Background: Since the efficacy of ranibizumab (RBZ), bevacizumab (BVZ) and aflibercept (AFB) is comparable in neovascular age-related macular degeneration (AMD), we conducted a systematic review and meta-analysis to evaluate the long-term safety profiles of these agents, including ocular safety. Methods: Systematic review identifying randomized controlled trials (RCTs) comparing RBZ, BVZ and AFB directly published before March 2019. Serious ocular adverse events (SOAE) of special interest were endophthalmitis, pseudo-endophthalmitis, retinal pigment epithelium tear and newly identified macular atrophy. Results: Thirteen RCTs selected for meta-analysis : 10 compared RBZ vs. BVZ and three RBZ vs. AFB. There were no significant differences in almost all adverse events (systemic and ocular) between BVZ, RBZ and AFB in up to two years’ follow-up. Macular atrophy was reported heterogeneously and not reported as SOAE in most trials. Conclusions: Direct comparison of RBZ, BVZ and AFB safety profiles in the RCT network meta-analytical setting have not revealed a consistent benefit of these three commonly used anti-vascular endothelial growth factor (anti-VEGF) agents in AMD. Network model ranking highlighted potential benefits of RBZ in terms of a systemic safety profile; however, this appears a hypothesis rather than a conclusion. Newly identified macular atrophy is underestimated in RCTs—future real-world data should be focused on SOAE. Age-related macular degeneration (AMD) is the leading cause of visual disability among patients over 60 years. The most prevalent major advanced form of the disease, the “dry” (atrophic) form, is characterized by a slow, progressive dysfunction of the retinal pigment epithelium, photoreceptor loss and retinal degeneration; on the contrary, the “wet” (neovascular) form is less frequent but responsible for 90% of acute blindness due to AMD . Wet AMDwww.aao.org available data). Appropriate drug use, even off-label use, is always a doctor’s decision, unless a specific law in some country limits the off-label prescription. In this context, the intraocular off-label use of BVZ is probably driven by the cost and not by clinical benefit [Even though the pharmacological targets of these three drugs is the same, the structures are different; therefore, the mechanism of action and the pharmacokinetics profile may differ ,5, with  benefit .As regards the efficacy, there are a several randomized controlled trials (RCT) studies and meta-analyses collecting the results of these three agents showing benefit over sham injections. No significant difference is revealed in terms of impact on visual acuity in neovascular age-related macular degeneration (nAMD), though the number of injections needed to achieve these clinical effects was reported lower for AFB. For instance, in nAMD , AFB andRecently, a review compared the effectiveness and safety of these three anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods  with no This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for meta-analyses  checklist, Study search was conducted using PubMed, Excerpta Medica data BASE ), and the Cochrane Library from their inception until 1 July 2018. Available systematic reviews were also analyzed to double-check comprehensiveness of the search conducted de novo. Search terms embracing all PICOTS (patient-intervention-comparison-outcome-timing-setting/study design) aspects were developed to construct the optimal search strategy and identify patients diagnosed with AMD and treated with BVZ, RBZ or AFB in direct comparative head-to-head trials. Included trials are provided in Search results were consolidated with all relevant abstracts screened and selected independently by two reviewers (A.A.P. and K.M.S.). In case of any uncertainty, full texts were additionally screened. Then, full-text manuscripts of preselected abstracts were retrieved and assessed based on eligibility criteria. All discrepancies in expert assessments were clarified in discussion. Reasons for study exclusions were aggregated and presented below .Additional note: During our work, unpublished Intravitreal Aflibercept for Neovascular Polypoidal Choroidal Vasculopathy clinical trial (RIVAL) study (NCT02092532) data on macular atrophy events became available, so we included it into the analysis as well.(P) Study population: patients diagnosed with neovascular AMD(I) Interventions of interest: intravitreal BVZ, RBZ or AFB(C) Treatment comparisons: BVZ, RBZ and AFB(O) Outcomes of interest: any safety data reported (T) Minimal follow-up period: 1 year(S) Studies were designed as RCTs. Studies published in English were eligible for inclusion in the review. Only studies that provided sufficient data of safety outcomes with at least 1-year follow-up and compared the safety of the following interventions: 1.25 mg BVZ or 0.5 mg RBZ monthly, as needed (pro re nata) or a treat-and-extend regimen, 2 mg AFB every 2 months or treat-and-extend regimen after 3 initial monthly doses (2q8), were included for network meta-analysis (NMA).Criteria of study inclusion in this systematic review were developed and defined as follows (PICOTS approach):Secondary analysis studies, reviews, were excluded. Studies on macular dystrophy/neovascularization of any other origin and studies with no control, sham control or active control other than BVZ, RBZ, AFB were excluded as well.Authors, year of publication, baseline characteristics of included studies and outcomes of interest were independently extracted by two reviewers (A.A.P. and K.M.S.). Any disagreement was resolved by discussion. We also contacted study sponsors and authors of the articles to request full information we were interested in.Primary outcomes were the (1) proportion of dead patients; (2) patients having experienced at least one serious systemic event; (3) at least one cardiovascular event: (3a) atherothrombotic event or (3b) venous thrombotic event and (4) at least one serious ocular event: (4a) endophthalmitis, (4b) pseudo-endophthalmitis, (4c) retinal epithelium tear or (4d) macular atrophy during follow-up.Two authors independently assessed and reported the methodological risk of bias of the included studies using the relevant Cochrane collaboration’s tool, assessing randomized trials according to the following domains of potential bias: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported result and overall bias . Systemip-values less than 0.05 were considered as statistically significant. Fixed effects and random effects meta-analytical model of Mantel-Haenszel was performed (based on incidence rate ratio) with a DerSimonian-Laird estimator for tau2 in frame of the R package “metaphor” (Viechtbauer 2010) for meta-analysis. Graph-theoretical method was applied for network meta-analysis using “netmeta” R package  [Mortality rate and other adverse events were presented as frequencies and percentages. We contacted sponsors or authors for providing aggregated data when data were not reported. Results of quantitative pair-wise analysis was presented using forest plots. R studio software (version 1.1.453) was used to perform meta-analysis and all statistical procedures. A two-sided test with pproach) . Trials pproach) . Only neWe planned to conduct sensitivity analyses to assess the impact of studies graded as having a high risk of bias on any parameter, unpublished data only or based on withdrawal rate. After assessing the data collected, we determined these analyses were not needed, since we did not identify highly heterogenous data that were worth a special quantitative analysis.Study selection flow chart of this systematic review is reported in Basic characteristics of the RCT included and the safety data availability there are given in the Details on the risk of bias assessment are presented as p = 0.035 in the pair-wise meta-analytical model). No relevant heterogeneity was identified among these trials , as also shown in a funnel plot in Since RIVAL data were not published fully when performing this meta-analysis, we included all available safety data regarding this pair-wise comparison based on VIEW1,2 studies, plus those received from a RIVAL study sponsor. Heterogeneity was suspected in newly identified atrophy between these two studies in spite of the fact that, formally, it was insignificant as per appropriate statistics , RBZ seems to have the potential of being superior over BVZ and AFB in terms of general surrogate safety parameters (dropout and death), over AFL in terms of CVD death and over BVZ in terms of systemic SAE ; however, qualitatively, we consider these data as heterogeneous. Other endpoints were considered homogenous.Besides the significant difference between RBZ and BVZ in the systemic SAE rate, no other significant difference was revealed in any BVZ vs. RBZ, RBZ vs. AFB or RBZ vs. AFB comparisons. Venous thrombotic events and pseudo-endophthalmitis events were not included in the network meta-analytic model, being available only in the RBZ vs. BVZ comparison. Cardiovascular diseases (CVD) death in the RBZ vs. AFB comparison was near the significance borderline. Considering the emic SAE . HeterogRBZ and AFB are commonly anti-VEGF drugs used in clinical practice to manage AMD. At the same time, other treatment off-label options are available, such as BVZ, this latter likely due also to cost. BVZ is the most commonly used option alternative to on-label anti-VEGF drugs. Even though these drugs  have the same pharmacological target, they have not the same structure and are not equivalent. It is noteworthy that the AFB/VEGFA complex is characterized by electrostatic stabilization with a high association rate and high stabilizing electrostatic energy, whereas RBZ and BVZ complexes were stabilized by Van der Waals energy term . RBZ is p = 0.035 in pair-wise RBZ vs. BVZ meta-analytical model) is mostly due to the The Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT2) study, and it is supposed to be related to different pharmacokinetics profiles. Noteworthy, recent pharmacokinetic (PK) clinical studies carried out in humans are in accordance with pre-clinical data. Thus, in 2014, Avery et al. published comparative PK data showing that systemic exposure to AFB after intravitreal injection was nine-fold higher than in RBZ, and for BVZ, this parameter was much more—35-fold higher than that in RBZ [p = 0.052). RIVAL study changed almost nothing in terms of this endpoint, since there were no CVD deaths registered. So, in the meta-analytical random effect model, the CVD death rate difference was still insignificant with p = 0.0625 . An interesting finding is that, in the RIVAL study, AFL was associated with 2.03 higher death incidences than RBZ; however, this difference was insignificant as well. Moreover, the AFB group ratio of subjects with atherothromboembolic anamnesis was 1.7 higher than in the RBZ group (18.0% vs. 10.6%), though considered as insignificant . Since no CVD death was reported, it is impossible to explain the overall death difference by atherothrombotic anamnesis adjustment. This probably will be reflected in RIVAL publications or may be considered statistically accidental.Systemic adverse events that proved to be significantly higher in BVZ than in RBZ ; BVZ 26 events/1000 people-year  and AFB 20 events/people-year . To have a significant difference in a setting with n = 500 in one trial, the difference should be at least 20 vs. 40 events, which means twice, not 1.5,-fold difference (Fisher’s exact test). Since some trials did not report a total ocular SAE number (LUCAS2 and BRAMD) or reported zero (Biswas and MANTA), our analysis is not comprehensive .Streptococcus species, which comprise more than 40% of culturable adult salivary flora [p = 0.03, Fisher’s exact test); in huge datasets, it was shown that there is no significant difference in endophthalmitis among RBZ, BVZ and AFB [Endophthalmitis does not seem to be associated to specific anti-VEGF treatments, whereas noncompliance with recognized hygiene standards and poor aseptic techniques are accounted responsible for the endophthalmitis outbreaks reported. Even such simple measurements as masks and silence are proven to be truly important, especially taking into account that, usually, the cause of endophthalmitis after intravitreal injections turns out to be a ry flora ,23. Our ry flora . Etiologry flora . However and AFB .When it comes to pigment epithelium tears, there have been a large number of reports describing this complication after intravitreal BVZ, RBZ and AFB therapy, almost always in eyes with vascularized pigment epithelial detachments (PED) and neovascular AMD. The pathogenesis of RPE tear formations continues to remain controversial; at the same time, it seems to be related to the size of the presenting PED at the baseline, stress on the RPE and the anti-VEGF treatment . This coFinally, macular atrophy is reported in RCT rarely, and this is probably the most intricating adverse event. First of all, it is critical from a clinical point of view. Secondly, atrophy developed de novo may be considered as a direct consequence of the anti-VEGF treatment and transforming wet AMD into dry . SurprisOnly the three-most common anti-VEGF treatments were included; no pegaptanib, no ziv-AFB or additional compounds that may be co-administrated with anti-VEGF molecules were included . Only AMD was under investigation without DME and RVO. Monthly and treat-to-extent regimens were aggregated and analyzed together, presuming a comparable safety profile of these treatment regimens. Sample size limitation of n = 50 per group led to a Subramanian study exclusion, which, however, does not seem to influence the results, since no systemic or ocular serious adverse events were reported in one year . No switOnly direct comparisons were considered to avoid heterogeneity and the cumulative incidence rate design of the analysis without dividing the results per years of follow-up. All zero event arms were included; new RIVAL data was included. The p-score network ranking was provided, and both random and fixed effects models were reported.Based on available direct comparative RCTs of RBZ, AFB and BVZ, it may be concluded that RBZ appears to have some benefits in terms of systemic adverse events, whereas in terms of ocular adverse events, no statement regarding the superiority of any of these three agents may be provided. At the same time, since the available studies were underpowered to figure out the safety difference, especially rare ocular adverse events, the former statement regarding systemic adverse events should be taken as a hypothesis for further studies, whereas no difference in ocular adverse events means only that insufficient data are available so far to draw a final conclusion. Therefore, both systemic and ocular safety profiles of anti-VEGF agents should be further evaluated in large-scale real-world data studies.


A 46-year-old man with hypertension and diabetes was admitted to the emergency departmentwith one day of left-sided weakness, mainly in the lower limb. He additionally reported painand weakness in the right hand, with impaired wrist and finger movements, as well as bluishdiscoloration and coolness to touch. The patient reported a dry cough and headache associatedwith anosmia for about 1 week.2 99% on room air).Facial inspection demonstrated slight erasure of the nasolabial groove on the left, as well asdifficulty in keeping the left eye closed, and loss of muscle strength in the left upper andlower limbs. The right limb demonstrated cyanotic and cool fingers with distal necrosis of thefourth right finger. The right radial pulse was not palpable; there was slow capillary fillingtime in the right hand.Upon physical examination, the patient was in no acute distress, hypertensive (160/70 mmHg),tachycardic (137 bpm), and eupneic  demonstrated sparse ground-glass opacities in both lungs,notably in the periphery :arrows,A non-contrast head CT demonstrated a cortico-subcortical hypodensity in the righttemporoparietal region :arrows,CT angiography of the right upper limb showed a filling defect in the distal brachial artery: arrows,Therapeutic anticoagulation and limb heating were initiated to limit ischemic injury asadvised by our vascular surgery colleagues. Antibiotics and corticosteroids were additionallyadded. The patient stabilized over the course of his hospital stay and was discharged withoutpatient follow-up.2 and elevatedD-dimer levels have been associated with increased mortality.3 The case reported shows a young patient, with no history of previous coagulopathy, whopresented with acute cerebral ischemia and artery occlusion of the right arm associated withCOVID-19, with important clinical repercussions, corroborating the prothrombotic effectassociated with the SARS-CoV-2 infection.Abnormal coagulation parameters have been reported in hospitalized patients with severecoronavirus disease (COVID-19)Vascular Medicine.Readers may submit original, unpublished images related to clinical vascular medicine.Submissions may be sent to: Heather Gornik, Editor in Chief, VascularMedicine, via the web-based submission system at http://mc.manuscriptcentral.com/vascular-medicine‘Images in vascular medicine’ is a regular feature of


In recent years, Function Focused Care (FFC) interventions have been developed and implemented in Dutch home care, nursing homes and acute care. These interventions aimed to train nursing staff to adapt their level of support to the capabilities of elderly and to maintain/optimize their self-reliance and physical functioning. After synthesizing knowledge and experiences from the existing FFC-interventions, an advanced FFC-intervention was developed for application in long-term care: ‘SELF’. SELF comprises seven interactive sessions, is theoretically grounded, primarily focuses on behavior change in nursing staff, is tailored to the ward’s needs, is multidisciplinary in nature, and focuses on all care interactions. Currently, SELF is pilot-tested in one psycho-geriatric ward with 17 nursing staff members. Questionnaires on outcome-expectations, self-efficacy and intention to stimulate elderly are assessed at baseline and after 3 months. Field notes and interviews are used to assess its feasibility and acceptability. Experiences will guide the further refinement of ‘SELF’. Part of a symposium sponsored by Nursing Care of Older Adults Interest Group.


Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the world. More than half of all CRC patients will eventually develop metastases and require treatment accordingly, but few validated predictive factors for response to systemic treatments exist. In order to ascertain which patients benefit from specific treatments, there is a strong need for new and reliable biomarkers. We conducted a comprehensive search using the PUBMED database, up to December 2019, in order to identify relevant studies on predictive biomarkers for treatment response in metastatic CRC. We will herein present the currently used and potential biomarkers for treatment response and bring up-to-date knowledge on the role of circulating microRNAs, associated with chemotherapy and targeted therapy regimens used in metastatic CRC treatment. Molecular, tumor-related, disease-related, clinical, and laboratory predictive markers for treatment response were identified, mostly proposed, with few validated. Several circulating microRNAs have already proven their role of prediction for treatment response in CRC, but future clinical studies are needed to confirm their role as biomarkers across large cohorts of patients. Colorectal cancer (CRC) represents a major public health concern as it is the third most frequently diagnosed cancer and the fourth cause of cancer-related mortality worldwide . The fivNevertheless, the potential of minimally-invasive biomarkers, such as those from blood, is still not validated. Due to their crucial role in cancer progression, but also to their high stability in blood, microRNAs (miRNAs) have shown great potential as new biomarkers for cancer detection, prognosis, and treatment response . Much reOur work intends to answer one of the questions asked by any clinician involved in the management of mCRC patients: what biomarkers of efficacy of systemic treatments are currently available and what are the perspectives for future development in this field, with focus on circulating miRNAs. Other well-documented works on this subject are available, such as the review article published by Taieb et al.,  that covThis article aimed to present up-to-date information concerning the current predictive factors for systemic therapy response in mCRC and the role of circulating miRNAs as predictors for response to systemic therapy in CRC, but also information about the miRNAs’ challenges in therapeutic use.https://www.ncbi.nlm.nih.gov/pubmed/) database, in order to identify relevant studies published up to December 2019, using Medical Subject Headings (MeSH) and keywords. Firstly, different string searches were performed to identify current predictive markers of response to both chemotherapy regimens and targeted treatments considered standard treatment for mCRC; we only included studies performed in stage IV disease. Secondly, we performed a search of circulating miRNAs with predictive value for treatment response in CRC; we included studies regardless the stage of the disease, due to limited research studies for stage IV-only in this area. Search terms were: metastatic colorectal cancer, mCRC, advanced colorectal cancer, colorectal cancer, prediction, efficacy, response, resistance, biomarkers, chemotherapy, targeted treatment, immunotherapy, systemic treatment, 5-Fluorouracil, Capecitabine, Oxaliplatin, Irinotecan, trifluridine/tipiracil, Bevacizumab, anti-EGFRs, Cetuximab, Panitumumab, Aflibercept, Ramucirumab, Regorafenib, Larotrectinib/Entrectinib, Pembrolizumab, Nivolumab, Ipilimumab, circulating miRNAs, serum miRNAs, plasma miRNAs, whole blood miRNAs, exosomes. We also checked the references of the selected studies in order to further identify papers of interest.We conducted a literature search on the PUBMED , capecitabine), Oxaliplatin, Irinotecan and Trifluridine/tipiracil, the latter only in case of refractory disease. 5-FU can be delivered with either Oxaliplatin or Irinotecan, a combination of both or administered as monotherapy in selected patients. Pivotal studies in mCRC treatment have shown that, while mono-chemotherapy with fluoropyrimidines  offered response rates (RR) of approximately 20–25% and a median OS of 12 months, by adding a second agent, such as Irinotecan or Oxaliplatin, a doubled RR, and a prolonged survival rate are achieved ,8. HowevThe sequential administration of combined regimens based on 5-FU + Irinotecan (FOLFIRI) followed by 5-FU + Oxaliplatin (FOLFOX) or vice versa, leads to a median survival of 21 months . HoweverTargeted therapies approved and most commonly used in mCRC are the epidermal growth factor receptors (EGFR) inhibitors in Rast Sarcoma RAS genes wild-type disease: Cetuximab, Panitumumab, the antiangiogenics: Bevacizumab, Aflibercept, Ramucirumab, Regorafenib. Larotrectinib or Entrectinib are indicated in any refractory, solid tumor that exhibits a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Immunotherapy in mCRC is approved in the US, but not in Europe and is recommended in microsatellite instability high (MSI-H) refractory tumors.The determinants in choosing the type and sequence of treatments in stage IV disease are related to patient , disease  and therapy itself , guidelines and approvals. Considering these, it has become more and more evident that an improvement of the therapy outcome has to be based on personalized features, including current approaches, but also new, specific biomarkers.We will present herein the up to date information about the known validated and potential markers related to general treatment efficacy in metastatic disease, but also for each chemotherapy, targeted treatment drug and immunotherapy , considePrevious data pointed out that there is no consistent data to support the advanced age, male sex, and high body mass index as negative predictive factors . Regardi9/L), high platelets (≥400 × 109/L), low hemoglobin (<11 g/dL), high alkaline phosphatase (>300 U/L) were associated with worse responses.5-FU inhibits the thymidylate synthase (TS), a crucial enzyme for DNA synthesis. An adequate inhibition of TS leads to chemosensitivity to 5-FU, while high TS levels and/or its gene polymorphisms (TSER*3/TSER*3) may be involved in 5-FU resistance, but its use is not recommended in clinical practice . SeveralCapecitabine is a 5-FU prodrug. Low levels of TS or certain TS promotor polymorphisms (homozygous for the genotype S/S versus S/L or L/L) , as wellIrinotecan exerts a cytotoxic action by inhibiting type 1 topoisomerase (TOPO 1). High gene expression of TOPO 1 enhances the response to Irinotecan and may be a predictor of Irinotecan responsiveness, as a biomarker analysis on 1313 people enrolled in the FOCUS trial showed . Freyer Oxaliplatin (L-OHP) exerts synergistic effects with fluoropyrimidines and has shown a wide range of RR of 28–65% in the metastatic setting, either in first- or second- line settings. DNA excision repair protein 1 (ERCC-1), ERCC-2 gene polymorphisms, X-ray repair cross-complementing protein 1 (XRCC-1) polymorphisms seem to be associated with tumor response. Amongst these, the most studied is ERCC-1: high level of its expression is predictive of a poor response to Oxaliplatin chemotherapy, but this still needs to be validated in prospective clinical trials . AccordiTrifluridin/tipiracil is an oral combination drug approved in 2015 in the US and in 2016 in the EU as a third- or fourth-line treatment of mCRC. There are currently no validated biomarkers for response prediction to this drug, although it was suggested that neutropenia after first administration could be an indicator of response .: About 40%–80% of CRC tumors present an over-expression of the EGFR [Monoclonal Antibody Therapies Targeting EGFR the EGFR . Clinicathe EGFR . Responsthe EGFR . They arthe EGFR .Currently validated biomarkers of efficacy are: RAS gene mutational status  and tumor sidedness  and leftBRAF mutations (V600E in the vast majority of cases) are present in up to 8%–12% of mCRC patients and in two-thirds of the cases the tumors are located on the right side of the colon. The BRAF mutation in mCRC implies a significantly negative prognosis , but not(KRAS), Erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) exon 20 mutation, alteration of phosphatase and tensin homolog (PTEN) [Other proposed positive predictive factors for response to EGFR inhibitors are the development of skin toxicity during the treatment and hypomagnesemia . Proposeg (PTEN) , increasg (PTEN) , amphireg (PTEN) .Bevacizumab: There are no validated predictive biomarkers for Bevacizumab efficacy . The potAflibercept is an antiangiogenic drug approved for administration in combination with FOLFIRI chemotherapy, after disease progression under first-line Oxaliplatin-based treatment in mCRC. An analysis of patients included in the phase II AFFIRM clinical trial showed that elevated baseline plasmatic levels of IL-8 and subsequent increases during the treatment were associated with worse PFS in patients treated with mFOLFOX6 + Aflibercept in first-line treatment of mCRC .Ramucirumab is a VEGFR2 - binding monoclonal antibody used in second-line treatment of mCRC that improves both PFS and OS, in combination with FOLFIRI. Data related to biomarker results in the RAISE study were available for 894 patients and showed that a high plasma level of VEGFD (>115 pg/mL) is a potential predictive biomarker for treatment response .Regorafenib is an antiangiogenic multi-kinase inhibitor used in mCRC for refractory tumors, that inhibits the VEGFR2-TIE2 tyrosine kinase pathway. There are not yet validated markers to predict tumor response to this drug. However, hand-foot skin reaction and lung nodule cavitation have been recently reported as potential clinical biomarkers for treatment response .Larotrectinib and Entrectinib are targeted therapies approved for the treatment of refractory advanced or metastatic solid tumors, including CRC, that exhibit a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, without other treatment options. The NTRK gene fusions are present in approximately 0.2% to 1% of CRC . No predImmunotherapy: Pembrolizumab and the combination of Nivolumab + Ipilimumab are FDA-approved in progressive unresectable/metastatic colorectal cancer displaying MSI-H status or deficient mismatch repair genes (dMMR) without other valid treatment options. A clinical study on Pembrolizumab showed that MMR tumors were associated with immune-related RR of 40% and six-months PFS of 78%, while proficient MMR showed RR of 0% and six-months PFS of 11% .MiRNAs are small, non-coding RNAs of 18–24 nucleotides that play a crucial role in controlling gene expression at the post-transcriptional level. However, in cancers, due to alteration of their levels, miRNAs are involved in and influence the majority of cancer hallmarks . DependiRegarding their biogenesis, miRNAs are firstly transcribed and preprocessed in the nucleus, then exported to the cytoplasm where are processed to mature miRNAs in association with RISC (RNA-induced silencing complex). Functionally mature miRNAs bind complementary regions of mRNA targets, inducing either inhibition of translation or mRNA degradation. While the majority of miRNAs are identified in the cellular environment, there are many miRNAs identified both in the tumor microenvironment and blood (serum and plasma), including exosomes .One of the most significant advantages of circulating extracellular miRNAs as biomarkers is due to their high stability during blood processing, providing reliable molecular data even from a low volume of serum/plasma or a reduced number of exosomes.Increasing evidence has suggested that both tissular and cell-free miRNAs represent useful tools for cancer management even if future multicenter studies still have to validate their role as tumor biomarkers before being implemented in clinical practice. In a previous study, Dong et al.  investigMoreover, this study was extended on a different set of 116 mCRC patients that received first-line 5-FU based chemotherapy, to explore the tissue levels of miR-429 with regards to chemotherapy response according to Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) criteria. Their data showed that the responders  had significantly lower levels of miR-429, with no differences between the type of 5 FU-based protocol administered  than non-responders (stable disease + progressive disease). Furthermore, on multivariate analysis, miR-429 was an independent prognostic factor for 5-FU-based first-line chemotherapy response. ROC-curve analysis revealed an area under the curve (AUC) for miR-429 of 0.721 (95% CI: 0.630–0.800) while the diagnostic sensitivity and specificity were 52.70% and 85.71%, respectively, certifying that miR-429 can be associated with 5-FU-based chemotherapy response.in vivo.In another study, Ren D et al.  tested tIn an attempt to identify CRC serum miRNA-based biomarkers, Qin Y et al. , performn = 41) compared to healthy subjects (n = 10), meaning that its plasmatic levels can be considered as noninvasive biomarkers of diagnosis and possible for drug resistance.Previous studies have shown that miR-143 is downregulated in cancer. Qian X et al. , tested In the same direction, miR-378 has been reported to be frequently downregulated in both CRC tissues and cell lines, but with discordant, elevated serum levels. In this regard, Wang et al. , tested st line FOLFOX in advanced CRC patients. The patients were separated depending on their response to the FOLFOX regimen: complete response, partial response, stable disease, and progressive disease. A miRNAs microarray assessment on eight serum samples from the response phase and eight from the resistance phase patients revealed 62 statistically different expressed miRNAs. Five out of these miRNAs  had a minimum 4.5-fold expression and were selected for validation in a larger population, included 36 response-phase patients and 36 resistance-phase patients. The validation data showed that the expression of serum miR-19a was significantly upregulated in the resistance phase versus the response phase, with no significant differential expression in the other four miRs . However, no significant differences were identified between the intrinsic resistance  and acquired resistance .The association of miRNAs predictive response with FOLFOX and FOLFIRI regimens has been also investigated. In this way, Chen Q et al. , evaluatP = 0.001); low miR-4772-3p and high CEA, but not tumor size, were significantly related to a higher risk of death. The only significant difference between the recurrence rates and miR-4772-3p was seen in stage III patients that received adjuvant FOLFOX: patients with low miR-4772-3p had higher recurrence rates than patients with high miR-4772-3p. The authors concluded that miR-4772-3p may serve as a biomarker for predicting tumor response to adjuvant FOLFOX chemotherapy, but it was unclear if it was a real predictive biomarker for chemo response or only a prognostic marker for tumor recurrence.The prognostic and predictive value of serum exosomal miRNAs on the clinical outcome of stage II-III CRC patients treated with adjuvant chemotherapy was investigated by Liu et al. . They inIn another approach, Kjersem et al.  tested tZhang et al. , also evn = 6), the levels of miR-155 were maintained low in responders while in non-responders were significantly elevated when compared to miR-200c and miR-210. The authors concluded that a new increasing or a sustained increase of post-therapy miR-155 serum levels predict chemoresistance, while elevated levels or re-elevation of miR-155, miR-200c and miR-210 witness about disease recurrence and represent a negative prognostic factor. Maintaining the same line, Shivapurkar et al. [st line treatment in this setting. Following an exploratory screening test including 380 serum miRNAs, miR-296 proved to have a significant correlation with patients’ clinical outcomes. Eight patients were included; one had an undetectable baseline and after therapy levels of miR-296, so only seven were considered for the analyses. Patients whose levels of miR-296 decreased had a lower OS and unfavorable clinical outcomes compared to the patients with an increase in serum miR-296 and opposite clinical outcomes. The expression of miR-296 is progressively lost during tumor progression and it correlates with evolution to metastatic disease. Such as the patients with a low serum level of microRNA after four weeks represented a tumor type with a more aggressive phenotype and higher potential of invasion and metastasis.In another study, Chen J et al.  wanted tr et al.  exploredIn order to identify whole blood miRs with prognostic value in mCRC, Schou et al.  performep < 0.0001). Taking into account their previous results, Hansen et al. [Exploring the miRNAs targeting endothelial cells, it was also of interest to identify predictive markers for chemotherapy response in CRC. MiR-126 is expressed in endothelial cells and is essential in maintaining the integrity of blood vessels. MiR-126 is a tumor suppressor miRNA, usually downregulated in cancer. It targets VEGF-A, but also EGFL7 which is upregulated in sites with pathological angiogenesis. In a study performed in 2012, Hansen et al.  showed tn et al. , performp = 0.0001). On the other hand, patients with decreasing miR-126 levels during chemotherapy had a marginally significantly better PFS (p = 0.07).Furthermore, Hansen’s group continued their research  and analUlivi and colleagues  also anaPrevious studies showed that miR-34a was down-regulated in multiple malignant tumors, CRC included. Sun et al.  investigmicroRNA-608 rs 4919510 was associated with a higher risk of disease recurrence and death, while microRNA-219 rs 213210 was associated with increased risk of death in patients with stage III disease treated with 5FU-based adjuvant chemotherapy. Furthermore, patients carrying both variant genotypes of these two SNPs had a 5.6-fold increased risk of death. Based on Lin et al.’s research, Pardini et al. [Alteration of miRNA expression in CRC, through the prism of single nucleotide polymorphisms (SNPs), was evaluated by Lin et al.  on 1097 i et al.  studied Polymorphisms of the miRNAs’ precursors alter either the expression of the miRNAs, its binding complementarities to mRNA targets, or both possibilities. Chen et al.  studied Extracellular miRNAs have two main sources: the miRNAs that cofractionate with Agonaut2 (Ago2) protein complexes which are thought to originate mainly from dead cells and the miRNAs that are released through extracellular vesicles (EV), mainly from viable cells and engaged in intracellular communication . The autA summary of all studies presented above, regarding the potential predictive role of miRNAs is provided in Firstly, there are not enough clinical studies to draw a robust conclusion on the role of miRNAs as biomarkers in CRC. The majority of the above-presented studies confirmed the diagnostic and/or prognostic role of specific miRNAs in CRC patients on tissues or blood/serum/plasma, but most of the studies of prediction were performed on in vitro and in vivo models. There is, however, a limited number of studies that tested the chemo-prediction potential of miRNAs in patients that had response evaluations by radiological assays and the clinical response was correlated with the baseline level of a specific circulating miRNA or with dynamic changes in the levels of circulating miRNAs during systemic treatment.Considering the role of miRNAs as modulators of protein-coding genes, suppressing the oncogenic miRNAs or substituting the tumor-suppressor-deficient miRNAs represents the premises of research centered on introducing miRNA-based cancer treatments so that benefits are drawn not only from their diagnostic, prognostic and predictive value but also from modulating their activities in order to achieve antitumor activity at reduced costs and possibly with no adverse events. Current anticancer treatments are mainly involved in antiproliferative and proapoptotic pathways or modulate the immune responses generated by the presence of the tumors. The tumor phenotype can be controlled by modulating microRNAs expressions and this can be the basis of new successful approaches in cancer therapy .There are several therapeutic approaches based on miRNA modulation and various ways to use the miRNA therapeutics, the vast majority being validated so far only by in vitro and in vivo studies. Firstly, the miRNA inhibitors oriented towards the oncogenic miRNAs: complementary single-stranded oligonucleotides that form, by binding to the miRNA, an unknown conformation leading to miRNA’s exclusion from the RISC complex where the miRNAs are typically processed; among the miRNA inhibitors, we mention AMOs (antisense antimiR oligonucleotides), LNAs (locked nucleic acids), antagomiRs, antimiRs, miRNA sponges, microRNA masks. Secondly, the miRNA mimetic agents (miRNA mimics), that use synthetic miRNA-like molecules that replace or substitute the lost tumor suppressor miRNA and can be loaded into the RISC complex and function as a miRNA, inhibiting the target mRNA. Besides the two mentioned above, the SMIRs  inhibit miRNAs biogenesis or interfere between miRNAs and their targets. A big challenge is to inhibit tumoral miRNAs’ and exosomes’ secretion, therefore suppressing the interaction between the tumor microenvironment’s components: cancer cells, immune cells, etc, as it is well known that miRNAs are transported through extracellular vesicles either between different cell types within the tumor microenvironment or from the primary tumor to metastatic sites .Epithelial to mesenchymal transition (EMT) is a biological process by which epithelial cells lose their intercellular adhesions, gain migratory and invasive capabilities, become mesenchymal cells and so, they enter the metastatic cascade, which is coordinated by multiple signaling pathways. MiRNAs are among the most important regulators of the EMT and so, they may become critical therapeutic agents to block EMT and, therefore, invasion and metastasis . MiR-625Despite the promising in vitro and in vivo results of the miRNA therapeutics, many challenges and questions need accurate answers that lack when it comes to the mechanisms that trigger miRNAs’ regulation and most of these are probably to be found in the tumor microenvironment. The fact that the same microRNA can have opposite effects on different or multiple targets is well known. There are still significant uncertainties regarding the proper formulations in order to obtain efficient and specific methods of delivery, as well as an increased in vivo stability. Nonetheless, their profile of adverse events needs to be better understood and the dosage established in order to obtain effective treatments with tolerable adverse events.The existence of predictive markers for tumor response to therapies allows a better selection of available treatment options, reduces unnecessary treatments, toxicities, costs, by allowing an adequate patient selection. Up to date research did not succeed in offering validated predictive biomarkers for systemic treatment response in mCRC. Regarding the above-mentioned standard drugs administered according to international guidelines, validated predictive factors exist only for the anti-EGFR targeted treatments and for immunotherapy used in refractory cases. Proposed predictive factors for chemotherapy or targeted treatment response are represented by gene expression, polymorphisms or mutations of genes involved in drug activity or levels of enzymes involved in drug metabolism or activity. Clinical features (PS), factors related to the natural history of the disease, and laboratory parameters, such as tumor markers or markers of baseline inflammation, are also among the proposed predictive factors. Treatment-related toxicity, either clinical or seen on the blood works often represents a surrogate marker for treatment efficacy.In this context, the emergence of novel biomarkers such as miRNAs, still under investigation, could represent the beginning of a paradigm shift in the management of mCRC; they can offer important molecular data, are stable, require minimum volumes of blood; although expensive when compared to currently proposed markers, the actual costs could be reduced by better choice of treatments.


Several recent publications have evaluated the prognostic value of preoperative hydronephrosis (HN) in patients with upper tract urinary carcinoma (UTUC). The aim of this meta-analysis was to explore the pooled effect of preoperative HN on the prognosis of UTUC patients treated with radical nephroureterectomy (RNU) based on current evidence.We performed a systematic search of Pubmed, Cochrane library, and Web of Science databases from inception to June 2020. The outcomes of interest included overall survival (OS), cancer-special survival (CSS), disease-free survival (DFS), and intravesical recurrence-free survival (IVRFS).P = 0.004), CSS (P < 0.001), and DFS (P = 0.005), but not IVRFS (P = 0.12). No obvious publication bias was detected by Begg’s test in all the analyses.Twenty-two studies with a total of 7,542 patients satisfied the eligibility criteria and were finally included in this meta-analysis. The percent of patients with preoperative HN varied in the eligible studies, ranging from 18 to 81%. The pooled results showed that preoperative HN was significantly associated with worse OS (The results drawn in our meta-analysis suggest that the presence of preoperative HN is associated with worse prognosis in patients treated with RNU for UTUC. Therefore, closer surveillance and more aggressive therapy may be needed for UTUC patients present with preoperative HN. Well-designed prospective studies are necessary to substantiate the prognostic value of HN in UTUC. UTUC caCurrently, many studies have discussed the prognostic factors for UTUC undergoing RNU, and accumulating knowledge of the factors would help the urologists better evaluate the outcome of UTUC, for a more effective therapy overall. Neutrophil-to-lymphocyte ratio (NLR), a blood-based biomarker, was reported to correlate with worse outcomes in various malignant tumors; a previous meta-analysis summarized that high preoperative blood-based NLR was obviously associated with poorer OS, RFS, and CSS in UTUC patients who underwent RNU . Ku et aPreoperative hydronephrosis (HN) status can be detected in patients with bladder cancer or UTUC. For bladder cancer patients, a meta-analysis summarized that the presence of preoperative HN was significantly correlated with worse OS and CSS after radical cystectomy . RecentlThis work was reported in line with PRISMA  . PublishStudies satisfying the following criteria were included: (i) studies that evaluated the association between preoperative HN and oncological outcomes in patients who underwent RNU for UTUC; (ii) studies that directly reported hazard ratios (HRs) with their corresponding 95% CIs of overall survival (OS), cancer-special survival (CSS), disease-free survival (RFS), and intravesical recurrence-free survival (IVRFS) in multivariable logistic regression analysis; (iii) studies that enrolled more than 100 participants, and (iv) the median follow-up >12 months. The exclusion criteria were as follows: (i) the literatures were non-original articles, comments, reviews, or meta-analysis; (ii) studies that included patients with recurrent UTUC, metastatic carcinoma, or receiving neoadjuvant chemotherapy were excluded; and (iii)  overlapping study populations were reported for the same outcome.A standardized-items form was used by two independent reviewers (TY and HL) to extract usable data from eligible full length articles. In our meta-analysis, OS and CSS were defined as the interval between surgery and any cause death and cancer-caused death, respectively; DFS was defined as the interval between surgery and local relapse or distant metastasis, excluding the recurrence in bladder, and these studies in which DFS was defined as recurrence both in bladder and non-bladder lesions were not considered for DFS analysis; IVRFS was defined as the interval between surgery and the recurrence in the bladder. The following information was recorded: first author’s name, publication year, country/region of origin, study period, study design, sample size, the number of patients with HN, patient characteristics (age and gender), follow-up duration, outcomes , tumor characteristics , and treatment management. Newcastle-Ottawa Scale was applied to determine the quality of the included studies . The sco2I statistics >50% and chi-squared test P value <0.1 demonstrated notable heterogeneity. A Galbraith plot was performed and a leave-one-out analysis was conducted to identify studies causing heterogeneity and evaluate their influence on the combined HRs  was applied to perform all the data analyses. HRs with their 95% CIs of OS, CSS, DFS, and IVRFS in multivariable logistic regression analysis from each study were used to obtain the combined HRs. A random-effect or fixed-effect model was chosen to pool the results based on the between-study heterogeneity. ined HRs . SensitiThe PRISMA flow chart of the search strategy for eligible studies is summarized in 2 = 23.1%), a fixed-effect model was used. The results showed that the patients with preoperative HN were subjected to unfavorable OS  (P = 0.175)  in the included studies, a random-effect model was used. The pooled HRs of these studies indicated that the presence of preoperative HN was obviously associated with shorter CSS  (P = 0.174) , and a fixed-effect model was applied to obtain the pooled HRs and corresponding 95% CIs. The result suggested that the presence of preoperative HN predicted a poor outcome of DFS  (P = 0.062) (P < 0.001), pathologic T stage (P < 0.001), and lymph node status (P = 0.002) between the HN and non-HN groups based on the included studies. However, no obvious difference was found in tumor grade between the two groups (P = 0.196)Pooled HRs and 95% CIs of DFS were collected in 11 studies with 2,800 patients. No obvious heterogeneity was detected among studies (IP = 0.12). The sensitivity analysis showed that the pooled HRs of IVRFS were stable , and distant metastasis are used as the most crucial prognostic factors for most kinds of malignancies, including UTUC. Despite great advances in medical imaging techniques, its ability to predict preoperative staging and degree of local invasion still has limited accuracy , while tP > 0.05); moreover, a trend of association between HN and pN stage, not pT stage, was found (P = 0.052)  . Using l= 0.052) . Otherwi= 0.052) .Overall, preoperative HN can be detected in 37–55% of UTUC patients, while the present knowledge regarding the effect of HN on UTUC prognosis is still inadequate. Our study revealed a significant association of preoperative HN with ureteral tumors, bigger tumor’s size, and positive lymph node status, which might affect the UTUC patients’ prognosis. In addition, it was speculated that HN might cause the outward expansion of high-pressure renal pelvic or ureter wall and increase outward centrifugal pressure, resulting in counter flow in lymphatics and vasculature, which might promote the cancer cells’ seeding to nearby or distant organs . To idenversus present”, but others as “none or mild versus severe”; in addition, the definite grade of HN and the influence of different HN grades on prognosis of UTUC patients were not reported in these included studies, which might limit the clinical application of preoperative HN as a adjunctive modality to ureteroscopic biopsy and urinary cytology when counseling UTUC patients on medical and surgical therapies. Third, due to the limited number of included studies, this meta-analysis failed to confirm the value of preoperative HN as a predictor of intravesical recurrence for UTUC after RNU. Finally, this study was performed using the pooled data reported by the eligible studies but not individual patient data, so it is not an individual patient-level meta-analysis. Despite these limitations, our study was the first meta-analysis to identify HN as a potential preoperative prognosticator for UTUC patients undergoing RNU. Well-designed prospective studies are still warranted to further substantiate the prognostic value of preoperative HN in patients with UTUC.Inevitably, our meta-analysis suffered from several limitations. First, all the enrolled studies were retrospectively designed. In spite of the fact that we reached the results by pooling the HRs in multivariate models, some underlying selection bias still existed, and we could not control all the confounding factors. Second, the classification and imaging evaluation method of HN were different: some studies classified HN as “none In this meta-analysis, our results showed that preoperative HN was significantly correlated with worse prognosis in patients with UTUC after RNU, and preoperative HN might serve as an independent prognostic factor. The determination of preoperative HN status might be helpful to identify UTUC patients at higher risk of worse oncological outcomes who could benefit from more aggressive preoperative planning and postoperative therapy.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.TY and XY analyzed the data and wrote the manuscript. PL and HL searched and collected the literatures. TY and HL contributed to statistical analysis. TY and ZY designed the study and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


At six-week follow-up there were significant differences between both groups in FMA-UE total score (p < 0.001), volitional movement within synergies (p < 0.001), wrist (p = 0.021), hand (p = 0.047), grasp (p = 0.006) and coordination/speed (p = 0.004), favoring the Xbox Kinect training group. Conclusion: To conclude, results indicate repetitive use of the hemiparetic upper extremity by Xbox Kinect-based upper limb rehabilitation training in addition to conventional therapy has a promising potential to enhance upper limb motor function for stroke patients.Background: Xbox Kinect-based virtual reality, being a novel approach, has therapeutic benefits in rehabilitation and its use is encouraged in stroke rehabilitation of upper extremities. Objective: Primary aim of the current study is to investigate the additional effects of Xbox Kinect training in combination with routine physiotherapy exercises based on each component of Fugl-Meyer Assessment Scale for Upper Extremity (FMA-UE). Moreover, effect of upper limb rehabilitation on cognitive functions was also assessed. Methods: This study was a parallel arm randomized control trial. Fifty-six participants were recruited and randomly allocated to either an Xbox Kinect training group (XKGT) or exercise training group (ETG). Measures of concern were recorded using FMA-UE, Box and Block Test (BBT), and Montreal Cognitive Assessment (MOCA). Evaluation was conducted at baseline and after completion of intervention at the sixth week. Results: There were significant differences from pre- to post-intervention scores of FMA-UE and BBT ( Despite the fact that stroke mortality is continually being reduced in the United States and globally, the number of individuals living with chronic post-stroke symptoms is still rising . This onIn strokes, motor function impairments are more frequent, as brain areas  being responsible for movement execution and planning are affected . Recent Therefore, the most common consequence of stroke is motor dysfunction. Other impairments include sensory deficits, impaired visual perception, speech dysfunction, swallowing problems and cognitive decline . Stroke Motor impairments related to upper extremities include altered muscle tone, impaired motor control, limited range of motion, muscle weakness, laxity or contractures . As actiA striking option for improving rehabilitation outcomes is through higher doses in terms of time, repetitions and intensity for every session . HoweverIn accordance with these facts, the need to focus on interventions offering a higher dose and intensity for functional recovery to minimize the stroke-related residual inabilities in chronic stroke patients is crucial .Recently, rapid increases in technology utilization for rehabilitation have been observed. Particularly, virtual reality has emerged as an effective intervention. Virtual reality using exer-gaming played on devices including the Nintendo Wii, PlayStation and Microsoft Xbox 360 Kinect are being utilized as interventions. Video games allow patients to practice activities in a familiar environment, thereby increasing the dose of intervention . Among tXbox Kinect training is considered a recent topic in stroke rehabilitation, as the first randomized clinical trial was published in 2013. Since then, a number of studies have been investigating its utilization, yet conclusive outcomes have not yet been developed, necessitating further investigation before adding Xbox Kinect training as part of routine care for stroke rehabilitation of upper extremities .Xbox Kinect is basically a device for playing video games and was not designed as a medical intervention. It recognizes individual movements using infrared camera sensors. It enables the user to see one’s posture and movement on screen and perform actions freely in a real-time virtual reality environment . A numbeVirtual reality Xbox Kinect is capable of administering an intervention with more repetitions and higher intensity while keeping the patient motivated and engaged, which is thereby helpful in introducing neuroplasticity ,21,22. FIn the current study, we focused on the effect of Xbox Kinect training-based rehabilitation on specific components of the Fugl-Meyer Assessment Scale for Upper Extremity (FMA-UE). In 2019, Jeon and Moon reported results of subscales of FMA-UE, but their sample size was very small. In 2018, Schuster-Anft et al.  investigRecently, a number of studies have investigated the effect of virtual reality on upper limb function after stroke. Laver et al., 2018 , in the A parallel arm randomized control trial was conducted in Railway General Hospital, Rawalpindi, Pakistan. The study was completed over six months from February 2019 to July 2019. The study was approved by the ethical committee of Riphah College of Rehabilitation Sciences (Reference number Riphah/RCRS/REC/00514). The clinical trial was registered retrospectively with ClinicalTrials.gov: NCT04669431.Participants recruited in the trial were stroke outpatients from the neuro-rehabilitation department of the hospital. Both genders within the range of 40–70 years, with their first stroke attack or 6 months or more since their last stroke, and with a score above 4 on the Modified Ashworth Scale (MAS) were included in the study. Those having severe arm or shoulder pain, severe spastic hemiplegia, severe cognitive or visual impairment and patients on drugs that alter functional performance were excluded from the study.Furthermore, participants were required to be able to read and write their name in the local national language, Urdu, and English. Patients were precisely informed about the procedure and possible risk factors of the study and signed written informed consent forms before participation. The sample size of the study was calculated using an open epi-tool  . The opeParticipants were given an intervention for six weeks. The experimental group was given Xbox Kinect training-based rehabilitation training for upper extremities along with the conventional exercise therapy, whereas the control group or exercise training group received only conventional exercise therapy for training upper limb function. The duration of intervention was the same for both intervention groups.A total of 28 participants in this group were trained using Xbox Kinect 360 . Games sIn this group, 28 participants were trained to improve their upper limb function by performing conventional physical therapy exercises. Each session was given by a trained physiotherapist in the specified cubical of a rehabilitation department. The session was initiated with mild-to-moderate sustained stretching in a pain-free range for 10–30 s. After that, the physiotherapist assisted in attaining a weight bearing position in upper limb extension and this was repeated 1–3 times. The third step included performing different exercises, including tasks related to activities of daily living like basket lifting, folding towels, turning a key into a lock, reaching forward, reaching sideways, ball grasping, picking up small blocks, and lifting cans and pencils, either with assistance of a physiotherapist or just under supervision. Each task was performed for 3–4 min. The time for each physical therapy session was 35–40 min and was given for 5 days a week, for a total duration of six weeks.The IBM Statistical Package for the Social Sciences version 20  was used for analysis. Demographic and baseline data were given as mean and standard deviation for both intervention groups. Normality of data was analyzed at baseline and the test application was decided based on the Shapiro-Wilk value. In terms of age, there was no statistically significant difference among both groups. The Montreal Cognitive Scale and Box and Block test scores showed skewed distribution, with a Shapiro-Wilk significance value of 0.003 and 0.014, respectively, so non-parametric tests  were applied. The Shapiro-Wilk value for FMA-UE was 0.219, so parametric tests (Independent Samples T-Test and Paired Samples T-Test) were applied for analysis.n = 28) and exercise training group (n = 28). There were six dropouts due to personal reasons and transportation issues. The final analysis included 50 participants. A detail of the recruitment and participants analyzed is given in Around 85 patients were screened for recruitment in the study. Fifty-six patients meeting the set criterion were divided into two groups: the Xbox Kinect training group , however, across group analysis statistically significant improvement was seen in the Xbox Kinect training group (p < 0.001). Each component of the FMA-UE was also analyzed, and detailed results are given in At post-treatment, FMA-UE showed significant improvements in both groups (p = 0.719 and p = 0.076). However, within-group analysis showed statistically significant results in both groups for the dominant hand, as well as the non-dominant hand (p < 0.001).As baseline data was not equally distributed among the two groups for the Box and Block test, both for dominant and non-dominant hands, nonparametric tests were applied . Across p = 0.477); likewise, within-group analysis (Wilcoxon Signed-Rank Test) also showed no difference after intervention in the Xbox Kinect training group (p = 0.417), as well as the exercise training group (p = 0.113).The Montreal Cognitive Scale (MOCA) assessed by the Mann-Whitney U Test  for diffGaming systems based on virtual reality help to perform intense, repetitive and targeted movements. Active movement and involvement of the patients also helps to increase the strength of the affected upper extremity . To our The results of our study showed statistically significant improvement in FMA-UE for the Xbox Kinect training group. However, there was no statistically significant difference for the Box and Block test and Montreal Cognitive Assessment among both groups. FMA-UE showed a statistically significant difference between baseline and post-intervention measurements among the two groups, yet the across-group analysis and mean scores clearly indicate significant improvement in the Xbox Kinect training group. Moreover, looking at the components of FMA-UE, the majority of components showed improvement within the two groups. However, the across-group analysis of effect difference clearly indicates a noticeably significant difference in volitional movement within synergies, volitional movement mixing synergies, hand, grasp and coordination/speed, favoring the Xbox Kinect training group.Several studies have been conducted to study the effect of Xbox Kinect training. Sin et al.  also invSchuster-Anft et al., 2018 also conducted a study to directly compare virtual reality-based training with conventional therapy for four weeks by using BBT as the primary outcome tool. They recorded outcome measures at two-months follow-up and found major improvement in first two weeks of training, with no significant difference among the two groups. In the current study, we recorded measurements only before and after the intervention, but our results contradict the similar effects of both conventional and virtual reality training . Jeon etStudies have shown a decline in upper limb function with a decline in cognitive function . TherefoTo conclude, results indicate repetitive use of the hemiparetic upper extremity by Xbox Kinect training-based upper limb rehabilitation training, in addition to conventional therapy, has a promising potential to enhance upper limb motor function for stroke patients. Results are consistent with previous studies and support the use of Xbox Kinect training in rehabilitation settings for chronic stroke patients. Moreover, Xbox Kinect training has prominent effects in enhancing volitional movement within synergies and wrist and hand function, along with coordination, but upper limb rehabilitation not designed specifically for targeting cognitive function has no effect on cognition. In the future, it would be favorable to investigate the effects of Xbox Kinect training with a larger sample size and factors like gender, age, multiple strokes, site of lesion and co-morbidities. There are some aspects that need to be addressed and clarified, such as the dosage of Xbox Kinect routine training and when to incorporate it. Future studies should also focus on developing specially designed games for different types of stroke patients based on their needs. Finally, in order to assess the changes at a CNS level induced by exer-gaming, functional MRI can also be incorporated.


A room-temperature strip-guided “manufacturable” Silicon-on-Insulator (SOI)/GeSn integrated-photonics quantum-gyroscope chip operating at 1550 nm is proposed and analysed. We demonstrate how the entangled photons generated in Si Spontaneous Four Wave Mixing (SFWM) can be used to improve the resolution of a Sagnac interferometric gyroscope. We propose different integrated architectures based on degenerate and non-degenerate SFWM. The chip comprises several beam splitters, two SFWM entangled photon sources, a pump filter, integrated Mach–Zehnder interferometric gyro, and an array of waveguide coupled GeSn/Ge/Si single-photon avalanche detectors. The laser pumped SWFM sources generate the signal-idler pairs, which, in turn, are used to measure the two-photon, four-photon, and higher order coincidences, resulting in an increasing of the gyro resolution by a factor of two and four, with respect to the classical approach. This theoretical paper proposes and analyses a fully integrated room-temperature entangled-photon gyroscope chip that uses path-entangled N00N-states and squeezed vacuum light to provide super-resolution and phase sensitivity beyond the classical shot-noise limit. The group-IV-on-SOI (Silicon on Insulator) platform is proposed.Silicon photonics (SiPh) has already proven to be important for actualizing several integrated quantum-photonic applications. Group IV photonics is an “expanded version” of SiPh with added capabilities in on-chip SiGeSn photodetectors and light sources. The group IV approach offers the possibility of replacing superconducting nanowire detectors with 300 K waveguide-integrated single-photon avalanche diodes (SPADs) . In the The novelty of the present work consists in the following aspects: (i) manufacturable SOI chip, including the monolithic integration of all parts of the quantum gyro chip; (ii) room temperature entangled-photon source using silicon Kerr-effect strip waveguides; (iii) room temperature GeSn/Ge/Si SPAD arrays that are waveguide-coupled to the interferometer section; and, (iv) an increase of 2× or 4× over classical gyro resolution using SPAD arrays and multiply-split Sagnac interferometers. At the present time, the GeSn SPADs are purely theoretical and experiments are required to verify the predicted efficient 300 K waveguide-coupled operation. Work is currently going on in several laboratories to provide this verification.An examination of recent literature shows that chip-scale integrated photonics provides practical realizations of complicated quantum functions, such as processing units in photonic quantum computation/simulation ,3,4,5,6,Practical implementations require compatible building-blocks, such as quantum light sources for biphoton state generation, optical interferometers for pump light manipulation and quantum state manipulation, and single-photon detectors for quantum state measurement. CMOS-compatible technologies promise bringing quantum photonics towards higher integration levels. However, the on-chip suppression of photonic noise leads to substantially higher pump intensity when compared to that of the photon-pairs. An externalized solution to this problem using fiber or bulk optical components hinders the compactness and stability of the system. Well-designed waveguided chips solve the compactness problem.We have decided to use third-order nonlinear optics to attain an on-chip, room-temperature telecom-compliant quantum light source. A review of the literature shows several viable approaches, such as the device that integrates on a single substrate a non-linear photon-pair generator and a passive pump rejection filter , using tPhotonic chips for quantum metrology and quantum sensing are also quite feasible. However, quantum photonic sensing has been less explored than the quantum photonic applications discussed above. In particular, the quantum gyroscope chip is a new frontier.Looking at the prior art, optical gyroscopes that are based on the Sagnac effect and optical interference have proven to be an invaluable tool in sensing and navigation. The Sagnac effect refers to the relative phase erometer . The effal space  and it hal space  and aircal space , as wellal space . Many ofal space , they haal space . Recentlal space  and antial space  symmetrial space  working al space .The most recent research efforts in the field of optical gyros are concerned with the reduction of noise components to improve the device resolution. High efficiency techniques of signal processing after the photo-detection step have been pointed out to compensate all of the errors by using a feedback system, especially in the IFOG based system . Howevern system . Therefoattering ,33. As aThis is true in the case of interferometric gyros under the classical state of light. However, quantum metrology provides a way to improve the precision of measurement beyond the levels obtained in the classical domain . Specifi photons . In this photons , where t photons .Some theoretical aspects of the present work are similar to those that are presented in the literature ,41. HoweThe goal of this section is to theoretically demonstrate the super-resolution beyond the shot-noise limit for several interferometric quantum gyro architectures. In this context, we will adopt the main building blocks well standardized in the silicon quantum photonic platform. Indeed, it is largely recognized that the photonic platform represents an efficient way to realize complicated quantum functions, such as the applications described in the previous section.S(Ω) see . The filapproach  shows thClassically, the phase shift 2. Among different excitation methods, the most efficient way to realise the condition Here, we demonstrate how the proposed quantum gyro devices can operate beyond the classical resolution. The SFWM process creates a signal-idler photon pair −18 m2/W (five times higher than stoichiometric silicon nitride) and a refractive index of 2.1 at 1550 nm that enables high optical field confinement, allowing high intensity nonlinear optics and light guidance, even with small bending radii. Despite these advantages, an increase of the propagation loss from 8.4 × 10−4 dB/cm up to 1 dB/cm is recorded, when changing the SiN platform from stoichiometric to silicon enriched, respectively. However, here, we mainly focus on foundry-compatible and CMOS-compatible silicon waveguides. The loss coefficient of 2 dB/cm is commonly adopted for silicon strip waveguides [2. With the aim of designing the waveguide cross section to induce the phase matching conditions between pumps, signal, and Idler waves, we evaluate the SOI GVD coefficient  shows that for bunch  into Equation (10), we obtain:In the previous relationship, we have set The next step is to increase the gyro resolution further by measuring higher order coincidences. We suggest employment of six single-photon detectors SPAD-i , as depicted in With reference to the Therefore, from Equations (10) and (14) and for architecture of Moreover, Equations (15) and (16) take the effect of the splitting ratio  and (17) show that the fringe patterns are proportional to The theory before described is summarized in We see that the architecture of For operation at 1550 nm, chip-scale room-temperature integrated quantum interferometric gyro architectures have been proposed for foundry implementation in the Group IV SOI/GeSn technological platform. The focus of this work has been to demonstrate that integrated architectures can induce super-resolution with respect to what is obtained with the classic approach. Basically, the proposed devices present the one-chip co-integration of entangled photon sources , beam splitters, MZI, phase shifter, gyro interferometer, and an array of single-photon detectors (SPADs). Moreover, the presented architectures can operate either with degenerate and non-degenerate SFWM effect. In the first case, the split or bunched (N00N) state has been used to measure the two-fold coincidences, recording an improvement of two times in the gyro resolution. Alternatively, two different gyro configurations that are based on two-mode squeezing (induced by non-degenerate SFWM) have been proposed to operate with four-fold and higher order coincidences. The theoretical investigations have demonstrated that an increase of a factor of four is also possible with a visibility of 100% for indistinguishable photons. We think that experiments should be feasible because many two-photon and four-photon interference effects have been observed in quantum Silicon photonics.


Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device.This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) . Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test).EX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls . Only dabigatran elicited a significant increase in CTECA-test compared to controls . CTECA-test correlated strongly with dabigatran plasma concentration  and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test , and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors.70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTIn emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking.DRKS00015302.German clinical trials database ID: The online version contains supplementary material available at 10.1186/s12959-021-00267-w. Patients with pre-existing cardiovascular disease are at increased risk of thromboembolic events. Considering the trend towards increased longevity among human populations across the world, the use of anticoagulation therapy has become widespread , 2. A raThus, in an unknown patient with emergency bleeding, it may be necessary to determine the presence and type of anticoagulant therapy by performing coagulation tests. Fast, reliable detection and differentiation are essential in patients with severe bleeding, to enable administration of the most effective reversal therapy . The results of standard laboratory tests , as well as standard viscoelastic tests (e.g. EXTEM clotting time (CT), TEG R-time), are affected by anticoagulant drugs –14. HoweA newly developed viscoelastometric device  using different methodology from ROTEM or TEG, provides rapid bedside evaluation of whole-blood coagulation , 18. MulThis in vivo, prospective, observational, single-center study was conducted between November 2018 and October 2019. It was registered at the German clinical trials database (ID: DRKS00015302), and the protocol was approved by the Ludwig-Maximilians-University ethics committee (No 17–525-4). The study was performed in accordance with the Declaration of Helsinki, with written informed consent being obtained from all participants before they undertook any of the study procedures.Adults who had been treated with any one of the following drugs for at least 7 days were eligible to participate: dabigatran, rivaroxaban, apixaban, edoxaban, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In each of these seven treatment groups, concurrent treatment with platelet inhibitors  was permissible. A control group of healthy volunteers was recruited, bringing the total number of study groups to eight. Exclusion criteria were as follows: age < 18 years, treatment with more than one anticoagulant, coagulation disorders (e.g. von Willebrand’s disease), and myelodysplastic syndrome.Each study participant provided a single blood sample for analysis. To reflect the clinical circumstances of patients in whom emergency bleeding may occur at any time, no measures were taken to control the time at which samples were taken.All samples were tested using a ClotPro device  within 2 h after blood withdrawal, under standardized conditions . Five assays were performed on each sample , and the following variables were documented: CT, clot formation time (CFT), clot amplitude at 5 and 10 min after CT , maximum clot firmness (MCF), maximum lysis (ML), as well as lysis time  and lysis onset time  for TPA-test. Standard laboratory tests were performed on each sample: INR , thrombin time (TT) , aPTT  and full blood count. Anti-activated factor X (anti-Xa) and anti-activated factor II (anti-IIa) tests were also performed, using Biophen Heparin LRT 7.5 .Quality controls were performed according to institutional and manufacturers standards.N = 80). This sample size was calculated from one-way analysis of variance of the magnitude of expected differences in CT between the oral anticoagulants included in the study and healthy controls. A large difference between the anticoagulants and healthy controls was assumed . The software used was G*Power 3.1 (provided by the University of Düsseldorf). This procedure was done due to preliminary work on in-vitro dose-effect curves with DOACs and the new tests.10 individuals per study group were recruited (p = 0·05/n). Associations between variables were assessed using Spearman’s correlation coefficient.Statistical analyses of the results were performed using Graph Pad Prism 8  and SPSS Version 25 . All data are presented as median with interquartile range  unless indicated otherwise. For statistical comparison of study groups, results from the three activated factor X (FXa) inhibitors were pooled. Differences between groups were analyzed using the Kruskal-Wallis-test and Dunn’s multiple comparison test. The significance level  was adjusted for multiple testing  analyses were performed to evaluate the sensitivity and specificity of test parameters for detecting anticoagulant drugs. Optimal cut-off values were determined by Youden’s Index.A total of 80 individuals were recruited for the study, and their characteristics are shown in Table EX-test was 44 s (IQR 38–47 s) in the control group ; p < 0.0001 versus controls. CTEX-test was not significantly prolonged versus controls by UFH or LMWH. None of the anticoagulant drugs produced statistically significant changes in A5EX-test or MCFEX-test compared to the control group , sensitivity of 70%, and specificity of 64%.Median CTsee Fig. A and B. IN-test was 142 s  of 0.768 (SE 0.056) and a sensitivity of 90% and a specificity of 67%.In the control group, the median CTRVV-test in controls was 63 s . Correlations were observed between CTRVV-test, and plasma FXa-inhibitor concentrations measured by anti-Xa activity , and statistical significance was reached with edoxaban . CTRVV-test also showed statistically significant correlation with anti-Xa activity of samples from patients in the LMWH group . In the ROC analysis, the optimal CTRVV-test cut-off for FXa-inhibitor detection was determined as 147 s. This cut-off was associated with an AUC of 0.721 , sensitivity of 83%, and specificity of 64%. T Detection of apixaban (apixaban vs. controls) was improved using RVV-test (90% sensitivity and 100% specificity) compared to EX-test (80% sensitivity and 80% specificity).CTRVV-test cut-off for UFH was determined as 194 s. This cut-off was associated with an AUC of 0.808 (SE 0.064) and a sensitivity of 90% and a specificity of 63%.The optimal CTECA-test . The optimal cut-off value of CTECA-test for detecting dabigatran was calculated as 128 s. This yielded an AUC for the ROC curve of 1.00 , with 100% sensitivity and 100% specificity.Dabigatran was the only anticoagulant to produce a significant change versus control in CTTPA-test were numerically comparable to those for CTEX-test. Accordingly, as with CTEX-test, CTTPA-test was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon .In all eight study groups, median values for CTmon Fig. A and B. mon Fig. A. The efp < 0.0001 for both comparisons). Phenprocoumon was the only anticoagulant with significant impact on INR versus controls (p < 0.0001). Compared with the control group (median 17 [IQR 17–18] seconds), TT was significantly prolonged by dabigatran . Statistically significant prolongation of TT was also observed with UFH , although the extent of this prolongation with UFH was much less than that with dabigatran.Standard laboratory test results are summarized in Supplementary Table This study demonstrates that viscoelastometry is sensitive to a range of anticoagulants, including DOACs. The effects of anticoagulants on the ‘conventional’ EX-test are not specific, while novel parameters  could be helpful in differentiating between DOAC classes (direct thrombin inhibitors and FXa-inhibitors).ECA-test, and it was also the only drug which shortened LOT in the TPA-test. FXa inhibitors prolonged CT in all assays except the ECA-test. The magnitude of effect of the FXa inhibitors on CT was less than dabigatran, except in the RVV-test where the median CT was similar in both the dabigatran and FXa-inhibitor groups. Compared with controls, phenprocoumon significantly prolonged CT in the TPA-test and the EX-test, UFH significantly prolonged CT in the IN-test and the RVV-test, and LMWH did not significantly prolong CT in any of the assays.The direct thrombin inhibitor dabigatran significantly prolonged CT in all five assays compared to controls. Of note, this was the only drug which prolonged CTECA-test and anti-IIa activity (a surrogate for the concentration of dabigatran). It enabled the calculation of a threshold CTECA-test value for detecting the presence of dabigatran, and the associated sensitivity and specificity values of 100% show possible capabilities in daily practice. Reliable quantification of dabigatran levels also appears possible, subject to appropriate calibration of CTECA-test. These data are in accordance with our earlier study using the ROTEM delta thromboelastometry device, showing that an ecarin-based test is highly specific and sensitive to direct thrombin inhibitors [RVV-test and anti-Xa activity (a surrogate for the concentration of FXa inhibitor or heparin). Further studies are planned to confirm the potential of CTRVV-test for quantifying FXa-inhibitor and LMWH plasma concentrations.Correlations observed in this study show that viscoelastometry by ClotPro is suitable for detecting a range of anticoagulants. We observed a strong correlation between CThibitors . CorrelaECA-test and CTRVV-test enable confident deduction that a patient is receiving dabigatran (or perhaps a different direct thrombin inhibitor). Prolongation of CTRVV-test but not CTECA-test is consistent with the patient receiving an FXa inhibitor. However, because CTRVV-test is also prolonged by heparin and (to a lesser extent) by phenprocoumon, it is not clear that the tests performed in this study enable reliable differentiation of FXa inhibitors from other anticoagulant types. Further work is clearly needed in this respect.The results of this study suggest that a combination of standard and newly developed viscoelastometric tests like the RVV-test and the ECA-test may provide benefits compared to conventional, standard viscoelastic coagulation monitoring for detection of and differentiation between DOACs , 20, 21.RVV-test and anti-Xa activity was seen with LMWH and, with UFH, the sensitivity for detection (90%) was as high as that with the IN-test.In addition to the device used here, there are at least two other devices for point-of-care assessment of DOAC anticoagulation. TEG 6 s is used with cartridges comprising four channels, each with separate reagents to enable four assays to be run simultaneously. In a study performed using an experimental cartridge, detection and classification of DOACs were reported to be achievable with TEG 6 s . The expStandard laboratory tests in the present study confirmed the presence of clinically relevant plasma concentrations of the anticoagulants. Dabigatran resulted in significant increases in aPTT and TT, while FXa inhibitors had no significant effect on standard laboratory coagulation tests. Phenprocoumon significantly increased INR and, like dabigatran, UFH produced significant increases in aPTT and TT. These results are consistent with previous observations. It has been reported that TT is sensitive to dabigatran but not to FXa inhibitors, while the calibrated anti-Xa test can be used for detection of FXa inhibitors but is not affected by dabigatran , 24. TheLimitations of the current study include the modest number of patients, questionable robustness of the sample size calculation (the effect size differs between drugs and tests included in the study), and the lack of blinding. Therefore, further data will be needed to confirm our results. The allowance for variability in dosing and the time between last intake and blood sampling in this study could be considered as further limitations, due to the resulting variability in plasma drug levels. On the other hand, the real-world approach may be considered as a strength of the study because it means the results are applicable to routine clinical practice. Study participants were not selected according to clinical circumstances and the results should be applicable to all patients receiving the drugs included in our study, regardless of the indication for anticoagulant therapy.This study has demonstrated that a combination of standard and newly developed viscoelastometric tests on the ClotPro device enable detection of a range of anticoagulants including DOACs. The ECA-test enables detection of dabigatran with 100% specificity and sensitivity. Using RVV-test improves detection of FXa-inhibitors but not differentiation. Quantification of some drugs such as edoxaban, LMWH and dabigatran may be possible; further studies are needed to ascertain whether sufficiently accurate calibration can be achieved. Thus, viscoelastometry may potentially be a useful alternative to standard laboratory methods for the detection and differentiation of anticoagulant drugs.Additional file 1 Supplemental Table 1A: Viscoelastometric and standard laboratory test results from the control group and the anticoagulant groups. Data are presented as median (interquartile range); p-values are for comparison with the control group. Supplemental Table 1B: Viscoelastometric CT results from the control group and the anticoagulant groups, with pooling of the FXa inhibitors. Data are presented as median (interquartile range); p-values are for comparison with the control group.


The Nutrition Environment Measures Surveys are valid and reliable measures of community and consumer food environments. This article describes the adaptation and evaluation of the Nutrition Environment Measures Survey in Stores (NEMS-S) for Mediterranean urban contexts (NEMS-S-MED). Trained raters used the adapted NEMS-S-MED tool to observe and rate food outlets in 21 census tracts and 43 food stores across the city of Madrid, Spain. We evaluated inter-rater and intra-rater reliabilities, construct validity, and the tool’s ability to discriminate between store types and between stores by area-level Socio-Economic Status (SES). Overall, the mean NEMS-S-MED score was 20.7 (SD = 9.8), which ranged from 7 to 43. Most food items displayed substantial or almost perfect inter-rater and intra-rater agreements; the percentage agreement across availability items was almost perfect and kappa statistics were also very high . Furthermore, the NEMS-S-MED tool was able to discriminate between store types and census tracts of different SES. The adapted NEMS-S-MED instrument is a reliable and valid audit tool to assess the consumer food environment in Mediterranean urban contexts. Well-constructed measurement tools, such as the NEMS-S-MED, may facilitate the development of effective policy interventions to increase healthy food access and affordability. Unhealthy diets are the leading cause of mortality worldwide . One of The retail food environment, as described by the conceptual model of Glanz et al., encompasses the community environment  and the consumer environment  . ExistinTo quantify and assess the consumer food environment, efficient, reliable, and valid measures are needed. Whereas a large number of tools have been developed, few of them have undergone reliability or validity testing ,11. To dYet, assessing the retail food environment is context-dependent . As suchTo address this gap, we have developed the Nutrition Environment Measures Survey in Stores for the Spanish setting. This study aimed to adapt and evaluate inter-rater reliability, intra-rater reliability, and construct validity of the Nutrition Environment Measures Survey in Stores adapted to the Mediterranean urban context (NEMS-S-MED).This study was part of the European-funded project “Heart Healthy Hoods”, which assesses the physical and social urban environment in relation to residents’ cardiovascular risk in Madrid . As partWe used census tracts to define our audit areas. For reference, census tracts  are the smallest administrative unit for the dissemination of statistical and cartographic information in Spain, in which demographic and socioeconomic data are released. Our study sample included 21 census tracts scattered around the city and encompassed a socioeconomically diverse sample. While details on this sampling strategy have been published elsewhere , Table SWe used the Nutrition Environment Measures Survey in Stores for Mediterranean contexts (NEMS-S-MED) to assess the availability and affordability of healthy foods in each food store. We adapted the NEMS-S-MED from the original NEMS-S, developed by Glanz et al. .The original NEMS-S was developed to assess the availability and cost of healthier options versus less-healthy options over 10 food groups based on a mainstream North American diet ,13. To aDuring modification, we considered the applicability of the NEMS-S instrument to the Mediterranean context by referring to the latest update of the Mediterranean Diet Pyramid, the most recent dietary guidelines for the Spanish setting, and current purchasing patterns of the Spanish population ,26,27. AWe operationalized the availability of food items using a variety of items in each food category. For example, we counted separately all available varieties of the same kind of fruit. We evaluated affordability through the price (either per grams or per item if sold only by the piece) and without considering promotion prices. Data collectors first recorded if a healthier option was available for each food category  and then, compared its price with the regular option .The outcome of the original NEMS-S score ranges from −8 to 50 . NEMS-S The training for the raters included taking the NEMS training modules , discussTwo raters completed all surveys on weekdays, between November and December 2019. They walked a predefined route within each census tract to guide the fieldwork. They assessed all food stores present in the census tracts and classified them into the following categories, adapted from Glanz et al. to the Mediterranean context ,24 as suWe integrated our modified NEMS-S-MED audit tool into an easy and freely accessible web-based app called Open Data Kit to facilitate data collection. Thereby, data were directly uploaded from portable devices (Android smartphones) using a wireless network connection.We analyzed the data in 2020. First, we assessed inter-rater reliability calculating both kappa statistics (κ) and intra-class correlation coefficients (ICC) and their 95% confidence interval (CI). We used kappa and percent agreement for all binary and categorical store parameters  items and ICC for continuous variables . According to guidelines from Landis and Koch, we used the following cutoff ranges for kappa values: 0.0–0.20 (slightly poor), 0.21–0.40 (fair), 0.41–0.60 (moderate), 0.61–0.80 , and 0.81–1.00  . An ICC Second, we assessed construct validity. We compared the NEMS-MED scoring across types of food stores with known differences regarding the foods they carry according to the original NEMS-S and previous research ,19. We hWe identified a total of 43 food stores in the selected 21 census tracts located across the city of Madrid. We found no food stores in two census tracts. Out of the other census tracts, the number of food stores varied from one to six. Among these, 10 were supermarkets, 22 convenience stores, and 11 specialized stores . From these stores, we used all 43 to assess inter-rater reliability and 42 for calculating intra-rater reliability .Inter-rater and intra-rater reliability for the availability dimension were consistently very high. As shown in Inter-rater and intra-rater reliability for the affordability dimension were also very high. As shown in Data presented in The present study adapted and evaluated an audit tool to measure the consumer food environment in the Spanish setting. Our results show that the adapted NEMS-S-MED instrument is a useful and reliable tool to measure the availability and affordability of healthy products in a large city like Madrid, with a Mediterranean retail food environment.Our main findings show that the NEMS-S-MED instrument is coherent and measures a uniform construct. The overall mean NEMS-S-MED score was 20.7 (SD = 9.8) and ranged from 7 to 43. Most food items displayed a substantial or almost perfect inter-rater and intra-rater agreement; the percentage agreement across NEMS-S-MED availability items was almost perfect and kappa statistics were also very high . For reference, the inter-rater kappa coefficient for the original NEMS-S ranged from 0.83 to 1.00 . LikewisFurthermore, our adapted NEMS-S-MED tool was able to discriminate between store types and census tracts of different socioeconomic status. Consistent with previous research, supermarkets appear to have greater overall availability of healthy products . In BrazThe mean NEMS-S-MED score and all subcomponent mean scores (except fruits and vegetables) were significantly lower in the low-SES areas. Although a larger sample is needed to confirm these findings, Black et al. also noted this reduced availability of healthy food items in food retailers from low-SES areas in their systematic review .The main differences between the original NEMS-S and our adapted version relate to the rationale for scoring and the food items included. Whereas the original NEMS-S considered the dietary guidelines for North Americans , our adan = 43) is similar to previous studies adapting the NEMS-S audit tool in China, Brazil, or Canada  [We acknowledge that this study presents several limitations. First, the original NEMS-S tool was developed to measure the availability and cost of healthy food options within food stores; however, it does not assess other determinants of the consumer food environment like promotion and marketing strategies. Moreover, our adapted NEMS-S-MED tool should be replicated in other Mediterranean cities to ensure validity and reliability in other settings. Yet, the sample of stores included in this study (ctively) ,18,19.Despite these limitations, this study also has important strengths. To the best of our knowledge, this is the first study to both adapt and test the validity of the NEMS tools to evaluate the consumer food environment in Europe. Southern European food environments are of particular interest because their urban form patterns differ greatly from the more sprawled North American or Australasian cities ,31. FurtFuture research should aim to track changes in the retail food environment over time using combined measures (including direct observations and GIS-based measures) to facilitate the understanding of how changes in the consumer food environment may deliver changes benefitting residents of low-SES areas.The adapted NEMS-S-MED instrument is a reliable audit tool to assess the consumer food environment in Mediterranean urban contexts. Like the original NEMS-S tool, our study showed almost perfect inter-rater and intra-rater agreement for availability and affordability dimensions. Furthermore, the NEMS-S-MED tool was able to discriminate between store types and census tracts of different socioeconomic status. Future research should apply this instrument in other Mediterranean cities. Adapting standardized measurement tools to assess context-dependent features of food environments may facilitate the development of effective policy interventions to increase healthy food access and affordability.