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Purpose Approximately 1–2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. Methods BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). Results In total, 330 blood samples (2–34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. Conclusions Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines, This project has been financed with SEOM and SEFF resources

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionized the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children and are either rare tumours with common NTRK fusions that may be diagnostic, or more common tumours with rare NTRK fusions. To assess the currently available evidence, 3key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathology (SEAP) and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical and therapeutic aspects of NTRK-fusion tumours. It also discusses the challenges related to the routine detection of these genetic alterations in a mostly public health care system.

[Background] Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain., [Methods] Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019., [Results] A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28–10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81–51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2–18 years of age compared with children 0–2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47)., [Conclusions] We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases., [Antecedentes] Las neumopatías intersticiales pediátricas, también conocidas con el acrónimo chILD (del inglés children's Interstitial Lung Diseases), es un grupo heterogéneo de enfermedades raras con morbimortalidad relevante, cuyo diagnóstico y clasificación son complejos. Los estudios epidemiológicos son escasos. El objetivo de este trabajo fue analizar la incidencia y la prevalencia de chILD en España., [Métodos] Estudio prospectivo observacional multicéntrico en pacientes de 0 a 18 años afectos de chILD para analizar la incidencia y la prevalencia en España, a partir de datos recogidos en 2018 y 2019., [Resultados] Se recogieron 381 casos de chILD entre 51 unidades de neumología pediátrica de toda España, que cubrían el 91,7% de la población pediátrica. La incidencia promedio fue 8,18 (IC 95%: 6,28-10,48) casos nuevos/millón de niños por año. La prevalencia promedio fue de 46,53 (IC 95%: 41,81-51,62) casos/millón de niños. El grupo de edad con mayor prevalencia fue el de niños menores de un año. Se observaron diferentes entidades en niños de 2 a 18 años en comparación con niños de 0 a 2 años. Los diagnósticos más frecuentes fueron: glucogenosis intersticial pulmonar primaria en neonatos (17/65), hiperplasia de células neuroendocrinas en lactantes de uno a 12 meses (44/144), hemosiderosis pulmonar idiopática en niños de uno a 5 años (13/74), neumonía por hipersensibilidad en niños de 5 a 10 años (9/51) y esclerodermia en mayores de 10 años (8/47)., [Conclusiones] Encontramos una mayor incidencia y prevalencia de chILD que las descritas previamente, probablemente debido a un mayor conocimiento y detección de estas enfermedades raras., ATV was supported by a grant from the Spanish Society of Paediatric Pulmonology and a Short Term Scientific Mission of the Cost CA 16125 ENTeR-chILD. This work was supported by a grant from the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2017/492). AMG was supported by a grant from the project HCQ4Surfdefect, in E-Rare-3, the ERA-Net for Research on Rare Diseases (Acciones complementarias en Salud, Instituto Carlos III, Madrid, Spain, AC16/00027) and Cost CA 16125 ENTeR-chILD.

The discovery of a high-energy cosmic neutrino flux has paved the way for the field of neutrino astronomy. For a large part of the flux, the sources remain unidentified. The KM3NeT detector, which is under construction in the Mediterranean sea, is designed to determine their origin. KM3NeT will instrument a cubic kilometre of seawater with photomultiplier tubes that detect Cherenkov radiation from neutrino interaction products with nanosecond precision. For single cascade event signatures, KM3NeT already showed that it can reach degree-level resolutions, greatly increasing the use of these neutrinos for astronomy. In this contribution, we further refine the cascade reconstruction by making a more detailed model of the neutrinos events and including additional information on the hit times. The arrival time of light can be used to improve the identification of double cascade signatures from tau neutrinos, and the angular resolution of both single and double cascade signatures. Sub-degree resolution is achieved in both cases., Comment: 10 pages, 5 figures, ICRC 2021 contribution

[EN] Prostate cancer is one of the main diseases affecting men worldwide. The gold standard for diagnosis and prognosis is the Gleason grading system. In this process, pathologists manually analyze prostate histology slides under microscope, in a high time-consuming and subjective task. In the last years, computer-aided-diagnosis (CAD) systems have emerged as a promising tool that could support pathologists in the daily clinical practice. Nevertheless, these systems are usually trained using tedious and prone-to-error pixel-level annotations of Gleason grades in the tissue. To alleviate the need of manual pixel-wise labeling, just a handful of works have been presented in the literature. Furthermore, despite the promising results achieved on global scoring the location of cancerous patterns in the tissue is only qualitatively addressed. These heatmaps of tumor regions, however, are crucial to the reliability of CAD systems as they provide explainability to the system's output and give confidence to pathologists that the model is focusing on medical relevant features. Motivated by this, we propose a novel weakly-supervised deeplearning model, based on self-learning CNNs, that leverages only the global Gleason score of gigapixel whole slide images during training to accurately perform both, grading of patch-level patterns and biopsy-level scoring. To evaluate the performance of the proposed method, we perform extensive experiments on three different external datasets for the patch-level Gleason grading, and on two different test sets for global Grade Group prediction. We empirically demonstrate that our approach outperforms its supervised counterpart on patch-level Gleason grading by a large margin, as well as state-of-the-art methods on global biopsylevel scoring. Particularly, the proposed model brings an average improvement on the Cohen's quadratic kappa (kappa) score of nearly 18% compared to full-supervision for the patch-level Gleason grading task. This suggests that the absence of the annotator's bias in our approach and the capability of using large weakly labeled datasets during training leads to higher performing and more robust models. Furthermore, raw features obtained from the patchlevel classifier showed to generalize better than previous approaches in the literature to the subjective global biopsylevel scoring., This work was supported by the Spanish Ministry of Economy and Competitiveness through Projects DPI2016-77869 and PID2019-105142RB-C21.

Susac-syndrome is a rare autoimmune disease that manifests with mood alterations in up to 15% of cases and is usually treated with corticosteroids. We present the case of a 41-year-old woman with a first manic episode and history of Susac-syndrome, secondary Cushing's syndrome after receiving high doses of corticosteroids and a previous depressive episode. Differentiating between primary and secondary mania is difficult, as people with bipolar disorder are prone to multiple psychiatric and nonpsychiatric comorbidities, in this case, the differential diagnosis included secondary mania, corticoid-induced manic episode and primary bipolar disorder. Upon admission, corticosteroid treatment was suspended, and the patient was started on lithium and risperidone. Secondary causes of mania were discarded and, assessing temporal and dosage criteria, it was deemed unlikely that the present episode was corticosteroid-induced. One-year outpatient follow-up pointed towards a primary bipolar type I disorder, as a separate entity from her Susac-syndrome. Corticosteroid use or abrupt withdrawal pose an underestimated risk of inducing depressive or manic symptoms, which may unmask affective disorders in susceptible individuals. Many medical conditions share CNS involvement and/or high-dose/prolonged corticosteroid treatment. In such cases, psychiatric manifestations such as mania or depression should be regarded as secondary and studied to determine the existence of medical complications before considering primary psychiatric conditions.

Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy characterized by the proliferation and accumulation of mature CD5+ B cells in the peripheral blood (PB), bone marrow (BM) and lymphoid ti...

Introduction: Unilateral resistance training has been shown to improve muscle strength in both the trained and the untrained limb. One of the most widely accepted theories is that this improved performance is due to nervous system adaptations, specifically in the primary motor cortex. According to this hypothesis, increased corticospinal excitability (CSE), measured with transcranial magnetic stimulation, is one of the main adaptations observed following prolonged periods of training. The principal aim of this review is to determine the degree of adaptation of CSE and its possible functional association with increased strength in the untrained limb. Development: We performed a systematic literature review of studies published between January 1970 and December 2016, extracted from Medline (via PubMed), Ovid, Web of Science, and Science Direct online databases. The search terms were as follows: (transcranial magnetic stimulation OR excitability) AND (strength training OR resistance training OR force) AND (cross transfer OR contralateral limb OR cross education). A total of 10 articles were found. Conclusion: Results regarding increased CSE were inconsistent. Although the possibility that the methodology had a role in this inconsistency cannot be ruled out, the results appear to suggest that there may not be a functional association between increases in muscle strength and in CSE. Resumen: Introducción: El entrenamiento de fuerza unilateral ha demostrado provocar aumentos de fuerza tanto en la extremidad entrenada como en la no entrenada. Una de las teorías actuales más aceptadas defiende que el origen de dicho aumento de rendimiento se encuentra en adaptaciones en el sistema nervioso, concretamente en la corteza motora primaria, siendo los aumentos en la excitabilidad corticoespinal (EC) medida con estimulación magnética transcraneal una de las principales adaptaciones observadas tras periodos crónicos de entrenamiento. Por ello, el principal objetivo es hacer un análisis de la literatura actual para determinar el grado de adaptación que se da en la EC y su posible relación funcional con el aumento de fuerza de la extremidad no entrenada. Desarrollo: Se llevó a cabo una búsqueda sistemática en la literatura existente entre enero de 1970 hasta diciembre de 2016 en las bases de datos online Medline (vía PubMed), Ovid, Web of Science y Science Direct con la siguiente estrategia de búsqueda: (Transcranial magnetic stimulation OR excitability) Y (strength training OR resistance training or force) Y (cross transfer OR contralateral limb OR cross education). Finalmente se incluyeron un total de 10 artículos. Conclusiones: Existe cierta inconsistencia en los resultados referentes al aumento de la EC. Aunque no se puede descartar que dicha inconsistencia se deba a aspectos metodológicos, los resultados parecen indicar que el aumento de fuerza y el incremento en la EC podrían no estar funcionalmente relacionados.

Resumen: Introducción: El entrenamiento de fuerza unilateral ha demostrado provocar aumentos de fuerza tanto en la extremidad entrenada como en la no entrenada. Una de las teorías actuales más aceptadas defiende que el origen de dicho aumento de rendimiento se encuentra en adaptaciones en el sistema nervioso, concretamente en la corteza motora primaria, siendo los aumentos en la excitabilidad corticoespinal (EC) medida con estimulación magnética transcraneal una de las principales adaptaciones observadas tras periodos crónicos de entrenamiento. Por ello, el principal objetivo es hacer un análisis de la literatura actual para determinar el grado de adaptación que se da en la EC y su posible relación funcional con el aumento de fuerza de la extremidad no entrenada. Desarrollo: Se llevó a cabo una búsqueda sistemática en la literatura existente entre enero de 1970 hasta diciembre de 2016 en las bases de datos online Medline (vía PubMed), Ovid, Web of Science y Science Direct con la siguiente estrategia de búsqueda: (Transcranial magnetic stimulation OR excitability) Y (strength training OR resistance training or force) Y (cross transfer OR contralateral limb OR cross education). Finalmente se incluyeron un total de 10 artículos. Conclusiones: Existe cierta inconsistencia en los resultados referentes al aumento de la EC. Aunque no se puede descartar que dicha inconsistencia se deba a aspectos metodológicos, los resultados parecen indicar que el aumento de fuerza y el incremento en la EC podrían no estar funcionalmente relacionados. Abstract: Introduction: Unilateral resistance training has been shown to improve muscle strength in both the trained and the untrained limb. One of the most widely accepted theories is that this improved performance is due to nervous system adaptations, specifically in the primary motor cortex. According to this hypothesis, increased corticospinal excitability (CSE), measured with transcranial magnetic stimulation, is one of the main adaptations observed following prolonged periods of training. The principal aim of this review is to determine the degree of adaptation of CSE and its possible functional association with increased strength in the untrained limb. Development: We performed a systematic literature review of studies published between January 1970 and December 2016, extracted from Medline (via PubMed), Ovid, Web of Science, and Science Direct online databases. The search terms were as follows: (transcranial magnetic stimulation OR excitability) AND (strength training OR resistance training OR force) AND (cross transfer OR contralateral limb OR cross education). A total of 10 articles were found. Conclusion: Results regarding increased CSE were inconsistent. Although the possibility that the methodology had a role in this inconsistency cannot be ruled out, the results appear to suggest that there may not be a functional association between increases in muscle strength and in CSE.

The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. Complex spine patients were defined as those with a Cobb angle greater than 50° and/or a history of spinal surgery, while the rest of patients were considered non-complex. Nusinersen was successfully administered through a conventional non-CT-guided lumbar puncture in all 14 non-complex spine patients (110 out of 110 procedures; 100%). The feasibility of the intrathecal injection in the 15 complex spine patients was assessed by 3D CT. Administration was considered unfeasible in 7 out of these 15 patients according to imaging. In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cut-off point of 50° in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration.

Background Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. Objectives The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. Methods This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. Results No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Conclusions Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses. Trial registration EUDRACT No. 2015-003721-33, filed 30 October 2015. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00797-x.

Objectives A case of perampanel-induced psychosis in a young woman is reported, a side effect that has only rarely been reported in the literature. Methods We describe a case of a young woman with epilepsy and no psychiatric history with perampanel-associated altered behavior and psychotic symptoms, requiring hospitalization in an acute psychiatry ward. We also provide a literature review on the possible neurobiological pathways implicated. Results Perampanel is believed to block a small proportion of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor current, retarding epileptiform discharges while sparing most normal synaptic transmission. Most common adverse events are related to central nervous system (including dizziness, drowsiness, blurred vision and imbalance) and psychiatric symptoms have been reported. Conclusions The biological vulnerability to psychiatric and behavioral adverse reactions of antiepileptic drugs is multifactorial and different mechanisms and clinical predisposing factors may interact. For this reason, patients starting these antiseizure drugs need long-term and comprehensive clinical monitoring.

The role of transcranial direct current stimulation (tDCS) as an ergogenic aid is receiving attention from scientists to optimize sport performance. Most studies have examined the effects of tDCS on endurance performance during continuous tasks, while the effect of tDCS on high-intensity intermittent tasks has been less investigated. Therefore, this study aimed to explore the acute effects of tDCS on sprint performance and ratings of perceived exertion (RPE) during a repeated sprint ability (RSA) task. Twenty-five healthy males (age: 22.0 ± 2.5 years) participated in a randomized crossover study consisting of three experimental sessions (anodal, cathodal or sham tDCS) separated by 1 week. Each session consisted of (I) tDCS protocol (15 min at 2 mA applied over the dorsolateral prefrontal cortex [DLPFC]), (II) warm-up and (III) RSA task (ten 30-m running sprints separated by 30 s). Total time and RPE values were recorded for each sprint. The two-way ANOVA applied on sprint time did not reveal a significant main effect of tDCS condition (

Aims and objectives To explore the knowledge, attitudes and practices related to cervical cancer and its prevention in Spain. Background Worldwide, women's knowledge about cervical cancer is low, and their attitudes towards its prevention are good, but they do not correlate with the screening uptake. Although the rates of Spanish women performing cervical cancer screening are mostly acceptable, their knowledge and attitudes about it have not been explored. Design Qualitative descriptive study. Methods Three focus groups were conducted, with 21 women aged 25 to 65 years. Participants were recruited through convenience sampling. For intragroup homogeneity, women participated in age groups. The COREQ reporting guidelines were used. Results Women expressed their knowledge about cervical cancer was low. None of the participants identified the human papillomavirus as a cause of cervical cancer, nor did they mention the vaccine as a preventive measure. They all knew about the screening existence, but not about its frequency nor target population. About the attitudes and practice, 18 women had an appropriate screening, and they were favourable to this health check, claiming an increase in its frequency. Nineteen women claimed they had not received enough information from the healthcare system and a lack of social awareness in comparison with breast cancer. They demanded from the professionals more health education, a reminder of their appointments and a report of the Pap test results. Conclusions There was a self-perceived low level of knowledge about cervical cancer risk factors and its prevention in the participants. However, they expressed favourable attitudes towards screening, and they demanded more information about cervical cancer and its prevention measures, and they regretted its low social awareness. Relevance to clinical practice Midwives, general nurses and other nurse specialists may have a leading position in health education for cervical cancer prevention in different population levels.

The purpose of this study was to determine the effects of training load (25% vs. 75% of one repetition maximum [1RM]) and fatigue (failure vs. non-failure) during four weeks of unilateral knee extension resistance training (RT) on maximal voluntary force in the trained and the untrained knee extensors. Healthy young adults (n = 42) were randomly assigned to control (CON, n = 9, 24 +/- 4.3 years), low-load RT to failure (LLF, n = 11, 21 +/- 1.3 years, three sets to failure at 25% of 1RM), high-load RT to failure (HLF, n = 11, 21 +/- 1.4 years, three sets to failure at 75% of 1RM), and high-load RT without failure (HLNF, n = 11, 22 +/- 1.5 years, six sets of five repetitions at 75% of 1RM) groups. Before and after the four weeks of training, 1RM, maximal voluntary isometric force, and corticospinal excitability (CSE) were measured. 1RM in the trained (20%, d = 0.70, 15%, d = 0.61) and the untrained knee extensors (5%, d = 0.27, 6%, d = 0.26) increased only in the HLF and HLNF groups, respectively. MVIC force increased only in the trained leg of the HLF (5%, d = 0.35) and HLNF groups (12%, d = 0.67). CSE decreased in the VL of both legs in the HLNF group (-19%, d = 0.44) and no changes occurred in the RF. In conclusion, high- but not low-load RT improves maximal voluntary force in the trained and the untrained knee extensors and fatigue did not further enhance these adaptations. Voluntary force improvements were unrelated to CSE changes in both legs.

Background & Aims Myeloproliferative neoplasms (MPNs) are the most frequent cause of non-tumoural non-cirrhotic splanchnic vein thrombosis (NC-SVT). Diagnosis of MPN is based on blood cell count alterations, bone marrow histology, and detection of specific gene mutations. Next-generation sequencing (NGS) allows the simultaneous evaluation of multiple genes implicated in myeloid clonal pathology. The aim of this study was to evaluate the potential role of NGS in elucidating the aetiology of NC-SVT. Methods DNA samples from 80 patients (75 with idiopathic or exclusively local factor [Idiop/loc-NC-SVT] and 5 with MPN and NC-SVT [SVT-MPN] negative for Janus kinase 2 gene [JAK2] [V617F and exon 12], calreticulin gene [CALR], and thrombopoietin gene [MPL] mutations by classic techniques) were analysed by NGS. Mutations involved in myeloid disorders different from JAK2, CALR, and MPL genes were categorised as high-molecular-risk (HMR) variants or variants of unknown significance. Results In 2/5 triple-negative SVT-MPN cases (40%), a mutation in exon 12 of JAK2 was identified. JAK2-exon 12 mutation was also identified in 1/75 patients with Idiop/loc-NC-SVT. Moreover, 28/74 (37.8%) of the remaining Idiop/loc-NC-SVT had at least 1 HMR variant. Sixty-two patients with Idiop/loc-NC-SVT were not receiving long-term anticoagulation and 5 of them (8.1%) had recurrent NC-SVT. This cumulative incidence was significantly higher in patients with HMR variants than in those without. Conclusions NGS identified JAK2-exon12 mutations not previously detected by conventional techniques. In addition, NGS detected HMR variants in approximately one-third of patients with Idiop/loc-NC-SVT. These patients seem to have a higher risk of splanchnic rethrombosis. NGS might be a useful diagnostic tool in NC-SVT. Lay summary Next-generation sequencing (NGS) performs massive sequencing of DNA allowing the simultaneous evaluation of multiple genes even at very low mutational levels. Application of this technique in a cohort of patients with non-cirrhotic non-tumoral portal vein thrombosis (NC-SVT) and a negative study for thrombophilic disorders was able to identify patients with a mutation in exon 12 not previously detected by conventional techniques. Moreover, NGS detected High Molecular Risk (HMR)-variants (Mutations involved in myeloid disorders different from JAK2, CALR and MPL genes) in approximately one third of patients. These patients appear to be at increased risk of rethrombosis. All these findings supports NGS as a potential useful tool in the management of NC-SVT.

Study design Cross-sectional construct validation study. Objectives To test the construct validity of the Leisure Time Physical Activity Questionnaire for People with Spinal Cord Injury (LTPAQ-SCI) by examining associations between the scale responses and cardiorespiratory fitness (CRF) in a sample of adults living with spinal cord injury (SCI). Setting Three university-based laboratories in Canada. Methods Participants were 39 adults (74% male; M age: 42 ± 11 years) with SCI who completed the LTPAQ-SCI and a graded exercise test to volitional exhaustion using an arm-crank ergometer. One-tailed Pearson's correlation coefficients were computed to examine the association between the LTPAQ-SCI measures of mild-, moderate-, heavy-intensity and total minutes per week of LTPA and CRF (peak volume of oxygen consumption [VO2peak] and peak power output [POpeak]). Results Minutes per week of mild-, moderate- and heavy-intensity LTPA and total LTPA were all positively correlated with VO2peak. The correlation between minutes per week of mild intensity LTPA and VO2peak was small-medium (r = 0.231, p = 0.079) while all other correlations were medium-large (rs ranged from 0.276 to 0.443, ps 0.05), except for a medium-sized correlation between heavy-intensity LTPA and POpeak (r = 0.294, p = 0.035). Conclusions People with SCI who report higher levels of LTPA on the LTPAQ-SCI also demonstrate greater levels of CRF, with stronger associations between moderate- and heavy-intensity LTPA and CRF than between mild-intensity LTPA and CRF. These results provide further support for the construct validity of the LTPAQ-SCI as a measure of LTPA among people with SCI.

Purpose Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. Patients and Methods Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. Results We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. Conclusions Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.

Excessive vibrations induced by trains and amplified or propagated through the ground can affect sensitive areas such as hospitals, residences, or telecommunication buildings. However, it has been found that the control of these vibrations can be improved by including materials with a high level of damping between the adjacent ground and the tunnel structure. In this study, the behavior of a new type of mortar called C-COM has been characterized through finite element simulations, and its effectiveness on mitigating vibrations in a tunnel is determined. Five parameters have been proposed to compare the response obtained with the new mortar and the one corresponding to a model with conventional materials. It was found that, using the C-COM mortar, vibration levels can be reduced by 10–20%.

The purpose of this study was to investigate the self-perception bias (SPB) in adolescents with attention-deficit hyperactivity disorder (ADHD). The SPB was defined as adolescent underestimation of their learning and behavior problems in comparison to parent- or teacher-reports or a standardized achievement test. The sample comprised 74 adolescents, ages 13 to 18 (40 ADHD; 34 comparison). Compared to adolescents without ADHD, adolescents with ADHD underreported their symptoms and impairment when parent-reports, but not teacher-reports were the indicator of performance. Adolescents with ADHD, however, reported more difficulties in all areas of functioning than adolescents without ADHD. In the sample of adolescents with ADHD, self- and parent-reports of learning problems, but not teacher-reports, were significantly associated with adolescent total academic achievement test score. Adolescents with learning problems as measured by the achievement test, and social problems as rated by parents, reported higher levels of these difficulties than adolescents whose functioning was in the average range; however, adolescents with clinical levels of oppositional behaviors, as rated by parents or teachers, did not report elevated levels of these behaviors. Depressive symptoms were associated with a lower SPB. Implications of these findings for psychologists’ use of self-report measures with adolescents with ADHD are discussed.

GMPPB mutations cause congenital myasthenic syndromes (CMS) overlapping with muscular dystrophy. Treatment with pyridostigmine has been reported to be effective in those patients. Nevertheless, results of functional motor assessments to determine its precise impact on the short and long term were not available. We describe the response to treatment with pyridostigmine in three siblings with GMPPB-related CMS using functional motor scales performed regularly over a period of 40 months. The beneficial effect of the treatment was outstanding within the first hours, with all the scales showing a dramatic increase in only two days. This remarkable improvement remained steady during 12 months but a moderate decrease was subsequently detected in two of the three patients. Despite this decline in the scores of the scales at the end of follow up, the functional motor status of the patients was still significantly better than it was before starting treatment. The introduction of pyridostigmine at an early age of the disease in one of the patients, before the onset of scoliosis, may have had a protective effect on it. (C) 2020 Elsevier B.V. All rights reserved.

ObjectivesTo describe patients with autoimmune inflammatory rheumatic diseases (AIRD) who had COVID-19 disease; to compare patients who required hospital admission with those who did not and assess risk factors for hospital admission related to COVID-19.MethodsAn observational longitudinal study was conducted during the pandemic peak of severe acute respiratory syndrome coronavirus 2 (1 March 2020 to 24 April). All patients attended at the rheumatology outpatient clinic of a tertiary hospital in Madrid, Spain with a medical diagnosis of AIRD and with symptomatic COVID-19 were included. The main outcome was hospital admission related to COVID-19. The covariates were sociodemographic, clinical and treatments. We ran a multivariable logistic regression model to assess risk factors for the hospital admission.ResultsThe study population included 123 patients with AIRD and COVID-19. Of these, 54 patients required hospital admission related to COVID-19. The mean age on admission was 69.7 (15.7) years, and the median time from onset of symptoms to hospital admission was 5 (3–10) days. The median length of stay was 9 (6–14) days. A total of 12 patients died (22%) during admission. Compared with outpatients, the factors independently associated with hospital admission were older age (OR: 1.08; p=0.00) and autoimmune systemic condition (vs chronic inflammatory arthritis) (OR: 3.55; p=0.01). No statistically significant findings for exposure to disease-modifying antirheumatic drugs were found in the final model.ConclusionOur results suggest that age and having a systemic autoimmune condition increased the risk of hospital admission, whereas disease-modifying antirheumatic drugs were not associated with hospital admission.

Clonal heterogeneity in multisited or recurrent lymphoid neoplasms is a phenomenon that has been increasingly studied in recent years. However, in mucosa-associated lymphoid tissue (MALT) lymphomas it remains largely unexplored. Patients diagnosed at our institution with multisited MALT lymphoma, from January 2009 to October 2018, were studied. Molecular studies were performed for the detection of clonally rearranged immunoglobulin by polymerase chain reaction.In all, 91 patients were included. Of those, 28 had a multisited disease and in 16 clonality studies were done. In eight cases, multifocal involvement was synchronous and in eight metachronous. Patients with non-gastric gastrointestinal tract involvement tended to disseminate within the same tract, without observing other specific dissemination patterns. Four cases (25%) had clonal heterogeneity at the different organs involved. All patients with late relapses (two patients) had different clones. The majority of patients with multisited MALT lymphomas presented with the same clone in the different involved organs, identifying a different clone in those with late relapses. These patients could represent de novo neoplasms, rather than a relapse. This could mean that some individuals might have a genetic predisposition to develop this type of lymphoma and it could also have clinical implications regarding therapeutic decisions.

Robust protocols and automation now enable large-scale single-cell RNA and ATAC sequencing experiments and their application on biobank and clinical cohorts. However, technical biases introduced during sample acquisition can hinder solid, reproducible results, and a systematic benchmarking is required before entering large-scale data production. Here, we report the existence and extent of gene expression and chromatin accessibility artifacts introduced during sampling and identify experimental and computational solutions for their prevention. HH is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). CM and MK are supported by AECC postdoctoral fellowships. This work has received funding from the Ministerio de Ciencia, Innovación y Universidades (SAF2017-89109-P; AEI/FEDER, UE). This study was further funded by the Spanish Ministry of Economy and Competitiveness (grant number: IPT-010000-2010- 36, cofunded by the European Regional Development Fund). Core funding is from the ISCIII and the Generalitat de Catalunya. We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the CERCA Programme/Generalitat de Catalunya, the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through the Instituto de Salud Carlos III and the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement. We also acknowledge the Co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014–2020 Smart Growth Operating Program. We acknowledge the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-736 (to JIMS) and 2017-SGR-1142 (to EC), and CIBERONC (CB16/12/00225 and CB16/12/00334). EC is an ICREA Academia Researcher. This project received support from the European Commission under the projects DocTIS (H2020, SEP-210574908). This publication is part of a project (BCLLATLAS) that has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 810287)

Purpose:We compared cancer detection rates in patients who underwent magnetic resonance imaging cognitive guided micro-ultrasound biopsy vs robotic ultrasound magnetic resonance imaging fusion biop...

OBJECTIVE: Multiple sclerosis (MS) is a heterogenous, inflammatory disease of the central nervous system. Microbiota alterations in MS versus healthy controls (HC) are observed, but results are inconsistent. We studied diversity, enterotypes, and specific gut microbial taxa variation between MS and HC, and between MS subgroups. METHODS: Amplicon sequencing of the 16S ribosomal RNA V4 region (Illumina MiSeq) was used to evaluate alpha and beta diversity, enterotypes, and relative taxa abundances on stool samples. MS subgroups were based on phenotype, disease course modifiers, and treatment status. Results were controlled for recently identified confounders of microbiota composition. RESULTS: Ninety-eight MS patients and 120 HC were included. Microbial richness was lower in interferon-treated (RRMS_I, N = 24) and untreated relapsing-remitting MS during relapse (RRMS_R, N = 4) when compared to benign (BMS, N = 20; Z = -3.07, Pcorr = 0.032 and Z = -2.68, Pcorr = 0.055) and primary progressive MS (PPMS, N = 26; Z = -2.39, Pcorr = 0.062 and Z = -2.26, Pcorr = 0.071). HC (N = 120) and active untreated MS (RRMS_U, N = 24) showed intermediate microbial richness. Enterotypes were associated with clinical subgroups (N = 218, χ2 = 36.10, P = 0.002), with Bacteroides 2 enterotype being more prevalent in RRMS_I. Butyricicoccus abundance was lower in PPMS than in RRMS_U (Z = -3.00, Pcorr = 0.014) and BMS (Z = -2.56, Pcorr = 0.031), lower in RRMS_I than in BMS (Z = -2.50, Pcorr = 0.034) and RRMS_U (Z = -2.91, Pcorr = 0.013), and inversely correlated with self-reported physical symptoms (rho = -0.400, Pcorr = 0.001) and disease severity (rho = -0.223, P = 0.027). INTERPRETATION: These results emphasize the importance of phenotypic subcategorization in MS-microbiome research, possibly explaining previous result heterogeneity, while showing the potential for specific microbiome-based biomarkers for disease activity and severity. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:7 issue:4 pages:406-419 ispartof: location:United States status: published

Objectives Systemic inflammatory response and survival has not been evaluated as a predictive factor of chemotherapy in metastatic pancreatic cancer. The aim of this study was to evaluate the prognostic and predictive value of a baseline Systemic Inflammation Response Index (SIRI) in metastatic pancreatic cancer. Methods Retrospective study of 164 metastatic pancreatic cancer patients. Associations between overall survival (OS), progression free survival (PFS), chemotherapy and SIRI were analyzed. SIRI is defined by neutrophil x monocyte/lymphocyte 109/L. Results Median age 66 years. 22 (13%) received mFOLFIRINOX, 59 (36%) gemcitabine + nab-paclitaxel, 40 (24%) gemcitabine, 13 (8%) other regimens and 30 (18%) had not received treatment. Patients with SIRI Conclusion An elevated SIRI (≥2.3 × 109/L) was an independent prognostic factor for patients with metastatic pancreatic cancer, warranting prospective evaluation.

Aims Atrial fibrillation (AF) has been associated with intracellular calcium disturbances in human atrial myocytes, but little is known about the potential influence of sex and we here aimed to address this issue. Methods and results Alterations in calcium regulatory mechanisms were assessed in human atrial myocytes from patients without AF or with long-standing persistent or permanent AF. Patch-clamp measurements revealed that L-type calcium current (ICa) density was significantly smaller in males with than without AF (¿1.15¿±¿0.37 vs. ¿2.06¿±¿0.29 pA/pF) but not in females with AF (¿1.88¿±¿0.40 vs. ¿2.21¿±¿0.0.30 pA/pF). In contrast, transient inward currents (ITi) were more frequent in females with than without AF (1.92¿±¿0.36 vs. 1.10¿±¿0.19 events/min) but not in males with AF. Moreover, confocal calcium imaging showed that females with AF had more calcium spark sites than those without AF (9.8¿±¿1.8 vs. 2.2¿±¿1.9 sites/µm2) and sparks were wider (3.0¿±¿0.3 vs. 2.2¿±¿0.3 µm) and lasted longer (79¿±¿6 vs. 55¿±¿8 ms), favouring their fusion into calcium waves that triggers ITIs and afterdepolarizations. This was linked to higher ryanodine receptor phosphorylation at s2808 in women with AF, and inhibition of adenosine A2A or beta-adrenergic receptors that modulate s2808 phosphorylation was able to reduce the higher incidence of ITI in women with AF. Conclusion Perturbations of the calcium homoeostasis in AF is sex-dependent, concurring with increased spontaneous SR calcium release-induced electrical activity in women but not in men, and with diminished ICa density in men only., This work was supported by grants from The Spanish Ministry of Science Innovation and Universities [SAF2017-88019-C3-1-R MICIU /AEI/ FEDER /UE] to L.H.-M. [SAF2017-88019-C3-2-R MICIU /AEI/ FEDER /UE] to R.B. and [ SAF2017-87349-R MICIU /AEI/ FEDER /UE] to F.C.; and from the Spanish Ministry of Health and Consume, ISCIII, CIBERCV [CB16/11/00276] and Fondo Europeo de Desarrollo Regional (FEDER) to J.C., Fundació Marato TV3 [20152030/31] to L.H.-M./F.C. Also supported by ISC III [PIE14/00034] and IWT [SBO-140028] to F.C., a PhD grant [FPU/01250] to S.C., a PERIS grant from Generalitat de Catalunya to A.L. and [SGR2017-1769] to L.H.-M.

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P, This work was supported by grants from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (PI17/01061 to Sílvia Beà, PI19/00887 to Armando López-Guillermo), Fundacion AECC/CIBERONC (PROYE18020BEA to Sílvia Beà), and CIBERONC (CB16/12/00334 to Dolors Colomer, and CB16/12/00225 to Elías Campo), Generalitat de Catalunya Suport Grups de Recerca AGAUR, 2017-SGR-709 (to Sílvia Beà) 2017-SGR-1009 (to Dolors Colomer), 2017-SGR-1142 (to Elías Campo), Ministerio de Ciencia e Innovación (MCI) [Grant No. RTI2018-094274-B-I00 (to Elías Campo)] and the European Regional Development Fund ‘Una manera de fer Europa’. Elías Campo is an Academia Researcher of the ‘Institució Catalana de Recerca i Estudis Avançats’ (ICREA) of the Generalitat de Catalunya.

This article reviews the most common non-psychiatric comorbidities associated with affective disorders, examining the implications of their possible bidirectional link. A narrative review was conducted on the association among the three most common non-psychiatric diseases in major depressive disorder and bipolar disorder (obesity, metabolic syndrome, and cardiovascular diseases) in articles published from January 1994 to April 2020. The evidence suggests that obesity, metabolic syndrome, and cardiovascular diseases are highly prevalent in patients diagnosed with affective disorders. The presence of non-psychiatric comorbidities significantly worsens the therapeutic management and prognosis of affective disorders and vice versa. In many cases, these comorbidities may precede the onset of affective disorders, although in most cases they appear after it. The presence of these concurrent non-psychiatric diseases in an individual diagnosed with an affective disorder is associated with a more complex disease presentation and management. For professionals, the evidence unequivocally supports routine surveillance of comorbidities from a multidisciplinary approach.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

[EN] Monte Carlo simulations are a unique tool to check the response of a detector and to monitor its performance. For a deep-sea neutrino telescope, the variability of the environmental conditions that can a ect the behaviour of the data acquisition system must be considered, in addition to a reliable description of the active parts of the detector and of the features of physics events, in order to produce a realistic set of simulated events. In this paper, the software tools used to produce neutrino and cosmic ray signatures in the telescope and the strategy developed to represent the time evolution of the natural environment and of the detector e ciency are described., The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariata l'energie atomique et auxenergies alternatives (CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), LabEx UnivEarthS (ANR-10-LABX-0023 and ANR18-IDEX-0001), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Istituto Nazionale di Fisica Nucleare (INFN), Italy; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia e Innovacion (MCI) and Agencia Estatal de Investigacion: Programa Estatal de Generacion de Conocimiento (refs. PGC2018-096663-B-C41, -A-C42, -B-C43, -BC44) (MCI/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider, Junta de Andaluca (ref. SOMM17/6104/UGR and A-FQM-053-UGR18), Generalitat Valenciana: Grisola (ref. GRISOLIA/2018/119), Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilities.

This paper introduces a novel unsupervised neural network model for visual information encoding which aims to address the problem of large-scale visual localization. Inspired by the structure of the visual cortex, the model (namely HSD) alternates layers of topologic sparse coding and pooling to build a more compact code of visual information. Intended for visual place recognition (VPR) systems that use local descriptors, the impact of its integration in a bio-inpired model for self-localization (LPMP) is evaluated. Our experimental results on the KITTI dataset show that HSD improves the runtime speed of LPMP by a factor of at least 2 and its localization accuracy by 10%. A comparison with CoHog, a state-of-the-art VPR approach, showed that our method achieves slightly better results.

Introduction Currently, about 10% of patients required unplanned readmissions within 30 days after discharge.1 2 This proportion has not changed substantially over the past several years despite intense efforts to improve the discharge process. Although several studies3 4 have been performed, including patients’ and physicians’ opinion on the preventability of readmissions and factors that would predict preventability, only a few studies have included nurses’ opinions and the consensus with all stakeholders.5 We aimed to determine the patient’s opinion on preventable readmission, associated factors and the extent to which patients, nurses and physicians agree on readmission preventability. Methods To achieve the proposed objectives, a descriptive transversal correlational multicentre study was developed. This study was approved by the Clinical Research Ethics Committee (reference number: PR114/17). From 2 April 2017 to 18 January 2019, all patients readmitted within 30 days to 2 medical and 2 surgical departments (internal medicine, pneumology, trauma and digestive surgery) at 4 university hospitals were identified. Patients who provided written informed consent were interviewed within 72 hours of readmission. Four research nurses were trained to deliver the interviews. The patient’s interview involved 23 questions6 about functional status at discharge, discharge process and follow-up care, including readmission preventability (online supplemental material). Two independent physicians and nurses of the research team concurrently reviewed electronic health records to identify factors contributing to potentially preventable readmissions.7 Clinical and demographic patients’ characteristics were also collected. We estimated that a total sample size of 276 patients was needed for a proportion of 11% of preventable readmission,7 95% confidence level and 0.04 precision and assuming 15% potentially missed cases. A logistic regression model has been used to assess the association between the patient profile and his answer to the main question of his readmission preventability. The conditions of application of the models have been validated and CIs at 95% of the estimator have been calculated whenever possible. Cohen’s kappa statistic has been calculated to assess the concordance between physicians’, nurses’ and patients’ answer to this preventability readmission question. All the analysis has been done with the statistic package R V.3.5.3 (11 March 2019) for Windows. Patients were not involved in the design, conduct, reporting or dissemination plans of this study. Results We assessed 805 consecutive patients for eligibility, of whom 529 were excluded refused or unavailable (314 presented haemodynamic instability, 107 were discharged early, 104 refused to participate and four had language barrier). Among 276 patients included, 44.2% were admitted to internal medicine, 13.8% pneumology, 8% trauma and 34.1% digestive surgery department, respectively. The mean age was 68 years and 65.9% were men. The median (IQR) time between discharge and readmission was 11 days (5–17 days) and the median (IQR) Charlson comorbidity index was 5 (3–6). Ninety-six (34.8%) patients reported that their readmission was preventable, 69 (25.0%) were undecided and 111 (40.2%) reported that their readmission was not preventable. Comparing patients who reported non-preventable readmissions to those who reported preventable readmissions or were undecided, the latter had less time between discharge and readmission, did not have a follow-up appointment scheduled with primary care or specialist at discharge, no medication reviewed and felt concerns were not addressed before discharge. Also, patients who were less satisfied with the hospital’s discharge team, who felt were discharged before being ready and felt concern during follow-up care were more likely to report preventable readmission or undecidedness

Summary Background A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved by the US Food and Drug Administration (FDA) on June 29, 2020. We report the primary analysis of the FeDeriCa study, which was designed to assess the pharmacokinetics, efficacy, and safety of the fixed-dose subcutaneous formulation compared to intravenous pertuzumab plus trastuzumab in patients with HER2-positive early breast cancer in the neoadjuvant–adjuvant setting. Methods FeDeriCa, a randomised, open-label, international, multicentre, non-inferiority, phase 3 study, was done across 106 sites in 19 countries. Patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1, HER2-positive, operable, locally advanced, or inflammatory stage II–IIIC breast cancer, and a left ventricular ejection fraction of 55% or more were randomly assigned (1:1), using a voice-based or web-based response system, to receive intravenous pertuzumab (840 mg loading dose, followed by 420 mg maintenance doses) plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance doses) or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (1200 mg pertuzumab plus 600 mg trastuzumab loading dose in 15 mL, followed by 600 mg pertuzumab plus 600 mg trastuzumab maintenance doses in 10 mL), both administered every 3 weeks with neoadjuvant chemotherapy. Patients were stratified by hormone receptor status, clinical stage, and chemotherapy regimen. The investigator selected one of the two protocol-approved standard chemotherapy regimens before randomisation. Four cycles of HER2-targeted therapy were administered concurrently with the taxane. After surgery, patients continued the HER2-targeted therapy to receive an additional 14 cycles (total of 18). The primary endpoint was non-inferiority of the cycle 7 pertuzumab serum trough concentration (Ctrough; ie, cycle 8 predose pertuzumab concentration) within the fixed-dose combination for subcutaneous injection versus intravenous pertuzumab plus trastuzumab in the per-protocol pharmacokinetic population (all enrolled patients who adhered to prespecified criteria for pharmacokinetic assessment). Non-inferiority was concluded if the lower bound of the 90% CI of the geometric mean ratio was 0·8 or higher. The safety population included all patients who received at least one dose of study medication, including chemotherapy or HER2-targeted therapy. Enrolment, neoadjuvant therapy, and surgery have been completed; adjuvant treatment and follow-up are ongoing. The trial is registered with ClinicalTrials.gov, NCT03493854. Findings Between June 14, 2018, and Dec 24, 2018, 252 patients were randomly assigned to the intravenous infusion group and 248 to the fixed-dose combination group. The geometric mean ratio of pertuzumab serum Ctrough subcutaneous to serum Ctrough intravenous was 1·22 (90% CI 1·14–1·31). The most common grade 3–4 adverse events occurring during neoadjuvant treatment with HER2-targeted therapy plus chemotherapy in 5% or more of patients were neutropenia (34 [13%] of 252 patients in the intravenous infusion group vs 35 [14%] of 248 patients in the fixed-dose combination group), decreased neutrophil count (31 [12%] vs 27 [11%]), febrile neutropenia (14 [6%] vs 16 [6%]), diarrhoea (12 [5%] vs 17 [7%]), and decreased white blood cell count (18 [7%] vs nine [4%]). At least one treatment-related serious adverse event was reported in 25 (10%) patients in the intravenous infusion group and 26 (10%) patients in the fixed-dose combination group. One patient in each treatment group had an adverse event that led to death (urosepsis in the intravenous infusion group and acute myocardial infarction in the fixed-dose combination group); neither death was related to HER2-targeted therapy. Interpretation The study met its primary endpoint: the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection provides non-inferior cycle 7 pertuzumab serum Ctrough concentrations to intravenous pertuzumab plus trastuzumab in the neoadjuvant setting with comparable total pathological complete response rates, supporting the FDA approval. Safety was similar between treatment groups, and in line with other pertuzumab, trastuzumab, and chemotherapy trials. Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety. Funding F Hoffmann-La Roche and Genentech.

This work was supported by a research grant from the Spanish Society of Community Pharmacy"and the Pharmaceutical Association of Valencia. Neither of these organisations influenced the study design, interpretation of data, writing of the manuscript, nor the decision to submit this manuscript for publication. The Pharmaceutical Association of Valencia assisted with initial selection of study locations and contacting community pharmacies., Background: Minor ailments are “self-limiting conditions which may be diagnosed and managed without a medical intervention”. A cluster randomised controlled trial (cRCT) was designed to evaluate the clinical, humanistic and economic outcomes of a Minor Ailment Service (MAS) in community pharmacy (CP) compared with usual care (UC). Methods: The cRCT was conducted for 6 months from December 2017. The pharmacist-patient intervention consisted of a standardised face-to-face consultation on a web-based program using co-developed protocols, pharmacists’ training, practice change facilitators and patients’ educational material. Patients requesting a non-prescription medication (direct product request) or presenting minor ailments received MAS or UC and were followed-up by telephone 10-days after the consultation. The primary economic outcomes were incremental cost-utility ratio (ICUR) of the service and health related quality of life (HRQoL). Total costs included health system, CPs and patient direct costs: health professionals’ consultation time, medication costs, pharmacists’ training costs, investment of the pharmacy and consultation costs within the 10 days following the initial consultation. The HRQoL was obtained using the EuroQoL 5D-5L at the time of the consultation and at 10-days follow up. A sensitivity analysis was carried out using bootstrapping. There were two sub-group analyses undertaken, for symptom presentation and direct product requests, to evaluate possible differences. Results: A total of 808 patients (323 MAS and 485 UC) were recruited in 27 CPs with 42 pharmacists (20 MAS and 22 UC). 64.7% (n = 523) of patients responded to follow-up after their consultation in CP. MAS patients gained an additional 0.0003 QALYs (p = 0.053). When considering only MAS patients presenting with symptoms, the ICUR was 24,733€/QALY with a 47.4% probability of cost-effectiveness (willingness to pay of 25,000€/QALY). Although when considering patients presenting for a direct product request, MAS was the dominant strategy with a 93.69% probability of cost-effectiveness. Conclusions: Expanding community pharmacists’ scope through MAS may benefit health systems. To be fully cost effective, MAS should not only include consultations arising from symptom presentation but also include an oversight of self-selected products by patients. MAS increase patient safety through the appropriate use of non-prescription medication and through the direct referral of patients to GP., Spanish Society of Community Pharmacy, Pharmaceutical Association of Valencia

Bipolar depression is the most prevalent phase of bipolar disorder (BD). There is a risk of inducing treatment-emergent affective switches (TEAS) with antidepressants (ADs). Hence, clinical guidelines do not recommend their use in monotherapy. Cariprazine is a dopamine-serotonin partial agonist, with a recent FDA approval as a monotherapy for BD type 1 (BD-I) depression. To our knowledge, there is no significant evidence of cariprazine-induced TEAS in bipolar depression. We describe three clinical cases of patients admitted to our acute psychiatric ward who developed manic episodes after the introduction of low doses of cariprazine. Two of the patients met the DSM-5 criteria for BD-I, and one for schizoaffective disorder, bipolar type. All patients were initially treated with low doses of cariprazine (1.5 mg) during a depressive phase. All three cases were simultaneously treated with mood stabilizers, regardless of which they switched to a manic episode when cariprazine was initiated. In our review of previous studies assessing the efficacy and side effects profile of cariprazine in BD-I, TEAS have not been found to be significant. However, according to our experience, cariprazine may induce affective switches in BD-I patients. Patients and psychiatrists should receive information regarding early warning symptoms and monitor possible cariprazine-induced mood switching.

Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to ClinicalTrials.gov registration : NCT01557400 .

Desde que en marzo de 2020 se declarara la pandemia COVID-19 hemos aprendido muchas cosas del coronavirus SARS-CoV-2, y de su papel en la enfermedad pediátrica. Los niños se infectan en un porcentaje bastante similar a los adultos, si bien en la mayoría de las ocasiones sufren cuadros leves o asintomáticos. Alrededor de un 1% de infectados precisan hospitalización, menos de un 0,02% precisan cuidados intensivos, y la mortalidad es muy baja y generalmente en niños con comorbilidades. Los cuadros clínicos más habituales son infecciones respiratorias de vías altas o bajas, cuadros gastrointestinales y con mayor gravedad el síndrome inflamatorio multisistémico (MIS-C). La mayoría de los episodios no precisan tratamiento, salvo el MIS-C. El remdesivir se ha empleado generalmente como tratamiento compasivo y aún está por definir su papel. El recién nacido puede infectarse, si bien la transmisión vertical es muy baja (

Background Neonatal sepsis is a condition with high mortality and morbidity that contributes to high rates of antibiotic therapy at birth. In addition, very low birth weight newborns (VLBWN) are particularly vulnerable. Interleukin 6 (IL-6) seems to be an early and effective marker that could help a better selection of patients to be treated. This study aimed to evaluate the use of antibiotics in the first 72 hours of life in VLBW infants before and after using IL-6 as an infection marker. Also, we wanted to analyze the differences in morbidity and mortality during admission and other factors associated with the decision to start antibiotic treatment. Methods We conducted a cohort retrospective study. We included VLBWN born in our hospital or admitted before 72 hours of life in two two-year periods (2007-2008 and 2011-2012). Results Antibiotics use during the first 72 hours of life was analyzed as the primary variable, which was reduced by 20% on the second period (p = 0.002). Regarding the analysis of secondary variables, we found no significant differences in mortality during hospital admission and the incidence of nosocomial sepsis, enterocolitis, or invasive fungal infection. The multivariate analysis indicated extreme prematurity and the study group as the most strongly related factors to the start of antibiotic therapy. Conclusions IL-6 was a useful marker of infection to reduce the use of antibiotic therapy in VLBW infants without increasing mortality.

Purpose Studies focusing on patients with and survivors of cancer during the COVID-19 pandemic highlight unique psychological and behavioral challenges. These findings were obtained in surveys using self-report questionnaires with pre-specified response options that may not capture the broad range of experiences of individuals affected by cancer, including people with cancer and informal caregivers, in this unprecedented situation. Online forums produce a large amount of valuable first-hand user-generated content that can be used to better understand their day-to-day lives. This study, based on the analysis of narratives in cancer online forums, aims to describe and categorize the experiences of people affected by cancer during the outbreak of the COVID-19 pandemic. Method An inductive, descriptive, thematic approach was applied to publicly available cancer forums from Germany, the USA, the UK, and Ireland posted between mid-March and mid-April 2020. Results An analysis of the content of 230 main posts revealed three major themes: (1) concerns related to the impact of COVID-19 on cancer care, the risks and fears of getting infected, logistic issues, and economic impact; (2) adaptation challenges faced at the individual and societal level; and (3) the need for advice including information about COVID-19 and the (self-)management of cancer symptoms and treatment. Conclusion Our qualitative description of the experiences of people affected by cancer during the COVID-19 pandemic outbreak can help to improve communication, education, and the development of supportive care strategies. Furthermore, the themes and subthemes identified could potentially inform item development for future self-report questionnaires.

INTRODUCTION AND OBJECTIVE:To validate a prognostic nomogram (Necchi et al, nomogram-doi:10.1016/j.clgc.2018.09.008) for exclusive locoregional recurrence after radical cystectomy and bilateral pel...

INTRODUCTION AND OBJECTIVE:To externally validate the COBRA score (tool predicting cancer-specific survival after radical cystectomy for urothelial carcinoma; Welty et al Cancer 2017, DOI: 10.1002/...