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Cutaneous angiosarcoma (CAS) is the most common type of angiosarcoma that predominantly affects older Caucasians. The outcomes of immunotherapy in CAS are currently under investigation in relation to the expression of programmed death ligand 1 (PD-L1) and other biomarkers. We performed a systematic review and metanalysis of data from the current literature reporting on PD-L1 immunohistochemistry expression. A systematic search of publications in the electronic databases PubMed, Web of Science, and Scopus was conducted using the following terms: “PD-L1” and “angiosarcomas”. A total of ten studies reporting on 279 cases were identified and included in the meta-analysis. The pooled prevalence of PD-L1 expression in CAS was 54% (95% CI 36–71%), with high heterogeneity (I2 = 84.81%, p < 0.001). In sub-group analysis, the proportion of PD-L1 expression in CAS was significantly (p = 0.049) lower in Asian studies (ES = 35%, 95% CI 28–42%, I2 = 0.0%, p = 0.46) than in European studies (ES = 71%, 95% CI 51–89%, I2 = 48.91%, p = 0.12).

The evidence is strong in favor of blood pressure (BP) control in robust older people as a way to reduce morbidity and mortality in the same way that treatment improves the lives of middle-aged people. Expert editorials have been written over the last five decades persuasively arguing for or against more intensive treatment of older people with hypertension, supported by the specificity of (then) contemporaneous randomized controlled trials (RCTs) or the generalizability of observational studies. But there are limitations.First, there has always been such a thing as too low. Early epidemiological studies showed an upward inflection in mortality curves that resemble a slanted letter J. Second, certain complex older people encountered routinely in a clinic, pharmacy, or nursing facility were often excluded from the RCTs showing benefit from intensive BP control. Cohort studies of these complex people showed a different truth, that the point of “too low” might move up and that BP targets for adults might be too low for select older people. Not all older people are the same. Some are burdened by frailty superimposed on cardiovascular disease and a limited life-expectancy. It is one thing not to start BP-lowering medications for this patient; it is an entirely different matter to stop.

The problem of polypharmacy is complex, pervasive, and expanding. Appropriate prescribing of antihypertensive therapy for older people might help reduce medication burden, but it begins with a better understanding of what the evidence offers and where the evidence is quiet.In the first of this three-part series on antihypertensive medications for older people, we will trace the history of treating blood pressure with medication, from the expert opinion opposing treatment, to the observational data that led to paradigm shifts. We will follow the trail of evidence to randomized controlled trials (RCT) demonstrating the clear benefit of better control of blood pressure for all adults, regardless of age.RCT first evaluated any treatment against placebo, then began comparing one medication with another, and finally, more intensive control compared with less intensive control. Eventually professional societies bundled the evidence into guidelines to help busy prescribers and pharmacists wisely advise the consumers at the coal-face.In this first part of this series, we will present the evidence that favors intensive therapy in older people, that lower is better. In the second part, we will present evidence that highlights the dangers of going too low, and that stopping blood pressure-lowering medication might help. In the third part, we will discuss the evidence, new and old, that shows what happens when you stop.

Introduction Narcolepsy, a condition adversely affecting psychological, social, and cognitive function, is more prevalent in females of childbearing age than the general population. Modafinil and armodafinil are central nervous system stimulants approved for treatment of narcolepsy. Infant exposure to these agents through human milk has not been investigated. Poor quality medication safety information during lactation is associated with early cessation of breastfeeding and suboptimal healthcare for the breastfeeding family. Main Issue In this case study, we measured the concentration of armodafinil (the most active form of modafinil) in human milk and infant plasma to quantify infant exposure. Management The participant was a 30-year-old primipara with narcolepsy, taking modafinil (300 mg morning, 100 mg noon) while breastfeeding her 6-week-old infant despite the paucity of safety information. Armodafinil concentrations were measured in eight serial human milk samples collected over a 26-hr period and in single maternal and infant plasma samples using ultra performance liquid chromatography - tandem mass spectrometry. The average concentration of armodafinil in human milk was 1.96 mg/L; the relative infant dose was 4.85%; the theoretical infant dose was 0.294 mg/kg/day. Maternal and infant plasma concentrations of armodafinil were 12.02 mg/L and 0.19 mg/L, respectively. The participant continued to exclusively breastfeed the infant, who had normal growth and development. Conclusion Based on these findings, relatively small amounts of armodafinil pass into human milk, with consequent limited infant exposure. Consideration can be given to the use of modafinil or armodafinil during breastfeeding, provided the infant is monitored. Further studies are needed to confirm these findings.

Tumor growth and progression are strictly dependent on the adequate blood supply of oxygen and nutrients. The formation of new blood vessels and vascular networks is essential to ensure this demand. Blood vessels also facilitate the invasion of cancer cells into nearby tissues and their subsequent metastasis. Tumor cells represent the main driver of the neovascularization process through the direct or indirect, by neighboring non-cancer cells, release of pro-angiogenic molecules. The mediators (e.g., growth factors and extracellular matrix components), signaling pathways, cellular components, and processes (e.g., endothelial cell proliferation and migration) activated in tumor angiogenesis are similar to those involved in normal vascular development, except they lack efficient control mechanisms. Consequently, newly formed tumor vessels are typically fragile and hyperpermeable with a reduced and erratic blood flow. Targeting the tumor vasculature has been the focus of intense research over the last 20 years. However, despite the initial interest and expectations, the systemic use of anti-angiogenic drugs has not always led to therapeutic breakthroughs and, in some cases, has been associated with the development of tumor adaptive resistance resulting in a more aggressive phenotype. Therefore, new therapeutic approaches have focused on combining anti-angiogenic agents with chemotherapy or immunotherapy and/or optimizing (normalizing) the structure and function of tumor blood vessels to ensure a more efficient drug delivery. In this context, nanomedicine offers the significant advantage of targeting and releasing anti-angiogenic drugs at specific sites, minimizing toxicity in healthy tissues. Several nanoparticles possess intrinsic modulatory effects on angiogenesis, while others have been developed to facilitate drug delivery in association with chemotherapy, thermotherapy, radiotherapy or in response to specific stimuli within the tumor environment (e.g., enzymes, ions, redox potential) or exogenous stimuli (e.g., temperature, electricity, magnetic fields, and ultrasound). Other nanoparticles can modify, under specific conditions, their physical properties (e.g., dimensions, structure, and interactions) to increase penetration in tumor cells. This review provides a comprehensive appraisal of the critical modulators of tumor vascular biology, the most promising nano-strategies that specifically target such modulators, and the directions for future research and clinical applications.

To evaluate the association between C-reactive protein (CRP) and 10-year risk of cardiovascular (CV) events using the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), based on conventional and RA-specific risk factors but not CRP, in RA patients without previous cardiovascular events.ERS-RA was calculated in 1,251 "Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)" database patients [(age 60.4(9.3) years; 78% female; disease duration, 11.6(8) years; CDAI, 9(9); CRP, 6.8(12) mg/L].The mean (SD) 10-year risk of CV events was 12.9% (10). After adjusting for the use of DMARDs and biologics, CRP concentrations were significantly associated with 10-year risk of CV events (coefficient=0.005 for each 10 mg/L CRP increment; 95%CI 0.000-0.111; p = 0.047). In mediation analysis, the association between CRP and ERS-RA was not explained by disease activity.In a large cohort of RA patients without previous cardiovascular events, a 20 mg/L increase in CRP concentrations was associated with a 1% increase in 10-year risk of CV events. This suggests that actively targeting residual inflammatory risk beyond conventional and RA-specific risk factors might further reduce CV event rates in RA patients.

Severe manifestations of coronavirus disease 2019 (COVID-19) are associated with alterations in blood cells that regulate immunity, inflammation, and hemostasis. We conducted an updated systematic review and meta-analysis of the association between the neutrophil, lymphocyte, and platelet count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), and COVID-19 progression and mortality.A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2020 and June 2022.In 71 studies reporting the investigated parameters within 48 hours of admission, higher NLR (HR 1.21, 95% CI 1.16 to 1.27, p 0.0001), relative neutrophilia (HR 1.62, 95% CI 1.46 to 1.80, p 0.0001), relative lymphopenia (HR 1.62, 95% CI 1.27 to 2.08, p 0.001), and relative thrombocytopenia (HR 1.74, 95% CI 1.36 to 2.22, p 0.001), but not PLR (p = 0.11), were significantly associated with disease progression and mortality. Between-study heterogeneity was large-to-extreme. The magnitude and direction of the effect size were not modified in sensitivity analysis.NLR and neutrophil, lymphocyte, and platelet count significantly discriminate COVID-19 patients with different progression and survival outcomes. (PROSPERO registration number: CRD42021267875).

Long-term hypertension control in the community significantly reduces cardiovascular risk. However, the benefit of controlling acute elevations of blood pressure in hospitalised patients is unclear. In-hospital elevations of blood pressure are relatively common and might not reflect poorly controlled blood pressure before admission. The measurement of blood pressure in hospital patients significantly differs from the best practice recommended for primary care and outpatients. Recent observational studies suggest that the pharmacological treatment of acute, asymptomatic, in-hospital elevations of blood pressure may have no benefit. However, it may increase the risk of in-hospital and post-discharge complications. Pending the development of robust inpatient measurement protocols, acute blood pressure elevations in hospitalised patients should not routinely require antihypertensive treatment in the absence of symptoms or acute end-organ damage. Rather, such elevations should facilitate follow-up of blood pressure and other cardiovascular risk factors after discharge.

We conducted an updated systematic review and meta-analysis of the effect of statins on serum or plasma concentrations of the endogenous inhibitor of endothelial nitric oxide synthase, asymmetric NA systematic literature search was conducted in the electronic databases PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for analytical studies and GRADE, respectively.In 23 studies, reporting 25 treatment arms in 845 participants (mean age 53 years, 57% males, treatment duration 4-48 weeks), statins significantly reduced ADMA concentrations (SMD = -0.39, 95% CI -0.62 to -0.16, p = 0.001; moderate certainty of evidence). The extreme heterogeneity observed was substantially reduced in study subgroups of specific class and individual statins, regional areas, and analytical methods for ADMA concentrations. There was no publication bias. In sensitivity analysis, the corresponding SMD values were not substantially modified when individual studies were sequentially removed. Significant associations were observed, in meta-regression, between the SMD and publication year (t = -3.25, p = 0.003), but not baseline cholesterol concentrations.Statin treatment significantly lowers ADMA concentrations. This effect is independent of baseline cholesterol. Prospective studies are required to determine whether ADMA-lowering mediates, at least partly, the protective effects of statins against atherosclerotic cardiovascular disease. (PROSPERO registration number: CRD42021275123).

Older adults represent a growing population amongst cancer survivors who require specific consideration given the complex and largely unknown interactions between cancer-related concerns and age-related conditions. The increasing use of geriatric assessment (GA) has enabled oncologists to appropriately assess older patients’ overall health status, personalise anti-cancer treatment and improve survival. However, whilst current research and practice focus on improving the management of older adults with cancer in the acute setting, the progress in the field of survivorship research in geriatric oncology is lagging. As cancer survivorship is a continuum, planning for a healthy survivorship should start at the time of cancer diagnosis. GA can play an important role in identifying potential survivorship issues and optimising delivery of survivorship care. A goal-directed, patient-focused geriatric survivorship care plan that involves a multidisciplinary team provides a framework for a personalised delivery of survivorship care in this patient group and there is a need for tailored interventions that support self-management and care integration. Research on the impact of cancer and its treatment on geriatric-specific outcomes needs to be prioritised through global initiatives to encompass a diverse and heterogenous population of adult cancer survivors.

Cardiovascular complications are the leading cause of death, and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2, and showed better endothelium-dependent relaxation. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.NEW & NOTEWORTHY We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.

Background: Concomitant use of proton pump inhibitors (PPIs) may negatively affect the efficacy of anticancer drugs such as fluoropyrimidines in patients with colorectal cancer (CRC). The primary objective of this study was to assess whether there is an association between concomitant PPI use and survival outcomes in patients with CRC treated with a fluoropyrimidine-based chemotherapy. Patients and Methods: A secondary analysis of 6 randomized controlled clinical trials in patients with advanced CRC was conducted using individual patient data through data-sharing platforms. The outcome measures were progression-free survival and overall survival in PPI users and nonusers. Subgroup analysis included the type of chemotherapy, capecitabine versus 5-FU, line of therapy, and addition of a vascular endothelial growth factor receptor inhibitor. Overall pooled hazard ratios (HRs) with 95% confidence intervals were calculated using a random effects model. Results: A total of 5,594 patients with advanced CRC across 6 trials and 11 trial arms were included; 902 patients were receiving a PPI at trial entry and initiation of chemotherapy. PPI use was significantly associated with worse overall survival (pooled HR, 1.20; 95% CI, 1.03–1.40; P=.02; I2 for heterogeneity = 69%) and progression-free survival (overall pooled HR, 1.20; 95% CI, 1.05–1.37; P=.009; I2 = 65%) after adjusting for clinical covariates. Furthermore, the association between concomitant PPI use and survival outcomes was similar across most treatment subgroups. Conclusions: We speculate that alterations in the gut microbiome, altered immune milieu within the tumor, and interactions through transporters are potential mechanisms behind this association between PPI use and chemotherapy in patients with CRC, which warrant further study. Concomitant use of PPIs is associated with worse survival outcomes in patients with CRC treated with fluoropyrimidine-based chemotherapy. Clinicians should cautiously consider the concomitant use of PPIs in such patients.

Background: A decrease in serum paraoxonase (PON-1) and arylesterase (ARE) activity has been reported in rheumatoid arthritis (RA) patients and linked to chronic inflammation and impaired antioxidant defense. Methods: A systematic review and meta-analysis were performed to critically appraise the current evidence on plasma/serum concentrations of PON-1 and ARE activity in RA patients and healthy controls. The Web of Science, PubMed, Scopus, and Google Scholar databases were searched from inception to November 2021. We used random-effects meta-analysis. The risk of bias was estimated using the Joanna Briggs Institute Critical Appraisal Checklist tool. The certainty of the evidence was assessed with GRADE. The study complied with the PRISMA statements and was registered in PROSPERO (CRD42022345380). Results: Seventeen studies reported PON-1 activity (1144 RA patients, 797 controls) and ten reported ARE activity (1367 RA patients, 1037 controls). RA patients had significantly lower PON-1 (SMD = −1.32, 95% CI −1.94 to −0.70; p < 0.001) and ARE activity (SMD = −0.91, 95% CI −1.37 to −0.46; p < 0.001). There was substantial heterogeneity (PON, I2 97%; ARE, 95.7%, p < 0.001 for both). There was no publication bias. The pooled SMD values did not significantly change after sensitivity analysis. The certainty of the evidence was very low due to the observational nature of the studies and the large heterogeneity. Conclusion: Our meta-analysis has shown that both serum PON-1 and ARE activity are significantly lower in RA patients, suggesting a deficit in antioxidant defense mechanisms in this disease.

Alterations in the volume of platelets (mean platelet volume, MPV; platelet distribution width, PDW) and erythrocytes (red blood cell distribution width, RDW) have been reported in rheumatoid arthritis (RA) and might serve as diagnostic biomarkers. We conducted a systematic review and meta-analysis of the MPV, PDW, and RDW in RA patients and healthy controls. Relevant articles were searched in PubMed, Web of Science, Scopus, and Google Scholar from inception to June 2022. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist and certainty of evidence was assessed using GRADE. In 23 studies (2194 RA patients and 1565 healthy controls), the RDW, but not MPV or PDW, was significantly higher in RA patients (standardized mean difference, SMD = 0.96, 95% CI 0.78 to 1.15, p < 0.001; moderate certainty of evidence). The substantial heterogeneity observed (I2 = 75.1%, p < 0.001) was virtually removed in a subgroup of prospective studies. In sensitivity analysis, the magnitude of the effect size was not substantially modified by sequentially removing individual studies. There was no significant publication bias. No significant associations were observed between the effect size and pre-defined study or patient characteristics. The results of our study suggest that the RDW might be a useful biomarker for the diagnosis of RA, and complement the clinical information provided by other patient characteristics and laboratory parameters (PROSPERO registration number: CRD42022349432).

Inflammatory indexes derived from routine haematological parameters, particularly the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), have been shown to discriminate between patients with and without rheumatoid arthritis (RA). However, their capacity to discriminate between RA patients with and without active disease has not been systematically appraised.We searched PubMed, Web of Science, Scopus and Google Scholar, from inception to June 2022, for studies comparing NLR and/or PLR values between RA patients with and without active disease. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively.In 18 studies (2122 RA patients with active disease, mean age 50 years, 20% males; 1071 RA patients with nonactive disease, mean age 50 years, 25% males), active disease was associated with significantly higher NLR (standard mean difference, SMD = 0.37, 95% CI 0.19 to 0.55, p .001; low certainty of evidence) and PLR values (SMD = 0.48, 95% CI 0.32 to 0.64, p .001; low certainty of evidence). In sensitivity analysis, the SMD values were not substantially influenced by sequentially removing individual studies. There was no publication bias. In meta-regression, the effect size was not associated with other study and patient characteristics, including sex, Disease Activity Score-28, C-reactive protein and erythrocyte sedimentation rate.NLR and PLR can significantly discriminate between RA patients with and without active disease. Further studies are required to determine their diagnostic performance, singly or in combination with other parameters, in routine practice.

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

There have been significant advances, particularly over the last 20 years, in the identification of non-coding RNAs (ncRNAs) and their pathophysiological role in a wide range of disease states, particularly cancer and other chronic conditions characterized by excess inflammation and oxidative stress such as atherosclerosis, diabetes, obesity, multiple sclerosis, osteoporosis, liver and lung fibrosis. Such discoveries have potential therapeutic implications as a better understanding of the molecular mechanisms underpinning the effects of ncRNAs on critical homeostatic control mechanisms and biochemical pathways might lead to the identification of novel druggable targets. In this context, increasing evidence suggests that several natural compounds can target ncRNAs at different levels and, consequently, influence processes involved in the onset and progression of disease states. The natural phenol resveratrol has been extensively studied for therapeutic purposes in view of its established anti-inflammatory and antioxidant effects, particularly in disease states such as cancer and cardiovascular disease that are associated with human aging. However, increasing in vitro and in vivo evidence also suggests that resveratrol can directly target various ncRNAs and that this mediates, at least in part, its potential therapeutic effects. This review critically appraises the available evidence regarding the resveratrol-mediated modulation of different ncRNAs in a wide range of disease states characterized by a pro-inflammatory state and oxidative stress, the potential therapeutic applications, and future research directions.

We sought to determine whether the increased risk of atrial fibrillation and stroke in rheumatoid arthritis (RA) can be accounted for by an increased prevalence of electrocardiographic markers of atrial myopathy.We retrospectively evaluated clinical and electrocardiographic data of 218 RA patients prospectively enrolled in the Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis study (EDRA study ClinicalTrials.gov: NCT02341066) and 109 controls matched by age and gender. The prevalence of interatrial blocks (IAB, partial - pIAB or advanced - aIAB), abnormal P-wave terminal force in lead V1 (aPtfV1) and atrial myopathy (electrocardiographically defined as the presence of 1) aIAB, or 2) pIAB plus abnormal aPtfV1) was assessed in each group. RA patients were followed-up for 5 years for incident atrial fibrillation and cardiovascular events.Barring the prevalence of hyperlipidaemia and obesity, the demographic characteristics and cardiovascular risk profile of RA patients and controls were comparable. All subjects enrolled in the study were free from previous cardiovascular disease and atrial fibrillation. Compared to controls, RA patients had longer P-wave duration (118±12 vs. 112±10 ms, p0.001) and higher prevalence of pIAB (43% vs. 21%, p0.001) and abnormal PtfV1 (27% vs. 10%, p0.001). Accordingly, atrial myopathy was significantly more prevalent (15% vs 4%, p=0.003) in RA patients. In multiple regression, male gender (OR [95% CI] = 3.09 [1.48-6.47], p=0.003) and RA (OR [95% CI] = 4.83 [1.58-14.73], p=0.006) were independently associated with atrial myopathy. Atrial myopathy was not significantly associated with incident atrial fibrillation or cardiovascular events in RA patients after 5 years of follow-up.Electrocardiographic markers of atrial myopathy are independently associated with RA. Further studies with larger sample size and longer follow-up are needed to determine whether the increased prevalence of atrial myopathy contributes to the increased risk of atrial fibrillation and stroke in this group.

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.

Although polysomnography is the gold standard method to diagnose obstructive sleep apnea syndrome (OSAS), there is an ongoing quest for simpler and relatively inexpensive biomarkers of disease presence and severity. To address this issue, we conducted a systematic review of the potential diagnostic role of the red blood cell distribution width (RDW), a routine hematological parameter of red blood cell volume variability, in OSAS. A total of 1478 articles were initially identified in the databases PubMed, Web of Science, Scopus, Embase, and Google Scholar, from their inception to February 2023, and 20 were selected for final analysis. The RDW was significantly higher in OSAS than in non-OSAS subjects (SMD = 0.44, 95% CI 0.20 to 0.67, p < 0.001; low certainty of evidence). In univariate meta-regression, the mean oxygen saturation (SpO2) was significantly associated with the effect size. No significant between-group differences were observed in subgroup analyses. Notably, in OSAS subjects, the RDW SMD progressively increased with disease severity. In conclusion, these results suggest that the RDW is a promising biomarker of OSAS (PROSPERO registration number: CRD42023398047).

The year 2020 was dominated by the COVID-19 pandemic, bringing with it unprecedented advancements in the fields of healthcare and therapeutic interventions as well as in vaccine and drug development. Nevertheless, several other advancements in various fields of medicine also deserve attention. Herein, the Senior Editors of Drugs in Context provide us with their expert opinion on the events of 2020 and what lies ahead in 2021.

Objectives Antihypertensives and cancer have a complex relationship. Among the antihypertensives, renin--angiotensin system inhibitors have strong immune modulatory activities that may affect immune check point inhibitors-related outcomes in cancer patients. We evaluated the association between concomitant use of renin--angiotensin system inhibitors and other antihypertensive agents with survival/toxicity outcomes from atezolizumab. Methods A post hoc analysis of individual patient data from seven clinical trials of lung, renal or urothelial cancers was performed. Users and nonusers of antihypertensive classes were compared for overall survival, progression-free survival and immune adverse events. Cox proportional hazards were calculated between the groups and reported as hazards ratio and 95% confidence interval (95% CI). Results Of the 3695 patients, 2539 were treated with atezolizumab and the rest with chemotherapy. Twenty-four percent of patients were on a renin--angiotensin system inhibitor at trial commencement. No statistically significant difference in overall survival (hazard ratio 0.92, 95% CI 0.79-1.07, P = 0.29), progression-free survival (hazard ratio 0.95, 95% CI 0.84-1.08, P = 0.42) or immune adverse events (odds ratio 0.94, 95% CI 0.76-1.15, P = 0.55) between renin--angiotensin system inhibitor users and nonusers were identified in the atezolizumab-treated cohort. Other classes of antihypertensives were also not associated with survival. Conclusion Concomitant use of antihypertensives including RASi was not associated with survival and immune-related safety outcomes during atezolizumab therapy for solid cancers. Future studies should evaluate the association between antihypertensives and other ICI as well as ICI combination interventions in clinical trials and real-world settings.

To summarize the main age-associated changes in drug metabolism and elimination and discuss their possible incorporation into personalised prescribing tools for the older patient population. There is currently limited knowledge regarding the impact of frailty, pharmacogenomics, drug–drug, drug–disease, and organ–organ interactions, on drug metabolism and elimination in the older population, particularly in subjects >80 years. However, easily measurable age-associated pharmacokinetic changes, particularly the reduced clearance of renally eliminated drugs, could be soon incorporated into personalised prescribing tools. Despite ongoing progress in the field, additional studies are required to justify the routine incorporation of data pertaining to drug metabolism and elimination into personalised prescribing tools for older patients. We discuss the known age-associated changes in drug metabolism and elimination, the potential use of this information when selecting specific therapeutic strategies in older patients, and the steps required to fill the knowledge gap in this field. We conducted a narrative review that encapsulates the current knowledge regarding the main age-associated changes in drug metabolism and elimination and discusses their possible inclusion in current and future personalised prescribing tools for the older patient population. Despite some progress in this field, the lack of specific information regarding the impact of frailty, pharmacogenomics, and drug–drug, drug–disease, and organ–organ interactions, particularly in subjects > 80 years, currently prevents the routine incorporation of pharmacokinetic data, barring measures of renal function, into personalised prescribing tools. The incorporation of pharmacokinetic data into personalised prescribing, an approach based on the consideration of a number of patient’s characteristics when selecting the right drug(s) and dose regimen(s) to maximize effectiveness and limit toxicity, remains a hypothetical construct in geriatric care. Pending the inclusion of frail and complex older patients in pre- and post-marketing studies, a better understanding of the key pharmacokinetic alterations of common medications in “real-life” patients, together with the implementation of effective strategies tackling inappropriate prescribing, is likely to improve clinical outcomes and reduce healthcare utilization in the older population.

OBJECTIVE While the global prevalence of antibiotic-resistant Helicobacter pylori (H. pylori) is increasing, there is much regional variation, and local data are required to guide eradication therapy. We performed a systematic review and meta-analysis to determine rates of H. pylori antibiotic resistance in Australia and New Zealand. STUDY DESIGN Random effects meta-analysis of data from 15 published studies and three published abstracts reporting prevalence of primary or secondary H. pylori antibiotic resistance in Australasia. DATA SOURCES PubMed, EMBASE, MEDLINE, PROSPERO, and the Cochrane Library were searched until August, 2020. DATA SYNTHESIS Fifteen published studies and three published abstracts were identified; one study was excluded due to high risk of bias. Seventeen studies conducted between 1996 and 2013 were included in the final analysis, 12 reporting primary and five reporting secondary antibiotic resistance. Prevalence of primary resistance was clarithromycin 7.4% (95% confidence interval [CI], 5.3-9.7%), metronidazole 50.0% (95%CI, 23.9-56.1%), fluoroquinolones 3.7% (95%CI, 0.004-14.8%), and both amoxicillin and tetracycline

SARS-CoV-2 is the agent responsible for the coronavirus disease (COVID-19), which has been declared a pandemic by the World Health Organization. The clinical evolution of COVID-19 ranges from asymptomatic infection to death. Older people and patients with underlying medical conditions, particularly diabetes, cardiovascular and chronic respiratory diseases are more susceptible to develop severe forms of COVID-19. Significant endothelial damage has been reported in COVID-19 and growing evidence supports the key pathophysiological role of this alteration in the onset and the progression of the disease. In particular, the impaired vascular homeostasis secondary to the structural and functional damage of the endothelium and its main component, the endothelial cells, contributes to the systemic proinflammatory state and the multiorgan involvement observed in COVID-19 patients. This review summarizes the current evidence supporting the proposition that the endothelium is a key target of SARS-CoV-2, with a focus on the molecular mechanisms involved in the interaction between SARS-CoV-2 and endothelial cells.