Optimal navigability of weighted human brain connectomes in physical space.

Communication protocols in the brain connectome describe how to transfer information from one region to another. Typically, these protocols hinge on either the spatial distances between brain regions or the intensity of their connections. Yet, none of them combine both factors to achieve optimal efficiency. Here, we introduce a continuous spectrum of decentralized routing strategies that integrates link weights and the spatial embedding of connectomes to route signal transmission. We implemented the protocols on connectomes from individuals in two cohorts and on group-representative connectomes designed to capture weighted connectivity properties. We identified an intermediate domain of routing strategies, a sweet spot, where navigation achieves maximum communication efficiency at low transmission cost. This phenomenon is robust and independent of the particular configuration of weights. Our findings suggest an interplay between the intensity of neural connections and their topology and geometry that amplifies communicability, where weights play the role of noise in a stochastic resonance phenomenon. Such enhancement may support more effective responses to external and internal stimuli, underscoring the intricate diversity of brain functions.

Evaluation of Eazyplex® LAMP test for fast Candida auris direct detection of colonized patients.

Candida auris is a multidrug-resistant pathogen yeast that produces nosocomial outbreaks, due to its ability in colonizing the skin, mucous membranes and surfaces. Rapid diagnosis is essential to control its spread. The aim of this study was to compare the Eazyplex® Candida auris kit (AmplexDiagnostics GmbH) for the rapid identification of patients colonized with C. auris, with the reference method used in our institution (culture and identification by MALDI-TOF). This easy-to-perform test allows obtaining a fast result, in ~30 min. First, we achieved a preliminary study from previously characterized Candida species colonies obtained from 51 clinical samples, with 100% agreement between culture isolation and the Eazyplex® Candida auris LAMP. Second, 152 epidemiological surveillance samples (pharyngeal and axillary-rectal swabs) were tested retrospectively. The sensitivity, specificity, positive and negative predictive values were 91.8%, 98.8%, 98.2% and 94.5%, respectively. Eazyplex® Candida auris showed acceptable results compared with culture in detecting C. auris from surveillance samples with the advantage of single-test and shorter time for handling and result than culture, in addition to its great specificity, positive and negative predictive values.

Scaling up real networks by geometric branching growth.

Real networks often grow through the sequential addition of new nodes that connect to older ones in the graph. However, many real systems evolve through the branching of fundamental units, whether those be scientific fields, countries, or species. Here, we provide empirical evidence for self-similar growth of network structure in the evolution of real systems-the journal-citation network and the world trade web-and present the geometric branching growth model, which predicts this evolution and explains the symmetries observed. The model produces multiscale unfolding of a network in a sequence of scaled-up replicas preserving network features, including clustering and community structure, at all scales. Practical applications in real instances include the tuning of network size for best response to external influence and finite-size scaling to assess critical behavior under random link failures.

Clinical and neuroanatomical predictors of post-stroke fatigue.

INTRODUCTION: Post-stroke fatigue (PSF) has been described as early exhaustion with tiredness that develops during physical or mental activity and generally does not improve with rest. There are inconsistent findings on the relationship between the characteristics of the ischemic brain lesion and PSF. However, some studies suggest that specific neuroanatomical and neuroplastic changes could explain post-stroke fatigue. The aim was to evaluate the severity of PSF in relation to the location and the size of the ischemic lesion in acute stroke patients to establish possible predictors of PSF. PATIENTS AND METHODS: We performed a prospective observational study to establish potential early predictors of long-term PSF, which was assessed using the Fatigue Assessment Scale six months after ischemic stroke. After segmenting brain infarcts on Diffusion-Weighted Imaging (DWI) images, we studied the association with PSF using Voxel-Based Lesion-Symptom Mapping (VLSM). RESULTS: Out of 104 patients, 61 (59 %) reported PSF. Female sex and history of diabetes mellitus were associated with a greater risk of developing PSF. The association of PSF with female sex was confirmed in a replication cohort of 50 patients. The ischemic lesion volume was not associated with PSF, and VBLSM analysis did not identify any specific brain area significantly associated with PSF. CONCLUSIONS: PSF is frequent in stroke patients, especially women, even after six months. The absence of neuroanatomical correlates of PSF suggests that it is a multifactorial process with biological, psychological, and social risk factors that require further study.

Geometric renormalization unravels self-similarity of the multiscale human connectome.

Structural connectivity in the brain is typically studied by reducing its observation to a single spatial resolution. However, the brain possesses a rich architecture organized over multiple scales linked to one another. We explored the multiscale organization of human connectomes using datasets of healthy subjects reconstructed at five different resolutions. We found that the structure of the human brain remains self-similar when the resolution of observation is progressively decreased by hierarchical coarse-graining of the anatomical regions. Strikingly, a geometric network model, where distances are not Euclidean, predicts the multiscale properties of connectomes, including self-similarity. The model relies on the application of a geometric renormalization protocol which decreases the resolution by coarse-graining and averaging over short similarity distances. Our results suggest that simple organizing principles underlie the multiscale architecture of human structural brain networks, where the same connectivity law dictates short- and long-range connections between different brain regions over many resolutions. The implications are varied and can be substantial for fundamental debates, such as whether the brain is working near a critical point, as well as for applications including advanced tools to simplify the digital reconstruction and simulation of the brain.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective.

The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

Mortality and Causes of Death After Liver Transplantation: Analysis of Sex Differences in a Large Nationwide Cohort.

In the last few years, several studies have analyzed sex and gender differences in liver transplantation (LT), but none have performed a disaggregated analysis of both mortality and causes of death. Data from 15,998 patients, 11,914 (74.5%) males and 4,069 (25.5%) females, transplanted between 2000 and 2016 were obtained from the Liver Transplantation Spanish Registry. Survival analysis was applied to explore recipient sex as a risk factor for death. The causes of death at different follow-up duration were disaggregated by recipient sex for analysis. Short-term survival was higher in males, whereas long-term survival was higher in females. Survival at 1, 5 and 10 years post-transplant was 87.43%, 73.83%, and 61.23%, respectively, in males and 86.28%, 74.19%, and 65.10%, respectively, in females (p = 0.05). Post-LT mortality related to previous liver disease also presented sex differences. Males had 37% increased overall mortality from acute liver failure (p = 0.035) and 37% from HCV-negative cirrhosis (p < 0.001). Females had approximately 16% increased mortality when the liver disease was HCV-positive cirrhosis (p = 0.003). Regarding causes of death, non-malignancy HCV+ recurrence (6.3% vs. 3.9% of patients; p < 0.001), was more frequently reported in females. By contrast, death because of malignancy recurrence (3.9% vs. 2.2% of patients; p = 0.003) and de novo malignancy (4.8% vs. 2.5% of patients; p < 0.001) were significantly more frequent in male recipients. Cardiovascular disease, renal failure, and surgical complications were similar in both. In summary, male patients have lower short-term mortality than females but higher long-term and overall mortality. In addition, the post-LT mortality risk related to previous liver disease and the causes of mortality differ between males and females.

Shaping the zebrafish myotome by intertissue friction and active stress.

Organ formation is an inherently biophysical process, requiring large-scale tissue deformations. Yet, understanding how complex organ shape emerges during development remains a major challenge. During zebrafish embryogenesis, large muscle segments, called myotomes, acquire a characteristic chevron morphology, which is believed to aid swimming. Myotome shape can be altered by perturbing muscle cell differentiation or the interaction between myotomes and surrounding tissues during morphogenesis. To disentangle the mechanisms contributing to shape formation of the myotome, we combine single-cell resolution live imaging with quantitative image analysis and theoretical modeling. We find that, soon after segmentation from the presomitic mesoderm, the future myotome spreads across the underlying tissues. The mechanical coupling between the future myotome and the surrounding tissues appears to spatially vary, effectively resulting in spatially heterogeneous friction. Using a vertex model combined with experimental validation, we show that the interplay of tissue spreading and friction is sufficient to drive the initial phase of chevron shape formation. However, local anisotropic stresses, generated during muscle cell differentiation, are necessary to reach the acute angle of the chevron in wild-type embryos. Finally, tissue plasticity is required for formation and maintenance of the chevron shape, which is mediated by orientated cellular rearrangements. Our work sheds light on how a spatiotemporal sequence of local cellular events can have a nonlocal and irreversible mechanical impact at the tissue scale, leading to robust organ shaping.

Prognostic factors for complications after loop ileostomy reversal.

BACKGROUND: Defunctioning ileostomy creation and closure are both associated with morbidity. There is little data available about complications after ileostomy closure. The aim of this study was to evaluate morbidity related to loop ileostomy closure (LIC) and to determine if patients with postoperative complications in primary surgery suffer from more postoperative complications during stoma closure. METHODS: This was a retrospective study on prospectively registered consecutive patients undergoing elective LIC in a single centre in Spain between April 2010 and December 2017. Baseline characteristics, postoperative complications after primary surgery and after stoma closure were recorded. Primary surgery included any colorectal resection, elective or urgent associated with a diverting loop ileostomy either as a protective stoma or rescue procedure. A logistic regression model was used to assess the effects of baseline variables and postoperative complications after primary surgery on the existence of postoperative complications related to LIC. RESULTS: Four hundred and twenty-eight patients (288 men, median age 64.5 years [IQR 55.1-72.3 years]) were included in the study, and 37.4%, developed complications after LIC. The most common was paralytic ileus. Only chronic kidney disease (OR 2.31; 95% CI 1.03-5.33, p = 0.043), existence of postoperative complications after primary surgery (OR 2.25; 95% CI 1.41-3.66, p = < 0.001) and ileostomy closure later than 10 months after primary surgery (OR 1.52; 95% CI 1.00-2.33, p = 0.049) were statistically significant in the multivariate analysis. CONCLUSIONS: Patients with chronic kidney disease, those who had any complication after primary surgery and those who had LIC > 10 months after primary surgery have a significantly higher risk of developing postoperative complications.

Liver stiffness change with HCV cure in HIV-infected patients on non-nucleoside analogues.

BACKGROUND: Liver stiffness (LS) at sustained viral response (SVR) is strongly associated with a lower incidence of subsequent hepatic events. HIV NNRTIs may have a beneficial impact on fibrogenesis. OBJECTIVES: Our aim was to analyse the influence of NNRTI-based therapy on the change in LS from starting direct-acting antiviral (DAA) therapy to achieving SVR in HIV/HCV-coinfected patients. METHODS: Three hundred and thirteen HIV/HCV-coinfected patients who fulfilled the following criteria were included: (i) had achieved SVR with an IFN-free, DAA-including regimen; (ii) LS ≥9.5 kPa before therapy; (iii) LS measurement available at SVR; (iv) seronegative for HBsAg; and (v) ART containing 2 NRTIs plus either 1 NNRTI or 1 integrase inhibitor (INI) or 1-2 NRTIs plus 1 PI. LS changes were assessed. RESULTS: Seventy-four patients received NNRTI-based combinations [53 (71.6%) rilpivirine and 16 (21.6%) efavirenz] and 239 patients received other regimens. At baseline, the median (IQR) LS was 16.7 kPa (11.8-25.6) in the NNRTI group and 17.3 kPa (11.9-27.4) in the non-NNRTI group (P = 0.278). The median (IQR) percentage of LS decrease from baseline to SVR was 35.2% (18.2%-52.3%) for NNRTI-based therapy and 29.5% (10%-45.9%) for PI- or INI-based therapy (P = 0.018). In multivariate analysis, adjusted for sex, age, HCV genotype, NRTI backbone and propensity score for HIV therapy, NNRTI-based regimen use was associated with a higher LS decrease [ß = 11.088 (95% CI = 1.67-20.51); P = 0.021]. CONCLUSIONS: Treatment with NNRTI plus 2 NRTI combinations is associated with a higher LS decline than other ART combinations in HIV/HCV-coinfected patients receiving DAA-based therapy.

Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families.

AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.

Navigable maps of structural brain networks across species.

Connectomes are spatially embedded networks whose architecture has been shaped by physical constraints and communication needs throughout evolution. Using a decentralized navigation protocol, we investigate the relationship between the structure of the connectomes of different species and their spatial layout. As a navigation strategy, we use greedy routing where nearest neighbors, in terms of geometric distance, are visited. We measure the fraction of successful greedy paths and their length as compared to shortest paths in the topology of connectomes. In Euclidean space, we find a striking difference between the navigability properties of mammalian and non-mammalian species, which implies the inability of Euclidean distances to fully explain the structural organization of their connectomes. In contrast, we find that hyperbolic space, the effective geometry of complex networks, provides almost perfectly navigable maps of connectomes for all species, meaning that hyperbolic distances are exceptionally congruent with the structure of connectomes. Hyperbolic maps therefore offer a quantitative meaningful representation of connectomes that suggests a new cartography of the brain based on the combination of its connectivity with its effective geometry rather than on its anatomy only. Hyperbolic maps also provide a universal framework to study decentralized communication processes in connectomes of different species and at different scales on an equal footing.

Proposal for a preventive protocol for medication-related osteonecrosis of the jaw.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some patients exposed to certain drugs (antiresorptives such as bisphosphonates or denosumab, and antiangiogenic drugs). From a review of the literature it appears that there is no uniform criterion when selecting preventive measures; these vary according to author. Likewise, the measures recommended are usually general, so that in few cases they result in specific actions to be applied depending on the different variables involved such as the type of drug used, the duration of its application, the underlying pathology, the presence or absence of risk factors, etc. The aim of this study has been to design a preventive protocol which can be easily applied in any clinic or by any dental care service. MATERIAL AND METHODS: We undertook an exhaustive literature review to find any articles related to the topic of study, namely, preventive measures for medication-related osteonecrosis of the jaw, on the one hand generically and on the other focusing on dental implant treatment. The most part the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. From 3946 items, we selected a total of 21 items. RESULTS: From the analysis of the selected articles, several protocols have been developed that are easy to apply in a dental clinic.: Protocol 1. Before starting treatment with antiresorptives (Patients who are going to be treated for osteoporosis / Patients who are going to be treated for cancer). Protocol 2. Once treatment is initiated with antiresorptives (Patients being treated for osteoporosis / Patients being treated for cancer). CONCLUSIONS: The application of these protocols requires an interdisciplinary team which can handle the various treatments and apply the measures contained in them. Along with a team of well-educated and trained dentists, it is equally important to maintain contact with the medical team involved in the treatment of the underlying pathology, especially rheumatologists, oncologists, internists and gynaecologists. All the above requires a great staff learning and organization effort, continuous training and coordination of the whole team involved in the preventive management of these patients.

POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

Epidemiology of Non-Tuberculous Mycobacteria isolated from clinical specimens in Madrid, Spain, from 2013 to 2017.

The epidemiology of non-tuberculous mycobacteria (NTM) in Spain is largely unknown because systematic reporting is not compulsory. The aim of our study was to describe the frequency and diversity of NTM species in our region and their distribution according to the source sample, gender, and age of the patients. We performed a multicenter study of all NTM isolated in 24 public hospitals in Madrid from 2013 to 2017. A total of 6.923 mycobacteria were isolated: 4535 (65.5%) NTM, and 2.388 (34.5%) Mycobacterium tuberculosis complex (MTB). Overall, 61 different NTM species were identified. The most frequently isolated species were Mycobacterium avium complex (47.7%), M. lentiflavum (12.2%), M. gordonae (9.2%), M. fortuitum (8.9%), and M. abscessus (3.9%). Whereas MTB cases were stable during the study period, the number of NTM isolates increased considerably from 930 isolates in 2013 to 1012 in 2017; a sharp increase occurred in the last year. The rise in NTM isolates was mostly due to M. lentiflavum, M. kansasii, and M. abscessus mainly isolated from respiratory specimens in patients older than 60. The increase in isolation rate of NTM in our region is consistent with the increasing rates reported worldwide in the last decades. The rise in NTM isolates was mainly attributed to M. lentiflavum but it also should be noted the increasing of species with high pathogenic potential such as M. kansasii and M. abscessus.

Short communication: Red deer (Cervus elaphus) colostrum during its transition to milk.

We studied changes in chemical composition, somatic cell count, and immunoglobulin G (IgG) and M (IgM) content in red deer (Cervus elaphus) colostrum during the transition to milk at different times after parturition (<5 h, 24 h, 48 h, 2 wk, and 4 wk). The production level was higher at 2 and 4 wk of lactation than during the first day after parturition, with intermediate values at 48 h postpartum. Fat content did not vary during the study period. However, total protein and casein contents were particularly high in the initial 5 h after parturition, decreasing to approximately 50% after 24 h postpartum. Conversely, lactose concentration was low in the beginning (<5 h), increasing gradually throughout the study. Similarly, dry matter dropped during the first 24 h and then remained constant throughout the study. Urea content decreased during the study, showing a slight recovery at 4 wk. Somatic cell count was higher during the first hours after parturition and gradually decreased throughout the study period. The IgG content was higher before 5 h postpartum than at 24 h postpartum. After 5 h, the level of IgG decreased progressively until it reached 0.18 mg/mL at 4 wk of lactation. We observed a similar pattern for IgM content, but it decreased more quickly than IgG and was not detected after 2 wk. In the case of deer, milk should be considered transitional from 24 to 48 h after parturition, and samples collected after 2 wk can be considered mature milk.

Metabolic plasticity in synthetic lethal mutants: Viability at higher cost.

The most frequent form of pairwise synthetic lethality (SL) in metabolic networks is known as plasticity synthetic lethality. It occurs when the simultaneous inhibition of paired functional and silent metabolic reactions or genes is lethal, while the default of the functional partner is backed up by the activation of the silent one. Using computational techniques on bacterial genome-scale metabolic reconstructions, we found that the failure of the functional partner triggers a critical reorganization of fluxes to ensure viability in the mutant which not only affects the SL pair but a significant fraction of other interconnected reactions, forming what we call a SL cluster. Interestingly, SL clusters show a strong entanglement both in terms of reactions and genes. This strong overlap mitigates the acquired vulnerabilities and increased structural and functional costs that pay for the robustness provided by essential plasticity. Finally, the participation of coessential reactions and genes in different SL clusters is very heterogeneous and those at the intersection of many SL clusters could serve as supertargets for more efficient drug action in the treatment of complex diseases and to elucidate improved strategies directed to reduce undesired resistance to chemicals in pathogens.

Effectiveness of a chat-bot for the adult population to quit smoking: protocol of a pragmatic clinical trial in primary care (Dejal@).

BACKGROUND: The wide scale and severity of consequences of tobacco use, benefits derived from cessation, low rates of intervention by healthcare professionals, and new opportunities stemming from novel communications technologies are the main factors motivating this project. Thus, the purpose of this study is to assess the effectiveness of an intervention that helps people cease smoking and increase their nicotine abstinence rates in the long term via a chat-bot, compared to usual practice, utilizing a chemical validation at 6 months. METHODS: Design: Randomized, controlled, multicentric, pragmatic clinical trial, with a 6-month follow-up. SETTING: Healthcare centers in the public healthcare system of the Community of Madrid (Madrid Regional Health Service). PARTICIPANTS: Smokers > 18 years of age who attend a healthcare center and accept help to quit smoking in the following month. N = 460 smokers (230 per arm) who will be recruited prior to randomization. Intervention group: use of a chat-bot with evidence-based contents to help quit smoking. CONTROL GROUP: Usual treatment (according to the protocol for tobacco cessation by the Madrid Regional Health Service Main variable: Continuous nicotine withdrawal with chemical validation (carbon monoxide in exhaled air). Intention-to-treat analysis. Difference between groups in continuous abstinence rates at 6 months with their corresponding 95% confidence interval. A logistic regression model will be built to adjust for confounding factors. RESULTS: First expected results in January 2020. DISCUSSION: Providing science-based evidence on the effectiveness of clinical interventions via information technologies, without the physical presence of a professional, is essential. In addition to being more efficient, the characteristics of these interventions can improve effectiveness, accessibility, and adherence to treatment. From an ethics perspective, this new type of intervention must be backed by scientific evidence to circumvent pressures from the market or particular interests, improve patient safety, and follow the standards of correct practices for clinical interventions. TRIAL REGISTRATION: ClinicalTrials.gov, reference number NCT03445507.

Circulating tumor cells criteria (CyCAR) versus standard RECIST criteria for treatment response assessment in metastatic colorectal cancer patients.

BACKGROUND: The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX-bevacizumab treatment response. METHODS: 77 mCRC blood samples from FOLFOX-bevacizumab treated patients were analyzed to isolate CTCs before and after (12 and 24 weeks) treatment, using an immunomagnetic separation method. VEGFR expression was identified by double immunostaining. RESULTS: We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02-0.58 and HR: 0.35, 95% CI 0.12-0.99 respectively). CONCLUSIONS: CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques.

Antiphospholipid syndrome and IgA anti-beta2-glycoprotein I antibodies: when Cinderella becomes a princess.

IgA anti-beta2-glycoprotein I (IgA-aB2GPI) antibodies are currently not included as a laboratory criterion of antiphospholipid syndrome (APS). In the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, (USA) in 2010, these antibodies were accepted as an APS laboratory criterion in patients who had clinical manifestations of APS but were negative for "consensus" antiphospholipid antibodies (aPL) (IgG and IgM isotypes). Consequently, individuals with thrombotic events who are negative for consensus aPL may be undiagnosed for APS. The most recent publications have confirmed that IgA-aB2GPI antibodies are a risk factor for thrombotic events. In this viewpoint, we propose that IgA-aB2GPI antibodies should be included as an APS consensus criterion and that we have to help Cinderella become a princess.