019 (COVID-19) is associated with high disease severity and mortality. Specific acute phase reactants might be useful for risk stratification. A systematic review and meta-analysis was conducted of studies on serum amyloid A (SAA) in patients with COVID-19. METHODS: The PubMed, Web of Science, and Scopus databases were searched, covering the period January 2020 to December 2020, for studies reporting SAA concentrations, COVID-19 severity, and survival status. RESULTS: Nineteen studies involving 5617 COVID-19 patients were included in the meta-analysis. Pooled results showed that SAA concentrations were significantly higher in patients with severe disease and non-survivors (standard mean difference (SMD) 1.20, 95% confidence interval 0.91-1.49, P < 0.001). Extreme between-study heterogeneity was observed (I2 = 92.4%, P < 0.001). In the sensitivity analysis, the effect size was not significantly affected when each study was removed in turn (range 1.10-1.29). The Begg test (P = 0.030), but not the Egger test (P = 0.385), revealed the presence of publication bias. Pooled SMD values were significantly and positively associated with sex (t = 2.20, P = 0.047) and aspartate aminotransferase (t = 3.44, P = 0.014). CONCLUSIONS: SAA concentrations were significantly and positively associated with higher COVID-19 severity and mortality. This acute phase reactant might assist with risk stratification and monitoring in this group.

Objectives We conducted a systematic review and meta-analysis with meta-regression of creatine kinase-MB (CK-MB), a biomarker of myocardial injury, in COVID-19 patients. Methods We searched PubMed, Web of Science and Scopus, for studies published between January 2020 and January 2021 that reported CK-MB, COVID-19 severity and mortality (PROSPERO registration number: CRD42021239657). Results Fifty-five studies in 11,791 COVID-19 patients were included in the meta-analysis. The pooled results showed that CK-MB concentrations were significantly higher in patients with high disease severity or non-survivor status than patients with low severity or survivor status (standardized mean difference, SMD, 0.81, 95% CI 0.61 to 1.01, p

Coagulation disorders, endotheliopathy and inflammation are the most common hallmarks in SARS-CoV-2 infection, largely determining COVID-19’s outcome and severity. Dysfunctions of endothelial cells and platelets are tightly linked in contributing to the systemic inflammatory response that appears to be both a cause and a consequence of COVID-19-associated coagulation disorders and thrombotic events. Indeed, elevated levels of circulating inflammatory cytokines are often associated with abnormal coagulation parameters in COVID-19 patients. Although treatments with low molecular weight heparin (LMWH) have shown beneficial effects in decreasing patient mortality with severe COVID-19, additional therapeutic strategies are urgently needed. Utilizing the anti-inflammatory and anti-thrombotic properties of natural compounds may provide alternative therapeutic approaches to prevent or reduce the risk factors associated with pre-existing conditions and comorbidities that can worsen COVID-19 patients’ outcomes. In this regard, resveratrol, a natural compound found in several plants and fruits such as grapes, blueberries and cranberries, may represent a promising coadjuvant for the prevention and treatment of COVID-19. By virtue of its anti-thrombotic and anti-inflammatory properties, resveratrol would be expected to lower COVID-19-associated mortality, which is well known to be increased by thrombosis and inflammation. This review analyzes and discusses resveratrol’s ability to modulate vascular hemostasis at different levels targeting both primary hemostasis (interfering with platelet activation and aggregation) and secondary hemostasis (modulating factors involved in coagulation cascade).

The pathological, clinical, and therapeutic features of colorectal cancer (CRC) depend on its anatomical localization. We investigated possible associations between the red blood cell distribution width (RDW) and CRC localization. Two-hundred eighty-eight consecutive patients with CRC were retrospectively studied. Demographic, clinical, pathological and laboratory data were retrieved from clinical records and reports. Median RDW values were significantly higher in patients with right-sided CRC when compared to those with CRC in other localizations (16.2, IQR: 14.5–20.0 vs 13.8, IQR: 13.0–16.1, p

Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the outcomes of modern targeted therapies, their global prognostic significance, and their mutual interaction in cases of co-occurrence.

Excessive inflammation and malnutrition are associated with coronavirus disease 2019 (COVID-19) severity and mortality. Combined biomarkers of malnutrition and inflammation, such as serum prealbumin, might be particularly attractive for early risk stratification. We conducted a systematic review and meta-analysis of studies reporting serum prealbumin in patients with COVID-19. We searched PubMed, Web of Science and Scopus, between January and November 2020, for studies reporting data on serum prealbumin, COVID-19 severity, defined as severe illness, prolonged viral load, receiving mechanical ventilation or admitted to intensive care unit (ICU), and mortality. Nineteen studies in 4,616 COVID-19 patients were included in the meta-analysis. Pooled results showed that serum prealbumin concentrations were significantly lower in patients with severe disease and non-survivors (standard mean difference, SMD, −0.92, 95% CI, −1.10 to −0.74, P < 0.001). Extreme heterogeneity was observed (I2 = 77.9%; P < 0.001). In sensitivity analysis, the effect size was not significantly affected when each study was in turn removed (range between −0.86 and −0.95). The Begg's (P = 0.06) and Egger's t-tests (P = 0.26) did not show publication bias. Pooled SMD values were significantly and negatively associated with age (t = −2.18, P = 0.045) and C-reactive protein (t = −3.85, P = 0.002). In our meta-analysis, lower serum prealbumin concentrations were significantly associated with COVID-19 severity and mortality. This combined marker of malnutrition and inflammation might assist with early risk stratification and management in this group.

Background and Objectives: There is general agreement on the benefits of laparoscopy for treatment of rectal and left colon cancers, whereas findings regarding the comparison of laparoscopic and open right colonic resections are discordant. The aim of this systematic review and meta-analysis was to assess the outcomes and advantages of laparoscopic versus transverse-incision open surgery for management of right colon cancer. Materials and Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Comparative studies evaluating the results of laparoscopic and transverse-incision open right hemicolectomies were analyzed. The measured outcomes were mean operative time, time to feeding, duration of hospital stay, and number of lymph nodes harvested. Results: A total of 5 studies including 318 patients met the inclusion criteria. Meta-analysis revealed no differences in time to resume oral feeding, hospital stay, and number of lymph nodes harvested in between groups, but mean length of surgery was significantly longer in the laparoscopic group. Conclusion: These data confirm that the preferred approach to right hemicolectomy is yet unclear. Laparoscopy has a longer operative time than transverse-incision open surgery, and no significant short-term benefits were observed for the studied parameters. Well-designed randomized control trials (RCTs) might help to identify the differences between these two techniques for the surgical treatment of right colon cancer.

Background. The rapid onset of a systemic pro-inflammatory state followed by acute respiratory distress syndrome is the leading cause of mortality in patients with COVID-19. We performed a retrospective observational study to explore the capacity of different complete blood cell count (CBC)-derived inflammation indexes to predict in-hospital mortality in this group. Methods. The neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), platelet to lymphocyte ratio (PLR), mean platelet volume to platelet ratio (MPR), neutrophil to lymphocyte &times, platelet ratio (NLPR), monocyte to lymphocyte ratio (MLR), systemic inflammation response index (SIRI), systemic inflammation index (SII), and the aggregate index of systemic inflammation (AISI) were calculated on hospital admission in 119 patients with laboratory confirmed COVID-19. Results. Non-survivors had significantly higher AISI, dNLR, NLPR, NLR, SII, and SIRI values when compared to survivors. Similarly, Kaplan&ndash, Meier survival curves showed significantly lower survival in patients with higher AISI, dNLR, MLR, NLPR, NLR, SII, and SIRI. However, after adjusting for confounders, only the SII remained significantly associated with survival (HR = 1.0001, 95% CI, 1.0000&ndash, 1.0001, p = 0.029) in multivariate Cox regression analysis. Conclusions. The SII on admission independently predicts in-hospital mortality in COVID-19 patients and may assist with early risk stratification in this group.

The aim of this systematic review and meta-analysis was to assess the blood concentrations of the total and reduced forms of the low-molecular-weight antioxidant thiol glutathione (GSH) in chronic obstructive pulmonary disease (COPD) patients in comparison to healthy individuals. A literature search was conducted in the PubMed and Web of Science databases from inception until June 2020. In the 18 studies identified (involving a total of 974 COPD patients and 631 healthy controls), the pooled reduced GSH concentrations were significantly lower in patients with COPD than controls (SMD = −3.04, 95% CI = −4.42 to −1.67; p < 0.001). By contrast, the pooled total GSH concentrations were significantly higher in patients with COPD than controls (SMD = 0.42, 95% CI = 0.11 to 0.73; p = 0.009). Our meta-analysis showed that the blood concentrations of reduced GSH, even in the presence of higher total GSH concentrations, were significantly lower in patients with COPD when compared to healthy controls. This suggests that an impaired antioxidant defense system plays an important role in the pathogenesis of COPD.

Increased concentrations of serum aspartate transaminase (AST) and alanine transaminase (ALT) are common in COVID‐19 patients. However, their capacity to predict mortality, particularly the AST/ALT ratio, commonly referred to as the De Ritis ratio, is unknown. We investigated the association between the De Ritis ratio on admission and in‐hospital mortality in 105 consecutive patients with coronavirus disease of 2019 (COVID‐19) admitted to three COVID‐19 referral centres in Sardinia, Italy. The De Ritis ratio was significantly lower in survivors than nonsurvivors (median: 1.25; IQR: 0.91‐1.64 vs 1.67; IQR: 1.38‐1.97, P = .002) whilst there were no significant between‐group differences in ALT and AST concentrations. In ROC curve analysis, the AUC value of the De Ritis ratio was 0.701 (95% CI 0.603‐0.787, P = .0006) with sensitivity and specificity of 74% and 70%, respectively. Kaplan‐Meier survival curves showed a significant association between the De Ritis ratio and mortality (logrank test P = .014). By contrast, no associations were observed between the ALT and AST concentrations and mortality (logrank test P = .83 and P = .62, respectively). In multivariate Cox regression analysis, the HR in patients with De Ritis ratios ≥1.63 (upper tertile of this parameter) remained significant after adjusting for age, gender, smoking status, cardiovascular disease, intensity of care, diabetes, respiratory diseases, malignancies and kidney disease (HR: 2.46, 95% CI 1.05‐5.73, P = .037). Therefore, the De Ritis ratio on admission was significantly associated with in‐hospital mortality in COVID‐19 patients. Larger studies are required to confirm the capacity of this parameter to independently predict mortality in this group.

Introduction: In vitro evidence suggests that pirfenidone and nintedanib, approved agents for the treatment of idiopathic pulmonary fibrosis (IPF), exert anti-inflammatory and anti-oxidant effects. We aimed to investigate such effects in vivo in IPF patients. Methods: Systemic circulating markers of oxidative stress [nuclear factor erythroid 2&ndash, related factor 2 (Nrf2), thiobarbituric acid- reactive substances (TBARS), homocysteine (Hcy), cysteine (Cys), asymmetric dimethylarginine (ADMA) and ADMA/Arginine ratio, glutathione (GSH), plasma protein &ndash, SH (PSH), and taurine (Tau)] and inflammation [Kynurenine (Kyn), Tryptophan (Trp) and Kyn/Trp ratio] were measured at baseline and after 24-week treatment in 18 IPF patients (10 treated with pirfenidone and 8 with nintedanib) and in 18 age- and sex-matched healthy controls. Results: Compared to controls, IPF patients had significantly lower concentrations of reduced blood GSH (457 &plusmn, 73 &micro, mol/L vs 880 &plusmn, 212 &micro, mol/L, p &lt, 0.001) and plasma PSH (4.24 &plusmn, 0.95 &micro, mol/g prot vs 5.28 &plusmn, 1.35 &micro, mol/g prot, p = 0.012). Pirfenidone treatment significantly decreased the Kyn/Trp ratio (0.030 &plusmn, 0.011 baseline vs 0.025 &plusmn, 0.010 post-treatment, p = 0.048) whilst nintedanib treatment significantly increased blood GSH (486 &plusmn, 70 &mu, mol/L vs 723 &plusmn, 194 &mu, mol/L, p = 0.006) and reduced ADMA concentrations (0.501 &plusmn, 0.094 vs. 0.468 &plusmn, 0.071 &mu, mol/L, p = 0.024). Conclusion: pirfenidone and nintedanib exert beneficial effects on specific markers of oxidative stress and inflammation in IPF patients.

Coronavirus disease 2019 (COVID-19) is a recently described infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since late 2019, COVID-19 has rapidly spread in virtually all countries, imposing the adoption of significant lockdown and social distancing measures. The activation of the coagulation cascade is a common feature of disseminated intravascular coagulation and adverse clinical outcomes in COVID-19 patients. In this study, we conducted a meta-analysis aiming to investigate differences in serum D-dimer concentrations in patients with and without severe COVID-19 disease. An electronic search in Medline (PubMed), Scopus and Web of Science was performed with no language restrictions, and 13 articles were reporting on 1,807 patients (585, 32.4% with severe disease) were finally identified and included in the meta-analysis. The pooled results of all studies revealed that the D-dimer concentrations were significantly higher in patients with more severe COVID-19 (SMD: 0.91 mg/L; 95% CI, 0.75 to 1.07 mg/L, p < 0.0001). The heterogeneity was moderate (I2 = 46.5%; p = 0.033). Sensitivity analysis showed that the effect size was not modified when any single study was in turn removed (effect size range, 0.87 mg/L to 0.93 mg/L). The Begg's (p = 0.76) and Egger's tests (p = 0.38) showed no publication bias. In conclusion, our systematic review and meta-analysis showed that serum D-dimer concentrations in patients with severe COVID-19 are significantly higher when compared to those with non-severe forms.

Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. Objective: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. Methods: Paroxonase-1 (PON-1), protein-SH (PSH), and malondialdehyde (MDA) were measured in 164 RA patient s and 100 age- and sex-matched healthy controls without previous cardiovascular events. Peripheral ED, evaluated by flow-mediated pulse amplitude tonometry, was defined by log-transformed reactive hyperemia index (Ln-RHI) values &lt, 0.51. Results: PON-1 activity and PSH concentrations were significantly reduced in RA patients compared to controls. In regression analysis, increased plasma MDA levels were significantly associated with reduced Ln-RHI [B coefficient (95% CI) = &minus, 0.003 (&minus, 0.005 to &minus, 0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06&ndash, 2.88), p = 0.028). Contrary to our expectations, increased PON-1 activity was significantly associated, albeit weakly, with the presence of ED (OR (95% CI) = 1.00 (1.00&ndash, 1.01), p = 0.017). Conclusions: In this first evidence of a link between oxidative stress and markers of atherosclerosis, MDA and PON-1 showed opposite associations with peripheral vasodilatory capacity and the presence of ED in RA. Further studies are needed to determine whether this association predicts atherosclerotic events in the RA population.

Background: There is a paucity of head-to-head comparisons of the efficacy and harms of pharmacological treatments for systemic sclerosis-related interstitial lung disease (SSc-ILD). Methods: We conducted a network meta-analysis (NMA) in order to compare the effects of different treatments with the placebo on change in forced vital capacity (FVC), change in diffusion lung capacity for CO (DLCO), serious adverse events (SAEs), discontinuation for adverse events and mortality in SSc-ILD. Standardized mean difference (SMD) and log odds ratio were estimated using NMA with fixed effects. Results: Nine randomized clinical trials (926 participants) comparing eight interventions and the placebo for an average follow-up of one year were included. Compared to the placebo, only rituximab significantly reduced FVC decline (SMD (95% CI) = 1.00 (0.39 to 1.61)). Suitable data on FVC outcome for nintedanib were not available for the analysis. No treatments influenced DLCO. Safety and mortality were also not different across treatments and the placebo, although there were few reported events. Cyclophosphamide and pomalidomide were less tolerated than the placebo, mycophenolate, and nintedanib. Conclusion: Only rituximab significantly reduced lung function decline compared to the placebo. However, direct head-to-head comparison studies are required to confirm these findings and to better determine the safety profile of various treatments.

To evaluate the role of some complete blood cell count (CBC)-derived measures in retinal vein occlusion (RVO).This was a retrospective case-control study, including 127 newly diagnosed RVO patients and 127 sex- and age-matched subjects without RVO. A blood sample was obtained and a complete blood cell count was performed. Neutrophil/lymphocyte ratio (NLR), derived NLR [dNLR = neutrophils/(white blood cells‒neutrophils)], and platelet/lymphocyte ratio (PLR) were calculated. We also performed a meta-analysis of the available data, ours included, on the correlation between mean platelet volume (MPV) and RVO. Standardized mean differences (SMD) were used to build forest plots and assess differences in MPV values between RVO patients and controls.Median MPV and red cell distribution width (RDW) were 8.7 fL (IQR = 7.8-9.5) and 13.2% (IQR = 12.4-14.2) in RVO patients and 7.8 fL (IQR = 7.1-8.5) and 13% (IQR = 12-14) in controls. RVO patients had significantly higher values of MPV (Results suggest lack of association between CBC-derived inflammatory indices and RVO. Conversely, MPV and, to a lesser extent, RDW may be disease biomarkers in RVO.

Background Triple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing “special types” to high-grade invasive breast carcinomas of no special type (IBC-NST). Methods This study was performed on data obtained from TNBC Database, including pathological features and clinical records of 1009 TNBCs patients diagnosed between 1994 and 2015 in the four most important Oncology Units located in different hospitals in Sardinia, Italy. Kaplan-Meier analysis, log-rank test and multivariate Cox proportional-hazards regression were applied for overall survival (OS) and disease free survival (DFS) according to TNBC histologic types. Results TNBC “special types” showed significant differences for several clinico-pathological features when compared to IBC-NST. We observed that in apocrine carcinomas as tumor size increased, the number of metastatic lymph nodes manifestly increased. Adenoid cystic carcinoma showed the smallest tumor size relative to IBC-NST. At five-year follow-up, OS was 92.1, 100.0, and 94.5% for patients with apocrine, adenoid cystic and medullary carcinoma, respectively; patients with lobular and metaplastic carcinoma showed the worst OS, with 79.7 and 84.3%, respectively. At ten-years, patients with adenoid cystic (100.0%) and medullary (94.5%) carcinoma showed a favourable prognosis, whereas patients with lobular carcinoma showed the worst prognosis (73.8%). TNBC medullary type was an independent prognostic factor for DFS compared to IBC-NST. Conclusions Our study confirms that an accurate and reliable histopathologic definition of TNBC subtypes has a significant clinical utility and is effective in the therapeutic decision-making process, with the aim to develop innovative and personalized treatments.

Purpose Inflammation and immunity play a pivotal but yet unclear role in idiopathic pulmonary fibrosis (IPF), a chronic disorder characterized by progressive damage of lung parenchyma and severe loss of lung function despite optimal treatment. However, the pathophysiological and predictive role of combined blood cell count indexes of inflammation in IPF is uncertain. Methods Seventy-three patients with IPF and 62 healthy subjects matched for age, gender and smoking status were included in this cross-sectional study. Results We found significant differences in neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), systemic inflammation response index (SIRI) and aggregate index of systemic inflammation (AISI) between IPF patients and healthy controls. In logistic regression, all combined blood inflammation indexes, barring PLR, were independently associated with the presence of IPF after adjusting for age, gender, body mass index and smoking status. Furthermore, significant associations between FVC% and NLR, LMR, SIRI and AISI, and between DLCO% and NLR, dNLR, LMR, SIRI and AISI, were observed. Conclusions In conclusion, our data indicate significant alterations of combined blood cell count indexes of inflammation in IPF.

Background The aim of this study was to evaluate a series of blood count inflammation indexes in predicting anastomotic leakage (AL) in elective colorectal surgery. Methods Demographic, pathologic, and clinical data of 1432 consecutive patients submitted to colorectal surgery in eight surgical centers were retrospectively evaluated. The neutrophil to lymphocyte (NLR), derived neutrophil to lymphocyte (dNLR), lymphocyte to monocyte (LMR), and platelet to lymphocyte (PLR) ratios were calculated before surgery and on the 1st and 4th postoperative days, in patients with or without AL. Results There were 106 patients with AL (65 males, mean age 67.4 years). The NLR, dNLR, and PLR were significantly higher in patients with AL in comparison to those without, on both the 1st and 4th postoperative days, but significance was greater on the 4th postoperative day. An NLR cutoff value of 7.1 on this day showed the best area under the curve (AUC 0.744; 95% CI 0.719–0.768) in predicting AL. Conclusions Among the blood cell indexes of inflammation evaluated, NLR on the 4th postoperative day showed the best ability to predict AL. NLR is a low cost, easy to perform, and widely available index, which might be potentially used in clinical practice as a predictor of AL in patients undergoing elective colorectal surgery.

Background The relationship between plasma arginine metabolites influencing vascular homeostasis and peripheral vasodilatory capacity in rheumatoid arthritis (RA) patients is not known. Methods L-arginine (Arg), monomethyl-L-arginine (MMA), L-homoarginine (hArg), asymmetric dimethyl-L-arginine (ADMA), symmetric dimethyl-L-arginine, and L-citrulline (Cit) were measured by LC-MS/MS in 164 RA patients and 100 age- and sex-matched healthy controls without previous cardiovascular events. Log-transformed reactive hyperemia index (Ln-RHI) evaluated by peripheral arterial tonometry (PAT, EndoPAT2000 device) was assessed as surrogate measure of peripheral vasodilatory capacity in RA patients. Ln-RHI values

BACKGROUND/PURPOSE The role of blood malondialdehyde (MDA) in age-related macular degeneration (AMD), the leading cause of new blindness in industrialized countries, is still matter of debate. We performed a systematic review and meta-analysis of the published data on the MDA levels in AMD patients. METHODS PubMed, ISI Web of Sciences, and Scopus searches were performed according to MOOSE guidelines. Case-control studies were eligible for inclusion. Participants and controls were AMD patients and subjects without AMD, respectively. The main outcome measures were wet AMD and dry AMD. MDA level was the main exposure variable. Data were pooled using a random-effects model. RESULTS Twelve case-control studies were identified. A total of 634 AMD patients (mean age 66.7 years) and 656 controls without AMD (mean age 67.8 years) were evaluated. Extreme between-study heterogeneity was observed (I = 96.8%, P < 0.001). Pooled standardized mean difference showed that MDA values were significantly higher in patients with AMD (standardized mean difference = 1.91 µmol/L, 95% confidence interval = 1.08-2.74; P < 0.001). In a model including five studies, homogenous for age, sample matrix, and laboratory testing for MDA, heterogeneity decreased from extreme to moderate (I = 46.4%, P = 0.113), and pooled standardized mean difference, though attenuated, remained significantly higher in AMD patients (standardized mean difference = 1.07 µmol/L, 95% confidence interval = 0.82-1.31; P < 0.001). CONCLUSION There is some evidence of higher levels of MDA in AMD patients compared with healthy controls; however, this result should be interpreted with caution because of extreme between-study heterogeneity and the possible effect of publication bias. Future studies, preferably well age-matched and of cohort design, are necessary before any firm conclusions on the putative role of elevated MDA on AMD can be drawn.