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Purpose: This study aims to map the clinical pathway for psoriasis and atopic dermatitis (AD) in a tertiary hospital to better understand patient needs and experiences, thereby suggesting improvements in patient-centered care., Methods: A mixed-method approach was utilised involving a literature review, a questionnaire for healthcare professionals (HCPs), and two focus groups (one with HCPs and the other with patients with psoriasis or AD). Ethical approvals were obtained, and informed consent was acquired from all participants., Results: Patients and HCPs identified significant delays in the pre-diagnosis phase, extending up to five years for psoriasis and three years for AD, adversely affecting the timely initiation of effective treatment. In addition, there were reported difficulties in obtaining appointments during flares, a lack of dermatologic emergencies, a need to increase human resources and physical space, and a need for telematic consultations for urgent cases. Discrepancies between HCPs' perceptions and patients' experiences highlighted unmet needs, particularly in primary care settings and emergency departments. Several strengths were also identified, including satisfactory experience in dermatology, the hospital's high level of specialisation in the management of complex patients, optimal communication between services, consideration of patient preferences, and proper advice on hospital pharmacy care and administration support of treatment and adherence monitoring., Conclusion: The findings underscore the necessity for interventions to reduce wait times and improve treatment immediacy and effectiveness post-diagnosis. The insights from this study can direct enhancements in patient management and satisfaction for individuals with psoriasis and AD., Competing Interests: HD.P. is employee of Outcomes’10, and they have received payments from the sponsor for support on design and methodology, conduction of the study and medical writing. Prof. Dr. Anna López-Ferrer reports personal fees, non-financial support from AbbVie, personal fees from Amgen, personal fees from Almirall, personal fees from Boehringer Ingelheim, personal fees from Bristol Myers Squibb, personal fees from Janssen, personal fees from Lilly, personal fees from Leo-Pharma, personal fees from Novartis, personal fees from UCB, outside the submitted work. Dr Esther Serra-Baldrich reports personal fees, non-financial support from Leo Pharma, personal fees, non-financial support from Sanofi, personal fees from AbbVie, personal fees from Amgen, personal fees from Lilly, personal fees, non-financial support from Pfizer, personal fees from Incyte, personal fees from Almirall, outside the submitted work. Dr Lluís Puig reports grants, personal fees from AbbVie, during the conduct of the study; grants, personal fees from AbbVie, grants, personal fees from Almirall, grants, personal fees from Amgen, personal fees from Biogen, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers-Squibb, personal fees from Fresenius-Kabi, personal fees from Horizon, personal fees from Johnson&Johnson Innovative Medicine, grants, personal fees from Leo-Pharma, grants, personal fees from Lilly, personal fees from Novartis, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from STADA, grants, personal fees from Sun Pharma, personal fees from Takeda, grants, personal fees from UCB, outside the submitted work; and Board member, International Psoriasis Council. The authors report no other conflict of interest in this work., (© 2024 Masip et al.)

Introduction: Pharmacogenetics (PGx) has the potential to improve patient care, allowing to transform medical interventions by providing personalized therapeutic strategies. Scientific evidence supports the use of PGx in clinical practice and international organizations are developing clinical guidelines to facilitate the utilization of PGx testing. However, clinical implementation of PGx is limited and unequal worldwide., Content: This review summarizes regional and national Spanish initiatives to implement PGx in the clinical practice., Summary and Outlook: Diverse strategies to implement PGx in healthcare are applied across countries or even in the different regions of a specific country. Such was the case of Spain, a European country with 17 Autonomous Regions and two Autonomous Cities, each one with capacity to manage their own healthcare systems. Nevertheless, during the past years, many initiatives and strategies have been launched in Spain to develop different aspects of PGx. Importantly, the National Healthcare System has approved a PGx testing catalogue. This review highlights the crucial work and efforts of scientific societies (like the Spanish Society of Pharmacogenetics and Pharmacogenomics), of experts in PGx, of healthcare providers and of governmental parties in the implementation of PGx to personalize patient therapy, focused in Spain., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Microplastics are present even in remote regions like the Southern Ocean. Once in the water, they are rapidly colonised by marine microorganisms, forming the plastisphere. To address this issue in Antarctic waters, we conducted a microcosm experiment by incubating polypropylene, polyethylene, polystyrene microplastic pellets, and quartz for 33 days on Livingston Island, South Shetland Islands, Antarctica. We analysed plastic colonisation and plastisphere dynamics using scanning electron microscopy, flow cytometry, bacterial cultivation, qPCR, and 16S rRNA gene metabarcoding. Our results show rapid and consistent colonisation, although biomass formation was slightly slower than in other oceans, indicating unique environmental constraints. Time was the main factor influencing biofilm communities, while plastic polymer types had little effect. We observed a transition in microbial communities from early- to late-biofilm stages between days 12 and 19. Additionally, we described the bacterial plastisphere composition in this Antarctic environment, including the presence of hydrocarbon-degrading bacteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate, in patients with chronic migraine (CM) in real-world conditions, the persistence, effectiveness, and tolerability of erenumab, fremanezumab, and galcanezumab anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) and the persistence and effects of switching., Background: Anti-CGRP mAbs represent a novel therapeutic approach to the management of CM; however, real-world data on persistence, effectiveness, and tolerability, especially after switching, are scarce., Methods: This was a retrospective observational cohort study including all patients with CM treated with erenumab, fremanezumab, and/or galcanezumab in a tertiary hospital between January 2019 and December 2022. Treatment persistence was measured as the number of days between treatment start and end dates or the end of follow-up and also as a percentage of persistent patients at 3, 6, and 12 months; effectiveness as a ≥50% reduction in monthly migraine days (MMD); and tolerability as the number and type of adverse events., Results: Included were 281 patients (383 treatments) with CM (91.5% [257/281] female) receiving anti-CGRP mAbs. Median (interquartile range [IQR]) treatment persistence was 267 (103-550) days. At 12 months, persistence was greater for the first (66.7%) compared to the second (49.8%) and third (37.2%) anti-CGRP mAb treatments (hazard ratio [HR] = 1.93, 95% confidence interval [CI]: 1.35-2.74; HR = 2.75, 95% CI: 1.69-4.47, respectively). Persistence minimum observed median (IQR) was also greater for the first (291 [112-594] days) compared to both the second (188 [90-403] days; p < 0.001) and third (167 [89-352] days; p < 0.001) anti-CGRP mAb treatments. For the first anti-CGRP mAb treatment, there were no differences in persistence among the different drugs. In terms of effectiveness of the first, second, and third anti-CGRP mAb treatments, a ≥50% reduction in MMD was achieved by 57.6% (117/203), 25.0% (11/44), and 11.8% (2/17) of patients, respectively, at 3 months, and by 55.8% (87/156), 29.6% (8/27), and 12.5% (1/8) of patients, respectively, at 6 months. At 12 months, no significant effectiveness differences were observed among anti-CGRP mAb treatments. As for tolerability, 55 adverse events were reported by 43 (15.3%) patients, mostly mild and leading to treatment discontinuation in only 14 (5.0%) patients. The most common adverse events were constipation, injection site reaction, and pruritus. Erenumab patients (3%, 3/99) experienced a higher rate of discontinuation for constipation., Conclusions: Our findings showed a 12-month higher treatment persistence with the use of a first anti-CGRP mAb treatment when the switch to a second treatment was due to ineffectiveness or severe side events. This persistence was lower after a second or third anti-CGRP. Additionally, in terms of effectiveness, the first anti-CGRP treatment achieved a higher response in terms of ≥50% reduction in MMD; however, some patients may benefit from a switching strategy. Finally, the tolerability profile for anti-CGRP mAbs was favorable. Further studies are needed to identify predictors of response after switching from the first anti-CGRP mAb treatment., (© 2024 American Headache Society.)

Introduction: Integrated care pathways (ICPs) are crucial for delivering individualised care. However, the development of ICPs is challenging and must be well designed to provide the expected benefits. Regarding this, healthcare organisations are increasingly adopting management systems based on Lean Thinking to improve their organisational processes by eliminating non-value-added steps. This study elucidates the process and evaluates the impact of applying Lean Thinking to redesign an ICP for patients with spondyloarthritis, a chronic inflammatory disease affecting young adults., Methods: A multidisciplinary team was assembled and trained in Lean Thinking. Patient's perspective was gathered through a focus group. Guided by an expert methodologist, the team constructed a value stream map of the entire care pathway and analysed each step. Five work streams were defined to increase value at each step, leading to targeted process improvements. Key process and outcome metrics were collected and compared in 2-month baseline and post-implementation audits., Results: A total of 118 patients were included in the baseline audit (September-October 2022), and 116 in the post-implementation audit (January-February 2023). Process redesign resulted in statistically significant improvements (p < 0.05), including a reduction in the mean number of hospital visits per patient over a 2-month period from 2.54 (SD = 0.93) to 1.84 (SD = 0.79), an increase in complementary exams scheduled on the same day (81.4% to 94.8%) and an increase in baseline disease and treatment education (from 22.2% to 84.2% and from 18.2% to 84.6%, respectively). Regarding standardisation of clinical practice, there were significant increases in collecting data for medical records on composite activity indices (76.3% to 95.7%), reporting of pharmacological treatment adherence (68.6% to 94%) and providing nonpharmacological recommendations (31.3% to 95.7%)., Conclusions: The application of Lean Thinking to redesign the spondyloarthritis ICP led to significant improvements in outpatient appointment scheduling, reduced patient hospital visits, improved interdepartmental coordination and standardised clinical practice., (© 2024 John Wiley & Sons Ltd.)

Ceftolozane-tazobactam (CT) is used for the treatment of complicated infections and for multidrug-resistant strains of Pseudomonas aeruginosa and extended-spectrum beta-lactamase-producing enterobacteria. In certain cases, simultaneous administration of CT and parenteral nutrition (PN) may be required, but compatibility of Y-site co-administration is unknown. The aim of this study was to analyse the physicochemical compatibility of CT Y-site administered with PN. We evaluated a protocolized PN approach for critical patients in our center. We studied both bolus infusion (2 g ceftolozane/1 g tazobactam in 1 h) and continuous infusion (CI) (6 g ceftolozane/3 g tazobactam) strategies. Samples were visually observed against light, microscopically inspected, and pH was analysed using a pH meter. The mean lipid droplet diameter (MDD) was determined via dynamic light scattering. CT concentration was quantified using HPLC-HRMS. No alterations were observed through visual or microscopic inspection. Changes in pH were ≤0.2, and changes in osmolarity were less than 5%. MDD remained below 500 nm (284.5 ± 2.1 for bolus CT and 286.8 ± 7.5 for CI CT). CT concentrations at t = 0 h and t = 24 h remained within prespecified parameters in both infusion strategies. CT is physiochemically compatible with PN during simulated Y-site administration at the tested concentration and infusion rates.

Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical efficacy., Methods: We studied 878 patients with persistent atrial fibrillation (AF) treated with a regimen of amiodarone and referred to electrical cardioversion (ECV), included prospectively in two Spanish registries. We analyzed the influence of body mass index (BMI), as well as overweight and obesity, in the efficacy of amiodarone for achieving pharmacologic cardioversion to sinus rhythm (SR) before ECV., Results: A total of 185 patients (21.1%) reverted to SR before ECV. Patients who reverted to SR had a lower BMI than those who did not revert (27.45 ± 4.36 kg/m 2 vs. 29.11 ± 4.09 kg/m 2 ; p < 0.001). We observed a progressively lower probability of reverting to SR in overweight and obese patients (normal weight 28.3%, overweight 21.3%, obesity 13.1%; p < 0.001). In the logistic regression, BMI (kg/m 2 ) adjusted for other related variables remained as the main factor inversely related to reversion to SR (OR = 0.904 × kg/m 2 ); CI 75% 0.864-0.946)., Conclusions: We observed a negative relationship between an increased BMI and the efficacy of amiodarone for reversion to SR, suggesting a negative clinical impact of excess body fat in its efficacy.

Automated speech and language analysis (ASLA) is a promising approach for capturing early markers of neurodegenerative diseases. However, its potential remains underexploited in research and translational settings, partly due to the lack of a unified tool for data collection, encryption, processing, download, and visualization. Here we introduce the Toolkit to Examine Lifelike Language (TELL) v.1.0.0, a web-based app designed to bridge such a gap. First, we outline general aspects of its development. Second, we list the steps to access and use the app. Third, we specify its data collection protocol, including a linguistic profile survey and 11 audio recording tasks. Fourth, we describe the outputs the app generates for researchers (downloadable files) and for clinicians (real-time metrics). Fifth, we survey published findings obtained through its tasks and metrics. Sixth, we refer to TELL's current limitations and prospects for expansion. Overall, with its current and planned features, TELL aims to facilitate ASLA for research and clinical aims in the neurodegeneration arena. A demo version can be accessed here:  https://demo.sci.tellapp.org/ ., (© 2023. The Psychonomic Society, Inc.)

Background: Histopathological and molecular features have been proposed to hold prognostic information, but few have been validated. The aim of this retrospective study was to validate the Genetic And Morphological Evaluation ('GAME') score and assess the impact of histological characteristics on the prognosis in patients with colorectal liver metastases., Methods: Data were collected from 176 patients with metastatic colorectal cancer undergoing liver resection at Hospital de la Santa Creu i Sant Pau. Patients were classified into Genetic And Morphological Evaluation score groups and relapse-free survival and overall survival were calculated. Histopathological changes in colorectal liver metastases were documented and prognostic variables were selected to create a post-surgery score, called the Histopathological, Clinical, And Molecular ('HICAM') score., Results: Regarding the Genetic And Morphological Evaluation score, the high-risk group had a median relapse-free survival of 8.8 months, compared with 20.5 months for the low-risk group (P = 0.005), and the high-risk group had a median overall survival of 37.8 months, compared with 67.0 months for the low-risk group (P = 0.005). Histological examination of 144 liver samples showed that the desertic immune phenotype was associated with worse overall survival in the multivariable analysis (P = 0.020). The Histopathological, Clinical, And Molecular score variables were age at diagnosis, tumour burden score, carcinoembryonic antigen levels greater than or equal to 20 ng/ml, primary tumour resection, TNM stage at diagnosis, molecular status, histopathological growth patterns, and immune phenotypes of the liver. The high-risk group had a median relapse-free survival of 8.4 months, compared with 20.4 months for the low-risk group (P < 0.001), and a median overall survival of 30.4 months, compared with 105.0 months for the low-risk group (P < 0.001)., Conclusion: The Genetic And Morphological Evaluation score was validated as a preoperative prognostic tool to predict candidacy for liver resection. The Histopathological, Clinical, And Molecular score could be useful to assess adjuvant treatment after hepatic resection., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Most neonatal deaths in industrialized countries follow a process of redirection of care. The objectives of this study were to describe how neonates die in a middle-income country, whether there was redirection of care, and the reason for this decision., Methods: This was a prospective, multicenter, cross-sectional study. Neonates who died in the delivery room or in the neonatal intensive care unit in 97 hospitals over a 6-month period were included. After each neonatal death, one investigator interviewed a member of the healthcare team who had been involved in the end-of-life care process. Perinatal data, conditions that led to death, whether there was redirection of care, and details of the end-of-life process were recorded., Results: Data from 697 neonatal deaths were analyzed, which represent 80% of the total deaths occurring in Argentina in that period. The main causes of death were complications of prematurity (47%) and congenital anomalies (27%). Overall, 32% of neonates died after a process of redirection of care, and this was less frequent in the neonatal intensive care unit (28%) than in the delivery room (70%, p < 0.001). The reasons for withholding/withdrawing care were inevitable death (75%) and severe compromise of expected quality of life (25%). Redirection of care consisted in withholding therapies in 66% and withdrawal in 34%. A diagnosis of a major congenital anomaly increased the odds of redirection of care (OR 5.45; 95% CI: 3.59-8.27)., Conclusion: Most neonates who die in Argentina do so while receiving full support. Redirection of care mainly follows a condition of inevitable death., (© 2024 S. Karger AG, Basel.)

Background: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes., Methods: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores., Results: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity., Conclusions: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA., (© 2023. The Author(s).)

Microdebris are ubiquitous and the Southern Ocean is no exception. Despite the recent increment in Antarctic studies assessing this threat, there is still scarce information available. Here, we quantified the microdebris in surface water, and their distribution within two bays of Livingston Island (South Shetlands, Antarctica). The two studied bays included one with human presence and one pristine, barely visited. Microdebris pollution was found in all samples with a mean concentration of 0.264 ± 0.185 items/m 3 . Fibres (82.19 %) were the main item, with polyester (61.67 %) as the main plastic polymer, followed by nylon (29.54 %). No differences in the distribution pattern were observed, with microdebris being homogeneously distributed along the two bays. Our results suggest that nearshore waters of Livingston Island are prone to the accumulation and retention of microdebris. The composition of the microdebris also points to Antarctic local activities as principal contamination contributors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients., Material and Methods: Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants., Results: Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants., Conclusions: Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen., (© The Author(s) 2023. Published by Oxford University Press.)

The use of pharmacogenetics to optimize pharmacotherapy is growing rapidly. This study evaluates the feasibility and operability of a collaborative circuit involving hospital and community pharmacists to implement clopidogrel pharmacogenetics in Barcelona, Catalonia, Spain. We aimed to enroll patients with a clopidogrel prescription from cardiologists at the collaborating hospital. Community pharmacists collected patients' pharmacotherapeutic profiles and saliva samples, which were then sent to the hospital for CYP2C19 genotyping. Hospital pharmacists collated the obtained data with patients' clinical records. Data were analyzed jointly with a cardiologist to assess the suitability of clopidogrel. The provincial pharmacists' association coordinated the project and provided IT and logistic support. The study began in January 2020. However, it was suspended in March 2020 due to the COVID-19 pandemic. At that moment, 120 patients had been assessed, 16 of whom met the inclusion criteria and were enrolled in the study. The processing of samples obtained before the pandemic had an average delay of 13.8 ± 5.4 days. A total of 37.5% patients were intermediate metabolizers and 18.8% were ultrarapid metabolizers. No poor metabolizers were detected. Pharmacists rated their experience with a 7.3 ± 2.7 likelihood of recommending that fellow pharmacists participate. The net promoter score among participating pharmacists was +10%. Our results show that the circuit is feasible and operable for further initiatives.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Assessing organic matter fluxes and species interactions in food webs is of main interest to understand the ecological functioning in bays and estuaries characterised by a wide diversity of primary producers and consumers. Demersal fish and cephalopod assemblages were studied across a network of 24 shallow subtidal stations in the bay of Saint-Brieuc for their diversity, stable isotope compositions and stomach contents. The community was composed of 21 taxa, eight species accounting for 94.4% of the total abundance. Three different assemblages were identified along bathymetric gradient and spatial patterns in fish dredging. Marine POM and SOM were the most likely bases of food webs regarding δ 13 C range displayed by fish and cephalopod without differences among assemblages. Amphipoda was the main prey item in stomachs leading to significant diet overlaps among fish species, with some variations in additional items. Sepia officinalis was characterised by a singular diet and very low dietary overlap with other species. Contrasted stable isotope values and niche overlaps among species were evidenced in the δ 13 C/δ 15 N space. Callionymus lyra and Buglossidium luteum, characterised by the widest isotopic niches, encompassed those of other species, except the singular 13 C-depleted Spondyliosoma cantharus. Coupling taxonomic assemblages, stomach contents and stable isotope analyses help disentangling the resources uses and evidencing trophic pathways. Contrasts in fish and cephalopod demersal assemblages occurring at different depths not necessarily imply differences in the trophic resources uses in such complex shallow coastal ecosystems under anthropogenic influences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: People living with human immunodeficiency virus could particularly benefit from mobile health (mHealth). The objective of the study was to  contribute to the design and development of a new standard of care for people  living with human immunodeficiency virus and the mHealth app needed to  support it by 1) exploring the view of people living with human  immunodeficiency virus and healthcare professionals on the possibilities of  mHealth tools on HIV care, and 2) implementing their feedback into the new  app and into the new journey of people living with human immunodeficiency  virus., Method: The study was conducted in two different phases: phase one was to  apprise patients' and healthcare professionals' perspectives on mHealth using  the qualitative methodology of the focus groups, whereas phase two aimed to  implement their feedback into the application., Results: A total of five people living with human immunodeficiency virus and  nine healthcare professionals (three clinical pharmacists, three nurses, two  physicians, and one pharmacy technician) participated in the focus groups. The  patients identified the following main aspects to be improved in the  current patients' journey: insufficient information (n = 5), lack of general  population disease awareness (n = 5), and medication dispensation model (n =  3). Moreover, healthcare professionals identified the next health outcomes  to be enhanced with mHealth tools: patients' quality of life (n = 7), control of  the disease (n = 5) and comorbidities (n = 3), and adherence to medication (n = 5). According to these needs, the new healthcare model was designed. The  mHealth was provided with different features, such as information about the  disease, health promotion and prevention, the possibility of two-way patient- healthcare professionals communication, or synchronization with other devices. The new human immunodeficiency virus care journey and the app are currently being tested in a group of people living with human immunodeficiency virus in real-world conditions in our hospital., Conclusions: Improving patients' quality of life, therapeutic adherence, or  disease control are key objectives for optimizing people living with human  immunodeficiency virus care. Our digital health tool and the new healthcare  model have been implemented based on end-users' feedback to achieve better  patients-healthcare professionals communication and patient engagement with their care., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Objective: Critically ill patients are at increased risk of drug-drug interactions  but their prevalence and clinical relevance remains unclear. The prevalence of  potential drug-drug interactions in an intensive care unit according to  Micromedex Drug-Reax® and Lexi-Interact® databases was studied and the  concordance between the two databases was assessed. In addition, drug-drug  interactions detected in 2013 were compared with those identified in 2018 to  determine updates between these years., Method: Between January and June 2013, 152 critical care patients were  prospectively included. Cardiac patients were excluded. Demographic and  clinical data together with the drugs administered on the first calendar day of  intensive care unit admission were recorded. Potential drug-drug interactions  were searched in both Drug-Reax® and Lexi-Interact ® and their prevalence,  level of severity and evidence were compared considering the same sample in  2013 and 2018., Results: In 2013, 1,025 potential drug-drug interactions were identified, corresponding to 438 unique pairs. Lexi-Interact® identified more  interactions (92.8%) than Drug-Reax® (34.0%). The percentage of agreement between databases was 27.4%. The number of interactions  included in both databases increased after the five years but their level of  evidence   decreased. The most common potential drug-drug interactions involved sedatives and analgesics, intentionally prescribed concomitantly. Only two potential drug-drug interactions were classified as contraindicated by both  databases. None of the potential drug-drug interactions identified had a  noticeable clinical impact. Neither did they imply a prescription change., Conclusions: This study shows that the prevalence of potential drugdrug interactions in the intensive care unit is high, although their clinical relevance is generally low. Our data also show a lack of concordance between Drug-Reax® and Lexi-Interact®, as well as their  updates., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Objective: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug's summary of product characteristics in  metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28  who are treated with the FOLFIRI regimen., Method: A systematic review of the literature was carried out in Medline and  Embase searching for articles published up to December 2021. The methods  used were based on the recommendations of the Preferred Reporting Items for  Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria  for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences  in clinical responses and 2) To study the magnitude of the differences in  adverse effects of irinotecan at high doses, as compared to the doses  described in the summary of product characteristics corresponding to the  FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes  UGT1A1*1/* 1 or *1/*28., Results: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six  only safety. With regard to the studies that evaluated both efficacy and safety,  six out of seven (85.7%) were in favor of increasing irinotecan dose according  to the objective response rate and progression-free survival. Two of them even  recommended dose increases based on overall survival. Irinotecan safety  studies suggest that doses higher than 180 mg/m2 are tolerated by  most UGT1A1*1/*1 and *1/*28 patients., Conclusions: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Background Guselkumab is indicated for moderate-to-severe plaque psoriasis. Data from real-life clinical practice regarding its use are scarce, especially concerning patients who relapse after previous biologic therapies. Aim This study aimed to evaluate the effectiveness, safety, and adherence to guselkumab in psoriasis refractory to biologic therapies. Method This real-life, retrospective study included patients who initiated guselkumab between February 2019 and October 2020. The main objective was to assess effectiveness, expressed as the psoriasis area and severity index (PASI) ≤5, ≤2 and 0, at the first follow-up medical visit. As secondary effectiveness outcomes, we assessed the body surface area (BSA) and dermatology life quality index (DLQI). We also evaluated adverse events and adherence (using the medication possession ratio [MPR]). Results The study included 35 patients who had previously received a median of two biologic drugs. The median basal PASI score (IQR) was 11 (7.3-15.9), decreasing to 0 (0-1.4) at first follow-up medical visit. At this point, 32 patients (94.1%) reached PASI ≤5, 28 (82.4%) PASI ≤2 and 19 (55.9%) PASI 0. We also found statistically significant improvements in PASI, BSA and DLQI at first follow-up (p<0.001). Three patients developed adverse events. Most patients (N=29, 85.3%) had an MPR ≥90%. The MPR was not associated with PASI score at first follow-up. Conclusion Our study supports evidence that guselkumab is an effective and safe drug in psoriasis refractory to biologic therapies. Adherence to treatment is not related to effectiveness, suggesting that, in some cases, the interval between doses could be increased., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Measuring human capabilities to synchronize in time, adapt to perturbations to timing sequences, or reproduce time intervals often requires experimental setups that allow recording response times with millisecond precision. Most setups present auditory stimuli using either MIDI devices or specialized hardware such as Arduino and are often expensive or require calibration and advanced programming skills. Here, we present in detail an experimental setup that only requires an external sound card and minor electronic skills, works on a conventional PC, is cheaper than alternatives, and requires almost no programming skills. It is intended for presenting any auditory stimuli and recording tapping response times with within 2-ms precision (up to - 2 ms lag). This paper shows why desired accuracy in recording response times against auditory stimuli is difficult to achieve in conventional computer setups, presents an experimental setup to overcome this, and explains in detail how to set it up and use the provided code. Finally, the code for analyzing the recorded tapping responses was evaluated, showing that no spurious or missing events were found in 94% of the analyzed recordings., (© 2021. The Psychonomic Society, Inc.)

Assessing fluxes of matter and energy in food webs within and across benthic habitats is important to understand the ecological functioning in bays and estuaries, where the productivity is favoured by a wide diversity of primary producers. The temporal variability (March vs September 2019) in the carbon and nitrogen stable isotope composition of primary food sources and benthic invertebrates consumers was investigated in a large intertidal area (Western English-Channel, France). The study area is influenced by megatidal conditions and characterised by salt marshes in the sheltered part, and seasonal Ulva spp. blooms. The spatio-temporal variability in the structure of the benthic food web was analysed at the scales of both the whole bay and the different assemblages, which constitute the mosaic of habitats. Inferences on potential sources fuelling the food web were supported by spatio-temporal patterns based on covariations and stable isotope trajectory analysis. Results highlighted that phytoplankton, microphytobenthos and SOM were, most likely, the main food sources. The trophic connectivity between salt marsh and benthic habitats within the bay was limited to some macrofauna species inhabiting muddy creeks within the salt marsh. Unexpectedly, the influence of Ulva spp. blooms appeared also limited. Spatial patterns illustrates the constancy of the spatial variability in the benthic pelagic coupling, with a higher influence of microphytobenthos in the upper shore compared to low shore assemblages. This first attempt to characterize intertidal benthic food web constitutes a relevant baseline for the conservation of the bay of Saint-Brieuc where a national Nature Reserve has been created in 1998 for the conservation of overwintering birds. The spatial and temporal patterns of the benthic food web observed in this study (1) confirm the importance to consider food web variability at spatial and temporal scales from sampling designs to data analysis, and (2) demonstrate the ability of the stable isotope trajectory analysis framework to highlight food web dynamics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Introduction: teduglutide (TED) is indicated for the treatment of patients with short-bowel syndrome (SBS) who are dependent on parenteral support. Case report: we report the case of a 60-year-old woman with SBS treated with TED. She had previously undergone multiple surgical resections due to Crohn's disease. Her remnant bowel included only the duodenum and 50-60 centimeters of jejunum. The patient was dependent on intravenous fluids (2,320 mL/48 h) and had a high stoma output (3,000 mL/day). After four months of TED the jejunostomy output had decreased to 2,200 mL/day with a thicker consistency, and intravenous fluid therapy was reduced to 2,010 mL/48 h. TED was withdrawn due to acute pancreatitis and enlargement of two supraumbilical hernias with high strangulation risk. Discussion: pancreatitis has been reported in clinical studies, and determination of amylase and lipase is recommended in all patients receiving TED. In contrast, there are no recommendations for the surveillance of hernia enlargement in patients on TED therapy, but we suggest the need for surveillance based on this case report.

Objective: To determine the prevalence of loss-of-function variants in the dihydropyrimidine dehydrogenase gene in patients with gastrointestinal neoplasms, assess their clinical relevance, and evaluate the  implementation of a multidisciplinary circuit at three months from its  implementation., Method: This is a descriptive, observational and retrospective study, which  included adult patients with gastrointestinal cancer treated at a tertiary  university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020. The  variables collected were sex, age, type of cancer, location, stage, treatment received, indication of treatment and degree of toxicity  developed during the first three cycles. The genotyped variants were  rs3918290 (c.1905+1G&gt;A), rs55886062 (c.1679T&gt;G), rs67376798  (c.2846A&gt;T) and rs75017182 (c.1129-5923C&gt;G)., Results: A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6% (11  patients). The most frequently identified variant was rs75017182 (6 patients). The second most common variant was rs67376798 (3 patients),  followed by rs3918290 (2 patients). No patients presented with the  rs55886062 variant. Two of the dihydropyrimidine dehydrogenase carriers  developed  grade 3-5 toxicity after the first cycle of a regimen that included  fluoropyrimidines. Both received full doses of fluoropyrimidine, since their  dihydropyrimidine dehydrogenase genotype was unknown before treatment  initiation. None of the dihydropyrimidine dehydrogenase carriers who began treatment with a reduced dose of fluoropyrimidine experienced grade 3-5  toxicity. Since the creation in October 2020 of a multidisciplinary team, with  the active participation of hospital pharmacists, the monthly average of dihydropyrimidine dehydrogenase genotyping studies has increased from 6.4  (January-October) to 17.5 (November-December)., Conclusions: The present study shows a relatively high prevalence of loss-of- function variants in the dihydropyrimidine dehydrogenase gene as well as the  importance of genotyping such variants before starting a treatment with  fluoropyrimidines. Hospital pharmacists can contribute to the implementation  of pharmacogenetics in daily clinical practice in a tertiary hospital., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Algal polysaccharides constitute a diverse and abundant reservoir of organic matter for marine heterotrophic bacteria, central to the oceanic carbon cycle. We investigated the uptake of alginate, a major brown macroalgal polysaccharide, by microbial communities from kelp-dominated coastal habitats. Congruent with cell growth and rapid substrate utilization, alginate amendments induced a decrease in bacterial diversity and a marked compositional shift towards copiotrophic bacteria. We traced 13 C derived from alginate into specific bacterial incorporators and quantified the uptake activity at the single-cell level, using halogen in situ hybridization coupled to nanoscale secondary ion mass spectrometry (HISH-SIMS) and DNA stable isotope probing (DNA-SIP). Cell-specific alginate uptake was observed for Gammaproteobacteria and Flavobacteriales, with carbon assimilation rates ranging from 0.14 to 27.50 fg C µm -3 h -1 . DNA-SIP revealed that only a few initially rare Flavobacteriaceae and Alteromonadales taxa incorporated 13 C from alginate into their biomass, accounting for most of the carbon assimilation based on bulk isotopic measurements. Functional screening of metagenomic libraries gave insights into the genes of alginolytic Alteromonadales active in situ. These results highlight the high degree of niche specialization in heterotrophic communities and help constraining the quantitative role of polysaccharide-degrading bacteria in coastal ecosystems., (© 2021. The Author(s).)

Introduction: Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking., Areas Covered: This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients., Expert Opinion: Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.

Syrphidae, more commonly known as flower flies, are considered one of the most important Diptera families worldwide because of their critical role in pollination, biological control and decomposition of organic matter. The study of these flies in Chile has stagnated due to a lack of local experts as well as the absence of an updated catalog of species. This study is an attempt to remedy the latter of these issues by providing an illustrated and updated catalog to the Syrphidae of Chile. Species are presented under currently accepted names, with synonyms and previous combinations listed and original references. Type localities, world and Chilean distribution by geopolitical Chilean regions, taxonomic and biological notes, a complete record of bibliographic references and extinction risk under IUCN Red List criteria are provided. This catalog recognizes 132 species of Syrphidae, belonging to four subfamilies (Eristalinae, Microdontinae, Pipizinae and Syrphinae), 13 tribes and 47 genera. A total of 46 species (34.84 %) is restricted to the geopolitical territory of Chile. Eight species are considered exotic, one is considered incertae sedis and three are based on doubtful records. Seventeen species of 10 different genera (Copestylum Macquart, 1846; Dolichogyna Macquart, 1842; Eosalpingogaster Hull, 1949b; Eupeodes Osten Sacken, 1877; Meromacrus Rondani, 1848; Palpada Macquart, 1834; Paragus Latreille, 1804; Sphiximorpha Rondani, 1850; Sterphus Philippi, 1865 and Toxomerus Macquart, 1855) are reported from Chile for the first time. A total of 44 species (33.33 %) reported from Chile are directly threatened by human activities such as agriculture, forestry, mining and/or urbanization and indirectly by climate change. The gaps found in the geographic distribution of Chilean flower fly species and what it means for its use by disciplines such as ecology, floral biology and agronomy, are discussed. In addition, the use of this illustrated catalog for biological conservation, the potential definition of priority areas and ecosystem management plans based on this group of Diptera are also discussed.

Introduction: Ensuring health and well-being during this pandemic is essential according to the United Nations Sustainable Development Goals. Physical exercise has an important role in the preservation of the immune system, which is vital to prevent infections. To promote physical exercise and maintain a healthy status, recent studies have suggested general exercise routines to be implemented during the quarantine period. However, to improve the health-related physical fitness components, any specific prescription should include intensity, volume, duration, and mode. Controversy persists about which is the best intensity of physical activity, while performing exercise at a moderate intensity could bring important benefits to asymptomatic people. High intensity or unaccustomed exercise should be restricted for older people, and for people of all ages with chronic diseases or compromised immune system, obesity, or upper respiratory tract infection with limited symptoms. Besides, physical activity guidelines should be particular to each population group, giving special consideration to those vulnerable to COVID-19 who are much more likely to suffer more self-isolation. Therefore, the present study is to provide specific physical activity recommendations for different populations during this pandemic.

Background: Dexmedetomidine is an α2-agonist used as a sedative agent in the intensive care setting. Simultaneous administration of dexmedetomidine and parenteral nutrition (PN) may be required. The aim of this study was to evaluate the physicochemical compatibility of dexmedetomidine Y-site administered with PN., Methods: Three PN and 3 dexmedetomidine solutions were compounded. The tested infusion rate for PN was 66 mL/h. For dexmedetomidine, we considered the initial and maximum infusion rates (0.7 and 1.4 µg/kg/h) detailed in the data sheet. Taking this into account and considering a weight range of 55-95 kg, we tested 2 dexmedetomidine infusion rates (10 and 36 mL/h). The samples obtained were examined visually against light. pH was analyzed with a pH meter. Mean fat droplet diameter was determined by dynamic light scattering. Quantification of dexmedetomidine concentration was carried out by ultraperformance liquid chromatography-high-resolution mass spectrometry. For each PN-dexmedetomidine admixture, tests were performed in triplicate., Results: No alterations were observed by visual inspection. Average pH was 6.25 ± 0.01. Droplet diameter remained below 500 nm (298 ± 10 nm for 10-mL/h rate and 303 ± 5 nm for 36-mL/h rate). Dexmedetomidine concentrations at t = 0 were 519 ± 31 ng/mL and 1391 ± 90 ng/mL for 10- and 36-mL/h infusion rates, respectively. At t = 24 hours, the concentrations obtained were 494 ± 22 and 1332 ± 102 ng/mL, which translates into ≥90% of the initial concentrations., Conclusion: Dexmedetomidine is physicochemically compatible with PN during simulated Y-site administration at the tested infusion rates., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response., Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results., Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R , T1156M in IRS2 ) and three in genes belonging to the LRIG family (T152T in LRIG1 , S697L in LRIG2 and V812M in LRIG3 ). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response., Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1 . P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis ( P =0.014 and P =0.002, respectively). Additionally, rs2032582 was associated with severe mucositis ( P <0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan., (Copyright © 2020 Riera, Artigas-Baleri, Salazar, Sebio, Virgili, Arranz and Páez.)

Purpose: Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia., Experimental Design: We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety., Results: Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC 50 ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient-derived HNSCCs. Finally, in vivo toxicity studies in Fanca -deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters., Conclusions: Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia., (©2020 American Association for Cancer Research.)

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN , NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.

Introduction: Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC., Materials and Methods: We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS)., Results: In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5-0.9); p = 0.026 and HR 1.5 (1.1-2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4-4.3; p = 0.002 and HR 0.6 (0.5-0.9); p = 0.013, respectively]., Conclusion: Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Background: Y-site administration of total parenteral nutrition (TPN) and drugs is frequently required in the intensive care setting. Amiodarone is commonly administered by continuous intravenous infusion and subject to be co-administered via a Y-site with TPN. The aim of this study is to determine the physicochemical stability of amiodarone Y-site administered with TPN., Methods: Two standard TPN and 2 amiodarone solutions were designed. The 2 TPN differed in the lipid source (Lipofundin MCT/LCT® 20% or SMOFlipid® 20%). The 2 amiodarone solutions were prepared at different concentrations (900 mg and 1200 mg in 250 mL of dextrose 5% in water). Each TPN and amiodarone solutions ran at a rate that simulated a 24-hour Y-site infusion to obtain different admixture samples. Each sample was then visually examined and further tested to determine the mean lipid droplet size distribution by dynamic light scattering and amiodarone concentrations by HPLC., Results: No alterations were detected by visual inspection. Average droplet size remained below 500 nm (252.5 ± 5.9 nm for Lipofundin MCT/LCT® TPN and 327.7 ± 14.4 nm for SMOFlipid® TPN). For the samples obtained after running 900 mg and 1200 mg amiodarone solutions with TPN, the concentrations observed at 24 hours were 0.4491 ± 0.0111 mg/mL and 0.5773 ± 0.0214 mg/mL, respectively. These results represent approximately 100% of the zero-time concentrations and are within ±15% of the predicted values. No degradation products were observed in the chromatograms., Conclusion: Amiodarone is physicochemically compatible with standard TPN via a Y-site administration at the tested amiodarone concentrations., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Background: Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients., Methods: Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m 2 for UGT1A1*1/*1 and 260 mg/m 2 for *1/*28 patients. In the control group, the dose was 180 mg/m 2 . We analysed the overall response rate (ORR), toxicity, and survival., Results: The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found., Conclusions: Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.

Several studies have examined how music may affect the evaluation of food and drink, but the vast majority have not observed how this interaction unfolds in time. This seems to be quite relevant, since both music and the consumer experience of food/drink are time-varying in nature. In the present study we sought to fix this gap, using Temporal Dominance of Sensations (TDS), a method developed to record the dominant sensory attribute at any given moment in time, to examine the impact of music on the wine taster's perception. More specifically, we assessed how the same red wine might be experienced differently when tasters were exposed to various sonic environments (two pieces of music plus a silent control condition). The results revealed diverse patterns of dominant flavours for each sound condition, with significant differences in flavour dominance in each music condition as compared to the silent control condition. Moreover, musical correspondence analysis revealed that differences in perceived dominance of acidity and bitterness in the wine were correlated in the temporality of the experience, with changes in basic auditory attributes. Potential implications for the role of attention in auditory flavour modification and opportunities for future studies are discussed.

Adaptations that allow teredinids to maintain and thrive on wood, a nutritionally unbalanced food, make these marine bivalves remarkable. Capable of filter-feeding, shipworms house endosymbiotic bacteria synthesizing cellulolytic enzymes for digestion of wood carbohydrates and providing nitrogen to their host through nitrogen fixation. To what extent each of these nutrition modes contributes to the shipworm's metabolism remains an open question. In this experimental study, we estimated source partitioning through the determination of δ 13 C and δ 15 N values in original biological samples. For this purpose, pieces of common alder (Alnus glutinosa) were immersed at a coastal station of the north-western Mediterranean Sea. The shipworm Bankia carinata infected wood logs and stable isotope mixing models suggested it got most of the carbon and nitrogen it needs from separate sources. From 71 to 77% of the carbon was derived from the digestion of wood carbohydrates, whereas between 42 and 82% of the nitrogen originated from N 2 fixation. These first semi-quantitative estimations suggest that the contribution of N 2 fixers to nitrogen requirements of this shipworm species is far from incidental., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Parenteral nutrition (PN) is frequently needed in neonatal intensive care. The use of standard PN has emerged as an easy-to-prescribe approach that allows one to have on-site, ready-to-use PN. The aim of this study was to test the physicochemical stability and sterility of 2 specific PN solutions as well as simulate Y-site compatibility with lipid injectable emulsions (ILE)., Methods: Our study considered 2 standard ILE-free PN solutions according to neonatal weight. These solutions were prepared in duplicate and stored at 4°C. The following physicochemical parameters were tested: visual alterations, turbidity, pH, osmolarity, and calcium concentration. Sterility was assessed by means of agar blood culture and glucose concentration determination. In addition, we assessed the stability of simulated Y-site admixtures. For each standard ILE-free PN solution, 2 3-in-1 PN admixtures were designed, considering extreme values of fluid requirements (50 and 150 ml/kg/d) and a fat supply of 2 g/kg/24 h. The physicochemical parameters tested were phase separation and fat mean droplet size distribution., Results: No alterations were detected by visual inspection. Calcium concentrations, turbidity, pH, and osmolarity values remained stable in all the determinations. All agar blood cultures were negative and glucose concentration was constant over time. Physical stability of simulated Y-site admixtures was considered acceptable as mean droplet size distribution remained below 500 nm in all the emulsions., Conclusion: The 2 tested standard ILE-free PN solutions for neonates are physicochemically stable and sterile for 31 days under refrigeration (4°C). These solutions are also stable in case of Y-site administration with ILE at the conditions tested., (© 2018 American Society for Parenteral and Enteral Nutrition.)

The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II-III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters.

Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity., (© 2018 The British Pharmacological Society.)

This study examined experimentally the combined effect of ocean acidification and warming on the productivity of rock pool multi-specific assemblages, composed of coralline algae, fleshy algae, and grazers. Natural rock pool communities experience high environmental fluctuations. This may confer physiological advantage to rock pool communities when facing predicted acidification and warming. The effect of ocean acidification and warming have been assessed at both individual and assemblage level to examine the importance of species interactions in the response of assemblages. We hypothesized that rock pool assemblages have physiological advantage when facing predicted ocean acidification and warming. Species exhibited species-specific responses to increased temperature and pCO 2 . Increased temperature and pCO 2 have no effect on assemblage photosynthesis, which was mostly influenced by fleshy algal primary production. The response of coralline algae to ocean acidification and warming depended on the season, which evidenced the importance of physiological adaptations to their environment in their response to climate change. We suggest that rock pool assemblages are relatively robust to changes in temperature and pCO 2 , in terms of primary production., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The invasive Japanese seaweed Gracilaria vermiculophylla has become established over the past several years in numerous European estuaries, from Portugal to Norway. In the Faou estuary (48.295°N-4.179°W, Brittany, France), it forms a dense population at the mud's surface. The effects of G. vermiculophylla on metabolism, diversity, and the food web were studied. Community gross primary production (GPP) and respiration (CR) during emersion, chlorophyll-a content, macrofaunal and meiofaunal diversity and abundance, and stable isotopes (δ 13 C and δ 15 N) of representative macrofaunal species and main food sources were measured at low tide in winter, spring, summer 2014, and winter 2015. Results show significant seasonal variation in GPP and CR. Moreover, GPP was significantly higher in areas where G. vermiculophylla was present than in the control area (bare mud). However, this high GPP appeared to be linked to the increase in biomass in primary producers, with their efficiency (primary productivity, i.e. assimilation number) remaining relatively stable compared with the control area. Significant variation in abundance of meiofauna and macrofauna was also detected and new epifaunal species were collected, mainly in Gracilaria-colonized areas. Isotopic food-web Bayesian mixing models strongly suggested that G. vermiculophylla plays a major role in the diet of some dominant species. Mechanisms interacting with the functioning and diversity of the mudflat are discussed. Finally, the invasive seaweed G. vermiculophylla affected the mudflat ecosystem in three ways: as a new primary producer (increase in metabolism), as a habitat-forming species (changes in diversity and abundance of macrofauna and meiofauna), and as a new abundant food source, likely through the detrital pathway., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Stable isotope analysis of organic matter in sediment records has long been used to track historical changes in productivity and carbon cycling in marine and lacustrine ecosystems. While flow dynamics preclude stratigraphic measurements of riverine sediments, such retrospective analysis is important for understanding biogeochemical cycling in running waters. Unique collections of riverine fish scales were used to analyse δ(15) N and δ(13) C variations in the food web of two European rivers that experience different degrees of anthropogenic pressure. Over the past four decades, dissolved inorganic N loading remained low and constant in the Teno River (70°N, Finland); in contrast, N loading increased fourfold in the Scorff River (47°N, France) over the same period. Archived scales of Atlantic salmon parr, a riverine life-stage that feeds on aquatic invertebrates, revealed high δ(15) N values in the Scorff River reflecting anthropogenic N inputs to that riverine environment. A strong correlation between dissolved inorganic N loads and δ(13) C values in fish scales was observed in the Scorff River, whereas no trend was found in the Teno River. This result suggests that anthropogenic N-nutrients enhanced atmospheric C uptake by primary producers and its transfer to fish. Our results illustrate for the first time that, as for lakes and marine ecosystems, historical changes in anthropogenic N loading can affect C cycling in riverine food webs, and confirm the long-term interactions between N and C biogeochemical cycles in running waters., (© 2013 John Wiley & Sons Ltd.)

What are the features that impersonators select to elicit a speaker's identity? We built a voice database of public figures (targets) and imitations produced by professional impersonators. They produced one imitation based on their memory of the target (caricature) and another one after listening to the target audio (replica). A set of naive participants then judged identity and similarity of pairs of voices. Identity was better evoked by the caricatures and replicas were perceived to be closer to the targets in terms of voice similarity. We used this data to map relevant acoustic dimensions for each task. Our results indicate that speaker identity is mainly associated with vocal tract features, while perception of voice similarity is related to vocal folds parameters. We therefore show the way in which acoustic caricatures emphasize identity features at the cost of loosing similarity, which allows drawing an analogy with caricatures in the visual space.