Update of the recommendations for the determination of biomarkers in colorectal carcinoma: National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology

In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplifcation of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly diferentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future

The Harvey–Bradshaw Index adapted to a mobile application compared with In-clinic assessment: the MediCrohn Study

[Abstract] Objectives: Mobile apps are useful tools in e-health and self-management strategies in disease monitoring. We evaluated the Harvey–Bradshaw index (HBI) mobile app self-administered by the patient to see if its results agreed with HBI in-clinic assessed by a physician. Methods: Patients were enrolled in a 4-month prospective study with clinical assessments at months 1 and 4. Patients completed mobile app HBI and within 48 h, HBI was performed by a physician (gold standard). HBI scores characterized Crohn's disease (CD) as remission <5 or active ≥5. We determined agreement per item and total HBI score and intraclass correlation coefficients (ICCs). Bland–Altman plot was performed. HBI changes in disease activity from month 1 to month 4 were determined. Results: A total of 219 patients were enrolled. All scheduled assessments (385 pairs of the HBI questionnaire) showed a high percentage of agreement for remission/activity (92.4%, κ = 0.796), positive predictive value (PPV) for remission of 98.2%, and negative predictive value of 76.7%. High agreement was also found at month 1 (93.15%, κ = 0.82) and month 4 (91.5%, κ = 0.75). Bland–Altman plot was more uniform when the HBI mean values were <5 (remission). ICC values were 0.82, 0.897, and 0.879 in all scheduled assessments, 1 and 4 months, respectively. Conclusions: We found a high percentage of agreement between patients' self-administered mobile app HBI and in-clinic physician assessment to detect CD activity with a remarkably high PPV for remission. The mobile app HBI might allow a strict control of inflammation by remote monitoring and flexible follow-up of CD patients. Reduction of sanitary costs could be possible

Paediatricians provide higher quality care to children and adolescents in primary care: A systematic review

Aim: The number of primary care paediatricians is decreasing in Europe without a justifiable reason. We aimed to compare the clinical practice of paediatricians and family doctors attending children and adolescents in primary care. Methods: MEDLINE, Embase, CENTRAL, TRIP and Google Scholar were searched from December 2008 to February 2018. No language or study design restrictions were applied. Three reviewers assessed eligibility of the studies. Seven pairs of reviewers performed the data extraction and assessed the methodological quality independently. Discrepancies were resolved by consensus. Results: Fifty-four, out of 1150 studies preselected, were included. We found that paediatricians show more appropriate pharmacology prescription patterns for the illness being treated; they achieve higher vaccination rates and have better knowledge of vaccines and fewer doubts about vaccine safety; their knowledge and implementation of different screening tests are better; they prescribe psychoactive drugs more cautiously and more in line with current practice guidelines; their evaluation and treatment of obesity and lipid disorders follow criteria more consistently with current clinical practice guidelines; and they perform fewer diagnostic test, show a more suitable use of the test and request fewer referrals to specialists. Conclusion: According to published data, in developed countries, paediatricians provide higher quality care to children than family doctors

Painlev\'e-Gullstrand synchronizations in spherical symmetry

A Painlev\'e-Gullstrand synchronization is a slicing of the space-time by a family of flat spacelike 3-surfaces. For spherically symmetric space-times, we show that a Painlev\'e-Gullstrand synchronization only exists in the region where $(dr)^2 \leq 1$, $r$ being the curvature radius of the isometry group orbits ($2$-spheres). This condition says that the Misner-Sharp gravitational energy of these 2-spheres is not negative and has an intrinsic meaning in terms of the norm of the mean extrinsic curvature vector. It also provides an algebraic inequality involving the Weyl curvature scalar and the Ricci eigenvalues. We prove that the energy and momentum densities associated with the Weinberg complex of a Painlev\'e-Gullstrand slice vanish in these curvature coordinates, and we give a new interpretation of these slices by using semi-metric Newtonian connections. It is also outlined that, by solving the vacuum Einstein's equations in a coordinate system adapted to a Painlev\'e-Gullstrand synchronization, the Schwarzschild solution is directly obtained in a whole coordinate domain that includes the horizon and both its interior and exterior regions.Comment: 16 page

Angular redistribution of near-infrared emission from quantum dots in 3D photonic crystals

We study the angle-resolved spontaneous emission of near-infrared light sources in 3D photonic crystals over a wavelength range from 1200 to 1550 nm. To this end PbSe quantum dots are used as light sources inside titania inverse opal photonic crystals. Strong deviations from the Lambertian emission profile are observed. An attenuation of 60 % is observed in the angle dependent radiant flux emitted from the samples due to photonic stop bands. At angles that correspond to the edges of the stop band the emitted flux is increased by up to 34 %. This increase is explained by the redistribution of Bragg-diffracted light over the available escape angles. The results are quantitatively explained by an expanded escape-function model. This model is based on diffusion theory and adapted to photonic crystals using band structure calculations. Our results are the first angular redistributions and escape functions measured at near-infrared, including telecom, wavelengths. In addition, this is the first time for this model to be applied to describe emission from samples that are optically thick for the excitation light and relatively thin for the photoluminesence light.Comment: 24 pages, 8 figures (current format = single column, double spaced

Disease severity in familial cases of IBD

Background: Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. Aim: To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. Methods: 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. Results: In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25–44] vs 37 years [IQR 27–49]; p b 0.0001); (CD: 27 years [IQR 21–35] vs 29 years [IQR 22–40]; p b 0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p = 0.04); (CD: 30.1% vs 23.6%; p b 0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p = 0.0001), penetrating behavior (21% vs 17.6%; p = 0.01) and perianal disease (32% vs 27.1%; p = 0.003). Differences are not influenced by degree of consanguinity. Conclusion: When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course

Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes

To the Editor: As of 2018, the majority of Western European countries – including Spain – have lifted restrictions to therapy based on disease severity in the context of HCV infections.1 Long overdue, most national elimination programmes now also include access to care for people who inject drugs (PWID), 2 who are at the core of ongoing HCV transmission.3 Macías et al.4 have recently shown in this Journal that high viral cure rates can be achieved in this group, hereby providing evidence that targeting PWID in treatment programmes is worthwhile. However, the extent to which such national efforts can reduce the HCV burden not only depends on the uptake into care and treatment success rates, it is also determined by the relative importance of within-country transmission and virus importation from elsewhere. As the chronic nature of most HCV infections hampers reliably reconstructing contact networks from patient interviews, virus genetic data can be a valuable alternative source of information for elucidating the geographic history of virus lineages (e.g. [5], [6]). Using such data, we have recently shown that for the most prevalent subtype among PWID in Spain (40%, 7), HCV1a, infections often link to infections abroad – in recent years >50% link to Western European countries, mostly European Union (EU) member states – as opposed to other infections ..

Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro

© 2021 The Authors.Therapeutic potential of metformin in obese/diabetic patients has been associated to its ability to combat insulin resistance. However, it remains largely unknown the signaling pathways involved and whether some cell types are particularly relevant for its beneficial effects. M1-activation of macrophages by bacterial lipopolysaccharide (LPS) promotes a paracrine activation of hypoxia-inducible factor-1α (HIF1α) in brown adipocytes which reduces insulin signaling and glucose uptake, as well as β-adrenergic sensitivity. Addition of metformin to M1-polarized macrophages blunted these signs of brown adipocyte dysfunction. At the molecular level, metformin inhibits an inflammatory program executed by HIF1α in macrophages by inducing its degradation through the inhibition of mitochondrial complex I activity, thereby reducing oxygen consumption in a reactive oxygen species (ROS)-independent manner. In obese mice, metformin reduced inflammatory features in brown adipose tissue (BAT) such as macrophage infiltration, proinflammatory signaling and gene expression, and restored the response to cold exposure. In conclusion, the impact of metformin on macrophages by suppressing a HIF1α-dependent proinflammatory program is likely responsible for a secondary beneficial effect on insulin-mediated glucose uptake and β-adrenergic responses in brown adipocytes.This work was funded by grants RTI2018-094052-B-100 (MCIN/AEI/10.13039/501100011033/FEDER) , S2017/BMD-3684 (Comunidad de Madrid, Spain), Fundación Ramón Areces (Spain) and CIBERdem (ISCIII) to A.M.V., grant S2010/BMD-2423 (Comunidad de Madrid, Spain) to M.J.O. and A.M.V., PID2019-106371RB-I00 (MCIN/ AEI /10.13039/501100011033/ FEDER) to J.A and PI16/00789 (ISCIII, Spain) to M.A.F.-M. We also acknowledge all members of AMV's laboratory for helpful discussions. M.F. and B.V were supported by Inserm, CNRS, Université de Paris, and Région Ile-de-France. We also acknowledge the EFSD Albert Reynolds travel grant fellowship to V.F

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients with Inflammatory Bowel Disease: Results from the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn''s disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response