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STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with cardiovascular events (CVEs), although recent randomized controlled trials have not demonstrated that long-term continuous positive airway pressure (CPAP) prevents CVEs. Our objective was to determine the effect of CPAP on older adults with moderate OSA regarding CVE reduction. METHODS: An observational and multicenter study of a cohort of older adults (> 70 years of age) diagnosed with moderate OSA (apnea-hypopnea index 15.0–29.9 events/h) was conducted. Two groups were formed: (1) CPAP treatment and (2) standard of care. The primary endpoint was CVE occurrence after OSA diagnosis. Association with CPAP treatment was assessed by propensity score matching and inverse weighting probability. Secondary endpoints were incidence of CVE separately and time to first CVE. RESULTS: A total of 614 patients were included. After matching, 236 older adults (111 men, mean age 75.9 ± 4.7 years) with a follow-up of 47 months (interquartile range: 29.6–64.0 months) were considered for primary and secondary endpoint evaluations. Forty-one patients presented at least 1 CVE (17.4%): 20 were in the standard-of-care group (16.9%) and 21 were in the CPAP group (17.8%), with a relative risk of 1.05 (95% confidence interval [CI], 0.60–1.83; P = .43) for CPAP treatment. Inverse probability weighting of the initial 614 patients determined an adjusted relative risk of 1.24 (95% CI, 0.79–1.96; P = .35) for CPAP treatment. No statistical differences were found in secondary endpoint analyses. CONCLUSIONS: CPAP should not be prescribed to reduce CVE probability in older adults with moderate OSA. CITATION: López-Padilla D, Terán-Tinedo J, Cerezo-Lajas A, et al. Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score–matched multicenter study (CPAGE-MODE study). J Clin Sleep Med. 2022;18(2):553–561.

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations. This research was funded by INSTITUTO DE SALUD CARLOS III, institutional project Spain UDP and grant PT20CIII/00009. Sí

Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021 Sep;29(9):1470-1471. doi: 10.1038/s41431-021-00937-3. The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV), the European Research Council (ERC to RH), the Well come Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH), and the Evelyn Trust (RH). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. Sí

The main objective of this study was to analyze the degree of knowledge and compliance of Spanish pediatricians with the "do not do" recommendations of the Spanish Association of Pediatrics. A nationwide cross-sectional, descriptive study was carried out using a 25-item questionnaire among Spanish pediatricians. Univariate, bivariate, and multivariate analyses were performed. A total of 1137 pediatricians participated in the study. Most of them were women (75.1%), older than 55 (28.3%), worked in specialized care (56.9%), with public financing (91.2%), and had been working for more than 20 years (44.9%). The median of inappropriate answers per question was 9.1%. The bivariate and multivariate analyses showed that the factors that influenced higher adequacy to the "do not do" recommendations were younger than 45 years, working in specialized care, and working in the public health system.This research is the first nationwide study in Spain to analyze the adequacy of "do not do" pediatric clinical recommendations. The study showed a high level of compliance by Spanish pediatricians with these recommendations. However, there is a lack of knowledge in less frequent infectious pathologies such as HIV or fungal infections, in not prolonging antibiotic treatment unnecessarily and directing it appropriately according to the antibiogram results. These aspects may be improved by designing measures to enhance pediatricians' knowledge in these specific aspects. Some demographical factors are related to higher adequacy. Performing this research in other countries may allow assessing the current clinical practice of pediatricians.• Low-value care is defined as care that delivers little or no benefit, may cause patients harm, or outcomes marginal benefits at a disproportionately increased cost. • Few nationwide studies have assessed adherence to "do not do" guidelines, especially in pediatric settings.• Albeit there is a high level of compliance by Spanish pediatricians with the «do not do» recommendations, there is a lack of knowledge in different aspects that may be improved. • Some demographical factors are related to higher adequacy. Performing this research in other countries may allow assessing the current clinical practice of pediatricians.

Selective stopping is demanded in situations where responses must be suppressed to certain signals, but not others. To explore this type of inhibition, the standard stop-signal task has been modified to include a selective implementation of response inhibition by introducing a new stimulus that participants should ignore. However, a stimulus-selective stop-signal task can be performed following different strategies. Some participants fulfill the selective implementation of the stopping process after discriminating the stop and ignore signals, but some others stop the ongoing response whenever any new stimulus appears. The factors that influence this strategy choice are being explored, where both task and participant variables are under consideration. This study aimed to investigate whether the difficulty in discriminating between stop and ignore signals influences strategy adoption. Additionally, we examined whether participants modify their strategy in a flexible manner throughout the task in alternating easy and hard discrimination condition blocks. In the easy discrimination condition, the stop and the ignore signals differed both in color and shape, whereas in the hard discrimination condition, they only differed in shape. Our results from 64 participants revealed that manipulating the difficulty of signal discrimination strongly influenced strategy choice. Also, we found that participants can adapt their strategy according to task demands. They preferentially adopted a selective stopping strategy when discrimination was easy, whereas they changed to a nonselective stopping strategy under the hard discrimination condition. Overall, results from the current study suggest that signal discrimination difficulty influences the adoption of strategies in selective stopping.

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19., This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202).

52-year-old male. The patient had a stage IV renal carcinoma with bone metastases. He started first-line treatment with nivolumab (3 mg/kg) associated with ipilimumab (1 mg/kg). After two cycles of treatment, the patient reported hemorrhagic diarrhoea (7 to 10 stools daily), with visceral nociceptive abdominal pain of moderate intensity and oral intolerance.

Background Scabies is a neglected tropical disease of the skin, causing severe itching, stigmatizing skin lesions and systemic complications. Since 2015, the DerMalawi project provide an integrated skin diseases clinics and Tele-dermatology care in Malawi. Clinic based data suggested a progressive increase in scabies cases observed. To better identify and treat individuals with scabies in the region, we shifted from a clinic-based model to a community based outreach programme. Methodology/Principal findings From May 2015, DerMalawi project provide integrated skin diseases and Tele-dermatological care in the Nkhotakota and Salima health districts in Malawi. Demographic and clinical data of all patients personally attended are recorded. Due to a progressive increase in the number of cases of scabies the project shifted to a community-based outreach programme. For the community outreach activities, we conducted three visits between 2018 to 2019 and undertook screening in schools and villages of Alinafe Hospital catchment area. Treatment was offered for all the cases and school or household contacts. Scabies increased from 2.9% to 39.2% of all cases seen by the DerMalawi project at clinics between 2015 to 2018. During the community-based activities approximately 50% of the population was assessed in each of three visits. The prevalence of scabies was similar in the first two rounds, 15.4% (2392) at the first visit and 17.2% at the second visit. The prevalence of scabies appeared to be lower (2.4%) at the third visit. The prevalence of impetigo appeared unchanged and was 6.7% at the first visit and 5.2% at the final visit. Conclusions/Significance Prevalence of scabies in our setting was very high suggesting that scabies is a major public health problem in parts of Malawi. Further work is required to more accurately assess the burden of disease and develop appropriate public health strategies for its control., Author summary Scabies is an infestation of the skin caused by a mite. There is limited data on how common scabies is in sub-Saharan Africa, including Malawi. The DerMalawi project has been providing care for dermatological conditions in rural Malawi since 2015. Between 2015 and 2018 we observed an increase in patients with scabies attending for treatment. In response the project shifted from providing care at clinics to an approach using community-based outreach. Between 2018 and 2019 we conducted community-based activities on three occasions in an area of approximately 30,000 individuals. The DerMalawi team visited schools and villages to identify and treat cases of scabies and their contacts. We were able to examine about 50% of the population on each visit. Initially a large proportion of the population had scabies (15%) and this was similar during our second community survey. At our third survey this appeared to have decreased to 2% but it is difficult for us to know if this is because of treatment given in the previous rounds. Scabies is a major problem in rural populations in Malawi and public health strategies are needed to reduce the disease burden.

The impact of Covid-19 pneumonia caused by SARS-CoV-2 on transplanted populations under chronic immunosuppression seems to be greater than in normal population. Clinical management of the disease, particularly in those patients worsening after a cytokine storm, with or without allograft impairment and using available therapeutic approaches in the absence of specific drugs to fight against the virus, involves a major challenge for physicians. We herein provide evidence of the usefulness of high-dose intravenous immunoglobulin (IVIG) combined with steroid pulses to successfully treat a case of Covid-19 pneumonia in a single-kidney transplanted patient with mechanical ventilation and hemodialysis requirements in the setting of a cytokine storm. A rapid decrease in the serum level of inflammatory cytokines, particularly IL-6, IL-8, TNF-α, MCP-1 and IL-10, as well as of acute-phase reactants such as ferritin, D-dimer and C-reactive protein was observed after the IVIG infusion and methylprednisolone bolus administration with a parallel clinical improvement and progressive allograft function recovery, allowing the patient’s final discharge 40 days after the treatment onset. The immunomodulatory effect of IVIG together with the anti-inflammatory and immunosuppressive potential of steroids could be an alternative strategy to treat severe cases of Covid-19 pneumonia associated with an uncontrolled inflammatory response in transplanted populations.

Introduction There is an outstanding need to identify predictors of driving under the influence of alcohol (DUI) among young adults, particularly women. Impulsivity, or the tendency to act without thinking, is a predictor of DUI, but the specific facets of impulsivity that predict DUI and their interaction with sex differences remain unclear. We aimed to investigate sex differences in the link between impulsivity facets and DUI. Moreover, we sought to replicate previous findings regarding sex differences on impulsivity, and associations between impulsivity facets and DUI. Method A total of 506 university students participated in the study (males, n = 128; females, n = 378). Participants completed measures of impulsivity (UPPS-P short version), alcohol use (AUDIT-C), frequency of DUI episodes and related perception of risk. The UPPS-P assesses five facets of impulsivity: sensation seeking, (lack of) premeditation and perseverance and positive and negative urgency. Results Men showed higher sensation seeking and lack of perseverance, alcohol use and DUI frequency and lower risk perception than women. DUI frequency was negatively associated with perception of risk and positively associated with alcohol use and the five impulsivity facets. After controlling for alcohol use and risk perception, only lack of premeditation was associated with DUI frequency in the whole sample. Sensation seeking was positively associated with DUI frequency only in women. Discussion The link between lack of premeditation and DUI suggest that pre-drinking planning strategies can contribute to prevent risky driving. In women, specific links between sensation seeking and DUI suggest the need for personality-tailored prevention strategies.

Plasma samples from 72 EGFR‐mutant advanced NSCLC patients, collected upon progression to first‐line TKI, were analyzed by seven methodologies (two NGS‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods). Our study demonstrates a good to excellent agreement between methodologies and supports the use of liquid biopsies for therapy decision‐making., Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next‐generation sequencing (NGS)‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods were compared using 72 plasma samples, from EGFR‐mutant non‐small‐cell lung cancer (NSCLC) patients progressing on a first‐line tyrosine kinase inhibitor (TKI). NGS platforms as well as high‐sensitivity PCR‐based methodologies showed excellent agreement for EGFR‐sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false‐positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.

The transition from acute to chronic pain results in maladaptive brain remodeling, as characterized by sensorial hypersensitivity and the ensuing appearance of emotional disorders. Using the chronic constriction injury of the sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats, we identified time-dependent plasticity of locus coeruleus (LC) neurons related to the site of injury, ipsilateral (LCipsi) or contralateral (LCcontra) to the lesion, hypothesizing that the LC→dorsal reticular nucleus (DRt) pathway is involved in the pathological nociception associated with chronic pain. LCipsi inactivation with lidocaine increased cold allodynia 2 days after nerve injury but not later. However, similar blockade of LCcontra reduced cold allodynia 7 and 30 days after inducing neuropathy but not earlier. Furthermore, lidocaine blockade of the LCipsi or LCcontra reversed pain-induced depression 30 days after neuropathy. Long-term pain enhances phosphorylated cAMP-response element binding protein expression in the DRtcontra but not in the DRtipsi. Moreover, inactivation of the LCcontra→DRtcontra pathway using dual viral-mediated gene transfer of designer receptor exclusively activated by designer drugs produced consistent analgesia in evoked and spontaneous pain 30 days postinjury. This analgesia was similar to that produced by spinal activation of α2-adrenoreceptors. Furthermore, chemogenetic inactivation of the LCcontra→DRtcontra pathway induced depressive-like behaviour in naïve animals, but it did not modify long-term pain-induced depression. Overall, nerve damage activates the LCipsi, which temporally dampens the neuropathic phenotype. However, the ensuing activation of a LCcontra→DRtcontra facilitatory pain projection contributes to chronic pain, whereas global bilateral LC activation contributes to associated depressive-like phenotype.

Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (totaln = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%,p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was approximate to 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%,p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty., This study received funding from the Ministry of Science and Innovation (RETOS 2019 Grant no. PID2019-107332RB-I00), from the Instituto de Salud Carlos III (ISCIII; PI16/02110) and the European Regional Development Fund (ERDF) A way of making Europe (#AC16/00021), and from the Spanish Society of Cardiology through a 2017 Translational Research grant. BI has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC-Consolidator Grant agreement no. 819775). M.L received support from a 2015 Severo Ochoa CNIC intramural grant. X.R. received support from the SEC-CNIC CARDIOJOVEN fellowship program. R.F-J is a recipient of funding from the Carlos III Institute of Health-Fondo de Investigacion Sanitaria (PI19/01704) and has received funding from the European Union Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No 707642. EO is recipient of funds from Programa de Atraccion de Talento (2017-T1/BMD-5185) of Comunidad de Madrid. The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovacion (MICINN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

BACKGROUND: Noninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe OSA. However, there is paucity of evidence in patients with OHS without severe OSA phenotype. RESEARCH QUESTION: Is NIV effective in OHS without severe OSA phenotype? STUDY DESIGN AND METHODS: In this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index < 30 events/h (ie, no severe OSA) to NIV or lifestyle modification (control group) using simple randomization through an electronic database. The primary end point was hospitalization days per year. Secondary end points included other hospital resource utilization, incident cardiovascular events, mortality, respiratory functional tests, BP, quality of life, sleepiness, and other clinical symptoms. Both investigators and patients were aware of the treatment allocation; however, treating physicians from the routine care team were not aware of patients' enrollment in the clinical trial. The study was stopped early in its eighth year because of difficulty identifying patients with OHS without severe OSA. The analysis was performed according to intention-to-treat and per-protocol principles and by adherence subgroups. RESULTS: Forty-nine patients in the NIV group and 49 in the control group were randomized, and 48 patients in each group were analyzed. During a median follow-up of 4.98 years (interquartile range, 2.98-6.62), the mean hospitalization days per year +/- SD was 2.60 +/- 5.31 in the control group and 2.71 +/- 4.52 in the NIV group (adjusted rate ratio, 1.07; 95% CI, 0.44-2.59; P 1/4 .882). NIV therapy, in contrast with the control group, produced significant longitudinal improvement in PaCO2, pH, bicarbonate, quality of life (Medical Outcome Survey Short Form 36 physical component), and daytime sleepiness. Moreover, per-protocol analysis showed a statistically significant difference for the time until the first ED visit favoring NIV. In the subgroup with high NIV adherence, the time until the first event of hospital admission, ED visit, and mortality was longer than in the low adherence subgroup. Adverse events were similar between arms. INTERPRETATION: In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days per year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS.

Background Obesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities. Objectives We performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure. Methods Hospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed. Results In total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91-3.14) years for NIV group and 3.00 (2.92-3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups. Conclusion CPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA. Trial registration number NCT01405976, Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo) PI050402, Spanish Respiratory Foundation 2005 (FEPAR) and Air Liquide Spain.

Introduction and objectives Area at risk (AAR) quantification is important to evaluate the efficacy of cardioprotective therapies. However, postinfarction AAR assessment could be influenced by the infarcted coronary territory. Our aim was to determine the accuracy of T 2 -weighted short tau triple-inversion recovery (T 2 W-STIR) cardiac magnetic resonance (CMR) imaging for accurate AAR quantification in anterior, lateral, and inferior myocardial infarctions. Methods Acute reperfused myocardial infarction was experimentally induced in 12 pigs, with 40-minute occlusion of the left anterior descending (n = 4), left circumflex (n = 4), and right coronary arteries (n = 4). Perfusion CMR was performed during selective intracoronary gadolinium injection at the coronary occlusion site (in vivo criterion standard) and, additionally, a 7-day CMR, including T 2 W-STIR sequences, was performed. Finally, all animals were sacrificed and underwent postmortem Evans blue staining (classic criterion standard). Results The concordance between the CMR-based criterion standard and T 2 W-STIR to quantify AAR was high for anterior and inferior infarctions ( r = 0.73; P = .001; mean error = 0.50%; limits = −12.68%-13.68% and r = 0.87; P = .001; mean error = −1.5%; limits = −8.0%-5.8%, respectively). Conversely, the correlation for the circumflex territories was poor ( r = 0.21, P = .37), showing a higher mean error and wider limits of agreement. A strong correlation between pathology and the CMR-based criterion standard was observed ( r = 0.84, P Conclusions T 2 W-STIR CMR sequences are accurate to determine the AAR for anterior and inferior infarctions; however, their accuracy for lateral infarctions is poor. These findings may have important implications for the design and interpretation of clinical trials evaluating the effectiveness of cardioprotective therapies.

Colchicine demonstrated clinical benefits in the treatment of stable coronary artery disease. Our aim was to evaluate the effects of colchicine on atherosclerotic plaque stabilization. Atherosclerosis was induced in the abdominal aorta of 20 rabbits with high-cholesterol diet and balloon endothelial denudation. Rabbits were randomized to receive either colchicine or placebo. All animals underwent MRI, 18F-FDG PET/CT, optical coherence tomography (OCT), and histology. Similar progression of atherosclerotic burden was observed in the two groups as relative increase of normalized wall index (NWI). Maximum 18F-FDG standardized uptake value (meanSUVmax) decreased after colchicine treatment, while it increased in the placebo group with a trend toward significance. Animals with higher levels of cholesterol showed significant differences in favor to colchicine group, both as NWI at the end of the protocol and as relative increase in meanSUVmax. Colchicine may stabilize atherosclerotic plaque by reducing inflammatory activity and plaque burden, without altering macrophage infiltration or plaque typology. This work was supported by a grant from the Sociedad Española de Cardiología, a grant from the Instituto de Salud Carlos III of Spain and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”) (FIS-FEDER PI14-01427 to J. Mateo) and a grant from Fundación BBVA to J. Ruiz-Cabello. The CNIC is supported by the Instituto de Salud Carlos III, the Ministry of Science and Innovation and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). CIC biomaGUNE is supported by the Spanish State Research Agency of MICIN under the María de Maeztu Units of Excellence Program from MDM-2017-0720. Sí

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child and adolescent population, with a known impact on learning, social relations and quality of life. However, the lifestyle habits of patients with this disorder have been poorly studied.A total of 160 children and adolescents, aged between 6 and 16 years, participated in the study. Half of them were treatment-naïve patients with a clinical diagnosis of ADHD according to DSM-IV-TR criteria, and without comorbidities. The remaining 80 participants were typically developing (TD) controls without known neurodevelopmental or psychiatric disorders. Parents of all participants completed a questionnaire about their children´s lifestyle habits (e.g, daily hours of sleep, media use and study).The groups had a similar socioeconomic background and did not differ with respect to age and sex distribution. However, patients with ADHD spent more time than TD children studying, and less time watching TV, playing video games, using computers and playing with other people. They also slept fewer hours per night than children and adolescents with TD. ADHD and TD groups spent similar time reading, listening to music and playing sports.The results of this study suggest that children and adolescents with ADHD have different lifestyle habits compared to age- and sex-matched controls. These findings are not explained by comorbid disorders or medication/ psychological treatment.

Prostate cancer; Systems pathology; Wnt/β-catenin pathway Càncer de pròstata; Patologia de sistemes; Via Wnt/β-catenina Cáncer de próstata; Patología de sistemas; Vía Wnt/β-catenina OBJECTIVES: To apply a systems pathology-based approach to the quantification of nuclear Active β-catenin and human leukocyte antigen class I, and assess the biomarker involvement in a cohort of prostate tumor patients. RESULTS: The systems pathology approach applied allows a precise quantification of the marker expression in the different cell compartments as well as the determination of the areas that coexpress two markers. Our data shows that the accumulation of β-catenin in the nuclear compartment is significantly decreased in the adjacent normal areas when compared to tumor of the same patients (p

Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis., This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (SAF2015-64171-R and RTI2018-098645-B-I00). J.A.A. and E.P.V. was supported by a MINECO (BFU2015-64536) grant. I.S.P., E.B. and L.B. were co-financed by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Ciencia, Innovación y Universidades” (RTI2018-099778-B-I00) and the Ministerio de Salud-Instituto de Salud Carlos III (PI18/01691), as well as funding from the “Consejería de Salud de la Junta de Andalucía” (PI-0134-2018); the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud, Junta de Andalucía” (PI-0080-2017); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510); and the “Centro de Investigación Biomédica en Red de Salud Mental- CIBERSAM” (CB/07/09/0033).

Memorizing emotional stimuli in a preferential way seems to be one of the adaptive strategies brought on by evolution for supporting survival. However, there is a lack of electrophysiological evidence on this bias in working memory. The present study analyzed the influence of emotion on the updating component of working memory. Behavioral and electrophysiological indices were measured from a 3-back task using negative, neutral, and positive faces. Electrophysiological data evidenced an emotional influence on the working memory sensitive P3 component, which presented larger amplitudes for negative matching faces compared to neutral ones. This effect originated in the superior parietal cortex, previously reported to be involved in N-back tasks. Additionally, P3 results showed a correlation with reaction times, where higher amplitudes were associated with faster responses for negative matching faces. These findings indicate that electrophysiological measures seem to be very suitable indices of the emotional influence on working memory.

BACKGROUND Pre-reperfusion administration of intravenous (IV) metoprolol reduces infarct size in ST-segment elevation myocardial infarction (STEMI). OBJECTIVES This study sought to determine how this cardioprotective effect is influenced by the timing of metoprolol therapy having either a long or short metoprolol bolus-to-reperfusion interval. METHODS We performed a post hoc analysis of the METOCARD-CNIC (effect of METOprolol of CARDioproteCtioN during an acute myocardial InfarCtion) trial, which randomized anterior STEMI patients to IV metoprolol or control before mechanical reperfusion. Treated patients were divided into short-and long-interval groups, split by the median time from 15 mg metoprolol bolus to reperfusion. We also performed a controlled validation study in 51 pigs subjected to 45 min ischemia/reperfusion. Pigs were allocated to IV metoprolol with a long (-25 min) or short (-5 min) pre-perfusion interval, IV metoprolol post-reperfusion (+60 min), or IV vehicle. Cardiac magnetic resonance (CMR) was performed in the acute and chronic phases in both clinical and experimental settings. RESULTS For 218 patients (105 receiving IV metoprolol), the median time from 15 mg metoprolol bolus to reperfusion was 53 min. Compared with patients in the short-interval group, those with longer metoprolol exposure had smaller infarcts (22.9 g vs. 28.1 g; p = 0.06) and higher left ventricular ejection fraction (LVEF) (48.3\% vs. 43.9\%; p = 0.019) on day 5 CMR. These differences occurred despite total ischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001). There was no between-group difference in the time from symptom onset to metoprolol bolus. In the animal study, the long-interval group (IV metoprolol 25 min before reperfusion) had the smallest infarcts (day 7 CMR) and highest long-term LVEF (day 45 CMR). CONCLUSIONS In anterior STEMI patients undergoing primary angioplasty, the sooner IV metoprolol is administered in the course of infarction, the smaller the infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicated experimental large animal study. (C) 2016 by the American College of Cardiology Foundation. The authors thank Noemi Escalera and Maite Rodriguez, who were outstanding in the management of the clinical trial and imaging analyses. The authors are also indebted to the generous dedication of time and effort to the METOCARD-CNIC trial by all coinvestigators from SUMMA112, 061 Galicia, and SAMUR. The coordinating center at SCU-SUMMA112 was crucial for the proper conduct of the trial. Tamara Cordoba, Oscar Sanz, Ruben Mota, Santiago Rodriguez, Eugenio Fernández, and the rest of the team at the CNIC Animal Facility and farm provided outstanding animal care and support. Simon Bartlett (CNIC) provided English editing. Sí

Background and Aim Intermediate-risk patients following a colorectal cancer screening program may have differential risk of advanced lesions depending on the findings of an index colonoscopy. The aim of the present study was to comparatively assess advanced colorectal neoplasia risk at the first follow-up colonoscopy among the different intermediate-risk subgroups with a focus on patients with three to four adenomas. Methods All patients recruited for a baseline screening colonoscopy between 2006 and 2011 were included. Number, size and histopathological characteristics of adenomas were collected. Main outcome was an advanced colorectal neoplasia detection rate (invasive carcinoma or advanced adenoma) at the first follow-up colonoscopy. Low- and high-risk patients were excluded. Results Five hundred and sixty-one intermediate-risk patients (63.3% men, mean age: 59.01 ± 6.16 years) underwent indexing and follow-up colonoscopy. By multivariate analysis, three to four adenomas (OR: 3.613 [95% CI: 1.661–7.859], P = 0.001) and adenoma size ≥10

Although response inhibition is thought to be important in borderline personality disorder (BPD), little is known about its neurophysiological basis. This study aimed to provide insight into this issue by capitalizaing on the high temporal resolution of electroencephalography and information provided by source localization methods. To this end, twenty unmedicated patients with BPD and 20 healthy control subjects performed a modified go/no-go task designed to better isolate the brain activity specifically associated with response inhibition. Event-related potentials (ERP) were measured and further analyzed at the scalp and source levels. Patients with BPD made more commission errors (failed inhibitions) than control subjects. Scalp ERP data showed that both groups displayed greater frontocentral P3 amplitude for no-go (response inhbition) than for go trials (response execution). However, source reconstruction data revealed that patients with BPD activated posterior parietal regions (precuneus) to inhibit their responses, whereas controls activated prefrontal regions (presupplementary motor area, preSMA). This dissociation was supported by a significant Region (precuneus, preSMA) x Trial Type (no-go, go) x Group (BPD, control) interaction. These findings extend our understanding of the neurophysiological basis of abnormal response inhibition in BPD, suggesting that patients with BPD recruit different brain regions for inhibiting prepotent responses compared to controls. Future research in larger, medication-naive samples of patients with BPD is required to confirm and extend these findings.

Introduction: the incidence of cystic pancreatic lesions (CPL) in the asymptomatic population is increasing. Achieving a preoperative diagnosis of CPL still remains a challenge. Objectives: to evaluate the diagnostic accuracy of the cytological diagnosis of CPL from samples obtained by cytology brush versus standard endoscopic ultrasound fine needle aspiration (EUS-FNA). Methods: a multicenter, randomized, open-label trial was performed of EUS-cytology brush (EUS-EB) versus EUS-FNA for the cytological diagnosis of CPL. Patients that underwent EUS-FNA with a CPL > 15 mm were included and randomized into two groups: group I, EUS-EB; group II, EUS-FNA. The final diagnosis was based on the histological evaluation of surgical specimens and clinical parameters, imaging and a five year follow-up in non-operated patients. The main outcome was the diagnostic accuracy of both methods. Secondary outcomes were the diagnostic adequacy of specimens and the rate of adverse events. Data were compared using the Chi-squared test. An intention to treat (ITT) and per-protocol (PP) analysis were performed. Results: sixty-five patients were included in the study, 31 in group I and 34 in group II. Three patients initially randomized to group I were changed to group II as it was impossible to obtain a sample using the brush. The mean size of the CPL was 28.2 mm (range 16-60 mm). The diagnostic accuracy of EUS-EB was not superior to EUS-FNA, neither in the ITT nor the PP analysis (44.8% vs 41.1%, p = 0.77 and 38.4% vs 45.9%, p = 0.55). Conclusions: EUS-EB does not improve the diagnostic accuracy of CPL in comparison with EUS-FNA.

Wild boar (Sus scrofa) population spread into urban and periurban areas has exacerbated conflicts with humans. There is a need for planned wild boar management strategies, and Population viability analysis (PVA) combined with perturbation analyses allow the assessment of the management effort of control methods. Our study aims to develop stochastic predictive models of the increasing wild boar population of the 80 km2 peri-urban Mediterranean area of Collserola Natural Park (CNP), located near Barcelona, Spain, as well as assessing specific management measures (including reduced food availability, selective harvest, and reduction in fertility). Population parameters were estimated from previously published census and hunting data provided by the CNP and the local hunting administration. The results revealed that under the current conditions the CNP wild boar population will continue to increase. The most efficient strategy to reduce wild boar abundance was a combination of reducing supplementary anthropogenic food resources and selective removal of juvenile (

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma. This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers. Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5–68.9%) and 36.4% (95% CI, 27.8–45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1–47.5%) and 21.6% (95% CI, 14.5–28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%). Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients’ prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.

Several lines of evidence suggest that the dopamine transporter gene (DAT1) plays a crucial role in attention deficit hyperactivity disorder (ADHD). Concretely, recent data indicate that the 10-repeat (10R) DAT1 allele may mediate neuropsychological functioning, response to methylphenidate, and even brain function and structure in children with ADHD. This study aimed to investigate the influence of 10R DAT1 on thickness of the prefrontal cortex in children and adolescents with ADHD. To this end, brain magnetic resonance images were acquired from 33 patients with homozygosity for the 10R allele and 30 patients with a single copy or no copy of the allele. The prefrontal cortex of each MRI scan was automatically parceled into regions of interest (ROIs) based on Brodmann areas (BA). The two groups were matched for age, gender, IQ, ADHD subtype, symptom severity, comorbidity and medication status. However, patients with two copies of the 10R allele exhibited significantly decreased cortical thickness in right BA 46 relative to patients with one or fewer copies of the allele. No other prefrontal ROI differed significantly between the two groups. Present findings suggest that cortical thickness of right lateral prefrontal cortex (BA 46) is influenced by the presence of the DAT1 10 repeat allele in children and adolescents with ADHD.

BackgroundAlthough both emotion and response inhibition are thought to be important in attention-deficit/hyperactivity disorder (ADHD), little is known about the neural mechanisms that underlie the interaction between these two processes in patients with this disorder. This study aimed at examining how emotional contexts affect inhibitory control in children with ADHD.MethodA total of 24 ADHD children and 24 healthy comparison subjects performed a modified go/no-go task during three different emotionally laden contexts: negative, neutral and positive. To explore the timing and the underlying neural substrates of emotion-modulated response inhibition, event-related potentials were measured and further analysed both at the scalp and at the voxel level.ResultsPatients with ADHD showed greater activation of inhibition-related neural mechanisms (i.e. no-go P3 amplitudes and orbitofrontal cortex activity) to maintain a similar level of performance as healthy comparison subjects, especially during the emotionally arousing contexts (negative and positive).ConclusionsThis study provides plausible neural mechanisms for the difficulty that ADHD children have in controlling their behaviour in highly emotional situations. Such emotional contexts might increase the need for top-down inhibitory control and put ADHD children at greater risk for impulsive behaviours and emotional dysregulation.

Nevus anemicus (NA) is a cutaneous anomaly characterized by pale, well-defined patches with limited vascularization after rubbing. They are largely known to be associated with neurofibromatosis 1 (NF1) and have received little attention in the literature until recently. We sought to characterize the prevalence and clinical features of patients with NA and NF1. We conducted an observational prospective study of 99 children with NF1 at the Hospital Niño Jesús, Madrid, Spain, from January 1, 2012, through July 31, 2013, and reviewed three other series of patients with NF1 and NA recently reported. The prevalence of NA in children with NF1 ranged from 8.8% to 51%, being much more prevalent at younger ages. Prospective studies yielded a higher prevalence than retrospective studies. NA was located most commonly on the trunk, particularly on the anterior chest wall, and was often multiple. Patients with segmental NF1 or isolated café au lait spots rarely had NA, and NA was absent in other genodermatoses. The collection of data was not homogeneous in all studies. NA has a high prevalence in individuals with NF1 patients but seems to be absent in connection with other genodermatoses, therefore its presence can assist in the diagnosis of suspected cases of NF1. The subtle clinical appearance of NA makes its detection difficult, and physicians involved in the care of children with NF1 must be aware of its possible presence and significance.

Background and Aim There are few data concerning emergency double-balloon enteroscopy (DBE) and its usefulness in the management of severe acute obscure gastrointestinal bleeding (OGIB). The aim of this retrospective study was to evaluate emergency DBE and capsule endoscopy (CE) in patients with overt OGIB, analyzing the feasibility of this combined approach. Methods Emergency DBE in patients with overt OGIB was defined as performance within 24 h of symptom onset. We reported 27 patients (16 men, mean age: 64.6 ± 17.9 years) with overt severe bleeding who underwent 29 emergency DBE (22 anterograde, 7 retrograde). Of 27 patients, 16 (59.3%) underwent CE with real time (RT) viewing. Results Patients were diagnosed with the following: Dieulafoy's lesion (DL; n = 11, 40.7%), angioectasia (n = 7, 25.9%), tumors (n = 4, 14.8%), diverticulum (n = 3, 11.1%), ulcers (n = 2, 7.4%). We diagnosed 23 lesions amenable to endoscopic hemostasis and successfully treated 21 of them (77.8%). DL detection rate was statistically higher in the emergency DBE group than in OGIB patients with DBE done 24 h after symptom onset (40.7% vs 0.9%, respectively, P

Introduction: Docetaxel and erlotinib are registered second line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial.Methods: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC.Results: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events.Conclusions: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p=0.24 for PFS and 0.45 for OS, stratified by study). (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Rationale: The impact of cardioprotective strategies and ischemia duration on postischemia/reperfusion (I/R) myocardial tissue composition (edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction) is not well understood. Objective: To study the effect of ischemia duration and protective interventions on the temporal dynamics of myocardial tissue composition in a translational animal model of I/R by the use of state-of-the-art imaging technology. Methods and Results: Four 5-pig groups underwent different I/R protocols: 40-minute I/R (prolonged ischemia, controls), 20-minute I/R (short-duration ischemia), prolonged ischemia preceded by preconditioning, or prolonged ischemia followed by postconditioning. Serial cardiac magnetic resonance (CMR)-based tissue characterization was done in all pigs at baseline and at 120 minutes, day 1, day 4, and day 7 after I/R. Reference myocardium at risk was assessed by multidetector computed tomography during the index coronary occlusion. After the final CMR, hearts were excised and processed for water content quantification and histology. Five additional healthy pigs were euthanized after baseline CMR as reference. Edema formation followed a bimodal pattern in all 40-minute I/R pigs, regardless of cardioprotective strategy and the degree of intramyocardial hemorrhage or microvascular obstruction. The hyperacute edematous wave was ameliorated only in pigs showing cardioprotection (ie, those undergoing short-duration ischemia or preconditioning). In all groups, CMR-measured edema was barely detectable at 24 hours postreperfusion. The deferred healing-related edematous wave was blunted or absent in pigs undergoing preconditioning or short-duration ischemia, respectively. CMR-measured infarct size declined progressively after reperfusion in all groups. CMR-measured myocardial salvage, and the extent of intramyocardial hemorrhage and microvascular obstruction varied dramatically according to CMR timing, ischemia duration, and cardioprotective strategy. Conclusions: Cardioprotective therapies, duration of index ischemia, and the interplay between these greatly influence temporal dynamics and extent of tissue composition changes after I/R. Consequently, imaging techniques and protocols for assessing edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction should be standardized accordingly.

Bladder cancer is the second most frequent malignancy of the urinary tract after prostate cancer. Current diagnostic techniques, such as cystoscopy and biopsies are highly invasive and accompanied of undesirable side effects. Moreover, there are no suitable biomarkers for relapse or progression prognosis. We analysed whether the specific composition of microRNAs (miRNAs) and proteins of extracellular vesicles (EVs) that urothelial tumour cells of bladder mucosa release into the urine, could reflect their pathologic condition. For this purpose, urinary EVs were isolated and their protein and miRNA composition evaluated in healthy donors and low or high-grade bladder cancer patients. Using a microarray platform containing probes for 851 human miRNAs we found 26 deregulated miRNAs in high-grade bladder cancer urine EVs, from which 23 were downregulated and 3 upregulated. Real-time PCR analysis pointed to miR-375 as a biomarker for high-grade bladder cancer while miR-146a could identify low-grade patients. Finally, several protein markers were also deregulated in EVs from tumour patients. Our data suggest that the presence of ApoB in the 100,000 pellet is a clear marker for malignancy., Instituto de Salud Carlos III (co-funded by Fondo Europeo de Desarrollo Regional (FEDER)) (PIE13/00041); BFU2014-55478-R from Ministerio de Economía y Competitividad (BFU2014-55478-R); and from Fundación Ramón Areces to MY-M. Z.A. was supported by Juan de la Cierva

Structural and functional brain studies on attention deficit/hyperactivity disorder (ADHD) have primarily examined anatomical abnormalities in the prefronto-striatal circuitry (especially, dorsal and lateral areas of the prefrontal cortex and dorsal striatum). There is, however, increased evidence that several temporal lobe regions could play an important role in ADHD. The present study used MRI-based measurements of cortical thickness to examine possible differences in both prefrontal and temporal lobe regions between medication-naive patients with ADHD ( N =50) and age- and sex-matched typically developing controls ( N =50). Subjects with ADHD exhibited significantly decreased cortical thickness in the right temporal pole and orbitofrontal cortex (OFC) relative to healthy comparison subjects. These differences remained significant after controlling for confounding effects of age, overall mean cortical thickness and comorbid externalizing conditions, such as oppositional defiant and conduct disorders. These results point to the involvement of the temporal pole and OFC in the neuropathology of ADHD. Moreover, present findings add evidence to the assumption that multiple brain regions and psychological processes are associated with ADHD.

Case report We describe an unusual clinical case with an 11Mb deletion at 4q27 (chr4: 123094652-134164491), craniosynostosis (CS), mild psychomotor retardation, and facial dysmorphic features. This deletion involves 18 genes; FGF2, NUDT6, and SPRY1 are primarily or secondarily implicated in human cranial bone and sagittal suture development and could play an important role in CS. Conclusions Clinicians should always contemplate genetic studies in patients with syndromic CS. Mutational targeted genetic testing is appropriate for patients with classical or specific CS syndrome. Nevertheless, array comparative genomichybridization(arrayCGH)shouldbeconsideredasafirstline test in nontypical syndromic CS phenotype. Cytogenetic studies are decisive for genetic counseling indeed.

(1) The present study aims to explore the impact of job demands and resources (JDR), personal resources, and the organizational culture on workers&rsquo, wellbeing and health. (2) A cross-sectional survey of Spanish workers in small and medium-sized enterprises (SMEs) was conducted with a sample of 1599 workers from 154 SMEs. A multivariate multilevel analysis was performed to analyze the different relationships. (3) In light of the results obtained, we observed that job demands were negatively associated with workers&rsquo, health, while job resources were positively correlated to workers&rsquo, health and wellbeing. Secondly, the different types of identification at work are positively related to job satisfaction and organizational citizenship behaviors (OCBs), but the intensity of this association differs with the form of identification. Finally, at the organization level, the dimensions of organizational culture are related differently to employees&rsquo, job satisfaction, OCBs, and health, (4) these results confirm the role of organizational culture and its association with desirable outcomes, allowing us to expand the JDR model.

Background Knee osteoarthritis mainly affecting the lateral facet of the patella, especially in young patients, is a definite challenge to the surgeon. Our purpose was to investigate the long-term outcome of a simple operation such as the partial lateral facetectomy on middle-aged to elderly patients with predominant lateral patellofemoral osteoarthritis. Methods A retrospective, long-term study of 39 knees (28 females, mean aged at surgery 61 years old) with a minimum follow-up of 10 years was performed. Evaluations included preoperative and postoperative questionnaires, physical examinations, and radiographs. Results The main outcomes included the initial anterior pain relief, with higher scores using the Knee Society Score (that improved in 84% of the knees), and the eventual failure of the technique, including percentage of patients that required secondary total knee replacement (30% of the knees). Conclusion Partial lateral facetectomy aiming to decrease the high pressure in the lateral facet of the patella confirmed frequent pain relief. This surgical procedure being minimally invasive, relatively simple, and effective in selected patients, is a valid early alternative to more complex operations and does not preclude further reconstructive surgery in case of disease progression.

Background: Although phase III studies have investigated the effect of adding bevacizumab to the 3-weekly capecitabine plus irinotecan (XELIRI) combination in the first-line treatment of metastatic colorectal cancer (mCRC), no phase III studies investigating the effects of adding bevacizumab to biweekly XELIRI have been published. Patients and Methods: A retrospective pooled analysis of 2 single-arm phase II studies was performed. Previously untreated patients with mCRC received irinotecan 175 mg/m2 on day 1 followed by capecitabine 1,000 mg/m2 twice daily on days 2-8 every 2 weeks with or without bevacizumab 5 mg/kg on day 1. Results: In total, 53 patients received XELIRI, and 46 patients received XELIRI plus bevacizumab. There was a statistically significant increase in partial response rate with XELIRI plus bevacizumab (63 vs. 26% for XELIRI; p = 0.0002) and overall response rate (67 vs. 32%; p = 0.0005). Median time to disease progression was significantly longer with XELIRI plus bevacizumab (12.3 vs. 9.0 months for XELIRI; p = 0.012); median overall survival did not differ significantly between treatments (23.7 vs. 19.3 months; p = 0.4997). The proportion of patients experiencing at least 1 grade 3/4 adverse event was similar with both treatments (XELIRI, 47%; XELIRI plus bevacizumab, 44%). Conclusion: This retrospective pooled analysis suggests that XELIRI plus bevacizumab has an acceptable tolerability profile and improves efficacy outcomes compared with XELIRI in the first-line treatment of mCRC.

Objective: This study aimed to examine the influence of dopamine transporter gene ( DAT1) 3’UTR genotype on cingulate cortical thickness in a large sample of children and adolescents with ADHD. Method: Brain MRIs were acquired from 46 ADHD patients with homozygosity for the 10-repeat allele and 52 ADHD patients with a single copy or no copy of the allele. The cingulate cortex of each MRI scan was automatically parceled into sulci and gyri as well as into Brodmann areas (BA). Results: There were no group differences in age, gender, full-scale intelligence quotient, symptom severity, treatment status, comorbidity, or mean overall cortical thickness. Sulcus/gyrus- and BA-based analyses revealed that patients homozygous for the 10-repeat allele showed significantly greater thickness in right cingulate gyrus and right BA 24 compared with 9-repeat carriers. Conclusion: These findings suggest that thickness of cingulate cortex is influenced by the presence of the 10-repeat allele in ADHD.

To compare presurgical hand hygiene with hydroalcoholic solution following the WHO protocol with traditional presurgical hand hygiene.Cultures of the hands of surgeons and surgical nurses were performed before and after presurgical hand hygiene and after removing gloves at the end of surgery. Cultures were done in 2different days: the first day after traditional presurgical hand hygiene, and the second day after presurgical hand hygiene with hydroalcoholic solution following the WHO protocol. The duration of the traditional hand hygiene was measured and compared with the duration (3min) of the WHO protocol. The cost of the products used in the traditional technique was compared with the cost of the hydroalcoholic solution used. The variability of the traditional technique was determined by observation.Following presurgical hand hygiene with hydroalcoholic solution, colony-forming units (CFU) were detected in 5 (7.3%) subjects, whereas after traditional presurgical hand hygiene CFU were detected in 14 subjects (20.5%) (p0.05). After glove removal, the numbers of CFU were similar. The time employed in hand hygiene with hydroalcoholic solution (3min) was inferior to the time employed in the traditional technique (p0.05), its cost was less than half, and there was no variability.Compared with other techniques, presurgical hand hygiene with hydroalcoholic solution significantly decreases CFU, has similar latency time, a lower cost, and saves time.

Background Obesity hypoventilation syndrome (OHS) is associated with a high burden of cardiovascular morbidity (CVM) and mortality. The majority of patients with OHS have concomitant OSA, but there is a paucity of data on the association between CVM and OSA severity in patients with OHS. The objective of our study was to assess the association between CVM and OSA severity in a large cohort of patients with OHS. Methods In a cross-sectional analysis, we examined the association between OSA severity based on tertiles of oxygen desaturation index (ODI) and CVM in 302 patients with OHS. Logistic regression models were constructed to quantify the independent association between OSA severity and prevalent CVM after adjusting for various important confounders. Results The prevalence of CVM decreased significantly with increasing severity of OSA based on ODI as a continuous variable or ODI tertiles. This inverse relationship between OSA severity and prevalence of CVM was seen in the highest ODI tertile and it persisted despite adjustment for multiple confounders. Chronic heart failure had the strongest negative association with the highest ODI tertile. No significant CVM risk change was observed between the first and second ODI tertiles. Patients in the highest ODI tertile were younger, predominantly male, more obese, more hypersomnolent, had worse nocturnal and daytime gas exchange, lower prevalence of hypertension, better exercise tolerance, and fewer days hospitalized than patients in the lowest ODI tertile. Conclusions In patients with OHS, the highest OSA severity phenotype was associated with reduced risk of CVM. This finding should guide the design of future clinical trials assessing the impact of interventions aimed at decreasing cardiovascular morbidity and mortality in patients with OHS. Trial Registry Clinicaltrial.gov; No.: NCT01405976 ; URL: www.clinicaltrials.gov

Background Non-invasive ventilation (NIV) is an effective form of treatment in patients with obesity hypoventilation syndrome (OHS) who have concomitant severe obstructive sleep apnoea (OSA). However, there is a paucity of evidence on the efficacy of NIV in patients with OHS without severe OSA. We performed a multicentre randomised clinical trial to determine the comparative efficacy of NIV versus lifestyle modification (control group) using daytime arterial carbon dioxide tension (PaCO2) as the main outcome measure. Methods Between May 2009 and December 2014 we sequentially screened patients with OHS without severe OSA. Participants were randomised to NIV versus lifestyle modification and were followed for 2 months. Arterial blood gas parameters, clinical symptoms, health-related quality of life assessments, polysomnography, spirometry, 6-min walk distance test, blood pressure measurements and healthcare resource utilisation were evaluated. Statistical analysis was performed using intention-to-treat analysis. Results A total of 365 patients were screened of whom 58 were excluded. Severe OSA was present in 221 and the remaining 86 patients without severe OSA were randomised. NIV led to a significantly larger improvement in PaCO2 of −6 (95% CI −7.7 to −4.2) mm Hg versus −2.8 (95% CI −4.3 to −1.3) mm Hg, (p

Negative stimuli have consistently been shown to efficiently attract exogenous attention. Two different types of unpleasant stimuli, disgusting and fearful, sharing similar arousal and valence, are usually employed as a single category. However, since they diverge in several important aspects (biological functionality, associated feelings, and central and peripheral physiological correlates), it may be expected that their potential to capture attention differs. Event-related potentials and behavioral indices were recorded while participants were engaged in a digit categorization task in response to three types of irrelevant, distracting pictures: disgusting, fearful and neutral. Disgusting trials were associated with worse performance than fearful trials in the digit categorization task as revealed by reaction times and number of errors. Moreover, P2-associated cuneus activation and scalp anterior P2 amplitude were greater for disgusting than for fearful distracters. All these indices reveal that, under the experimental conditions employed in the present study, disgusting distracters are more efficient at attracting exogenous attention than are fearful distracters.

One of the IRDiRC goals for 2017–2027 is to achieve definitive diagnosis for rare undiagnosed diseases within one year, as delay in diagnosis remains one of the pending issues in the rare diseases field. The Spanish Undiagnosed Rare Diseases Program (SpainUDP) was created in response to this challenging scenario to cover patients’ needs and after seeing the success of the Undiagnosed Diseases Program (UDP) in the USA. SpainUDP offers a multidisciplinary approach to those patients who have long sought a diagnosis without any success. During the first phase of the protocol, undiagnosed cases are sent to SpainUDP by individual patients or families, patient organizations or hospitals. After careful analysis of phenotype, data from sequencing experiments (WES) is processed with a standard pipeline and detailed standardized phenotypic information (mapped to the Human Phenotype Ontology, HPO) is connected to genetic data. In addition, the participation of SpainUDP in international initiatives such as the European projects RD-Connect and Solve RD, the Undiagnosed Diseases Network International (UDNI), and the MatchMaker Exchange (MME) platform, allows the establishment of a global data sharing strategy across multiple projects submitting data to these international initiatives. From the official beginning of the program (at the end of 2015) until early 2018, 147 cases were accepted in SpainUDP. During this time, 37 cases (25%) dropped out the program due to several reasons. The remaining 110 cases are distributed as follows: phenotypic and genotypic (WES) characterization was finished in 30 cases, of which 20 (67%) were diagnosed, 21 cases are pending on variants’ validation by Sanger sequencing, in 25 cases, WES is ongoing and 34 cases are being studied for deep phenotypic characterization. In conclusion, SpainUDP aims to achieve a diagnosis following two recommendations of the IRDiRC: the patients’ diagnosis in as short a time as possible and the promotion of data sharing (especially genomic) at the international level.