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Jaime Barceló-Vidal,1 Eva Rodríguez-García,2 Santiago Grau3 1Department of Pharmacy, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain; 2Department of Nephrology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain; 3Department of Pharmacy, Hospital del Mar, Parc de Salut Mar, Universitat Autònoma de Barcelona, Barcelona, Spain Abstract: Vancomycin has usually been associated with nephrotoxicity. Generally, this ­toxicity is presented as proximal tubular cells injury with or without necrosis and as acute interstitial nephritis. However, development of both lesions is uncommonly described in literature. We present a case of vancomycin-induced nephrotoxicity resulting in both acute interstitial nephritis and tubular cells damage confirmed by renal biopsy. Peak and trough levels of 77.11 and 63.60 μg /mL, respectively, were obtained at the first plasma determination. After 8 more plasma determinations and several hemodialysis sessions, vancomycin levels were undetectable 1 month after therapy was stopped. To our knowledge, this is the case report with the highest vancomycin trough levels developing both lesions and describing total vancomycin washout after a biopsy-proven vancomycin toxicity. In conclusion, early vancomycin therapeutic drug monitoring should be performed in order to avoid toxicities where, as seen in our patient, antibiotic exposure could last around 1 month after last dose administration. Keywords: vancomycin, therapeutic drug monitoring, nephrotoxicity

Changes in land-use patterns are a major driver of global environmental change. Cessation of traditional land-use practices has led to forest expansion and shifts in forest composition. Consequently, former monospecific forests maintained by traditional management are progressing towards mixed forests. However, knowledge is scarce on how the presence of other tree species will affect reproduction of formerly dominant species. We explored this question in the wind-pollinated tree Juniperus thurifera. We hypothesised that the presence of heterospecific trees would have a negative effect on cone production and on the proportion of cones attacked by specialised predators., We assessed the relative importance of forest composition on cone production, seed development and pre-dispersal cone damage on nine paired pure and mixed J. thurifera forests in three regions across the Iberian Peninsula. The effects of forest composition on crop size, cone and seed characteristics, as well as damage by pre-dispersal arthropods were tested using mixed models., Cone production was lower and seed abortion higher in mixed forests, suggesting higher pollination failure. In contrast, cone damage by arthropods was higher in pure forests, supporting the hypothesis that presence of non-host plants reduces damage rates. However, the response of each arthropod to forest composition was species-specific and the relative rates of cone damage varied depending on individual tree crops., Larger crop sizes in pure forests compensated for the higher cone damage rates, leading to a higher net production of sound seeds compared to mixed forests. This study indicates that ongoing changes in forest composition after land abandonment may impact tree reproduction. [ABSTRACT FROM AUTHOR]

Fruit production in animal-dispersed plants has a strong influence on fitness because large crops increase the number of seeds dispersed by frugivores. Large crops are costly, and environmental control of plant resources is likely play a role in shaping temporal and spatial variations in seed production, particularly in fluctuating environments such as the Mediterranean. The number of fruits that start to develop and the proportion of viable seeds produced are also linked to the number of flowers formed and the efficiency of pollination in wind-pollinated plants. Finally, large fruit displays also attract seed predators, having a negative effect on seed output. We assessed the relative impact of environmental conditions on fruit production, and their combined effect on seed production, abortion and seed loss through three predispersal predators in Juniperus thurifera L., sampling 14 populations across the Iberian Peninsula. Wetter than average conditions during flowering and early fruit development led to larger crop sizes; this effect was amplified at tree level, with the most productive trees during more favourable years yielding fruits with more viable seeds and less empty and aborted seeds. In addition, large crops satiated the less mobile seed predator. The other two predispersal predators responded to plant traits, the presence of other seed predators and environmental conditions, but did not show a satiation response to the current-year crop. Our large-scale study on a dioecious, wind-pollinated Mediterranean juniper indicates that pollination efficiency and satiation of seed predators, mediated by environmental conditions, are important determinants of reproductive output in this juniper species. [ABSTRACT FROM AUTHOR]

Background: For many years, peritoneal carcinomatosis (PC) entitled poor prognosis until the development of the cytoreductive surgery technique associated with hyperthermic intraperitoneal chemotherapy. Imaging of peritoneal carcinomatosis plays an essential role in the diagnosis and management of the patients being considered for cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC)., Main Body: The key role of imaging in patients with peritoneal malignancy is to aid surgical decision making. A standardized peritoneal magnetic resonance (MR) imaging protocol, including T2-weighted fat suppressed, diffusion-weighted and gadolinium-enhanced sequences, allows to detect small peritoneal tumours that are often missed on other imaging. A systematic approach to MR imaging and a close collaboration between the radiologist and the oncologic surgeon are key elements for an accurate evaluation of candidate patients for CRS and HIPEC., Conclusion: MR imaging provides a powerful tool for accurate preoperative imaging in patients considered for curative surgery and assists the surgeon in evaluating patients for CRS and HIPEC., 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 B.V. All rights reserved.)

Objective: Pre-existing neutralising antibodies (NAbs) to adeno-associated viruses (AAVs) remain an impediment for systemically administered AAV-mediated gene therapy treatment in many patients, and various strategies are under investigation to overcome this limitation. Here, IgG-degrading enzymes (Ides) derived from bacteria of the genus Streptococcus were tested for their ability to cleave human IgG and allow AAV-mediated transduction in individuals with pre-existing NAbs., Methods: Cleavage activity of three different Ides was evaluated in vitro in serum from different species. Passively immunised mice or non-human primates (NHP) with naturally occurring anti-AAV NAbs were used to define the optimal IdeS dose and administration window for AAVAnc80 and AAV8 vectors in mice and AAV3B in NHPs., Results: The selected candidate, IdeS, was found to be highly efficient at cleaving human IgG, less efficient against NHP IgG and inefficient against mouse IgG. In vivo , we observed differences in how IdeS affected liver transduction in the presence of NAbs depending on the AAV serotype. For AAVAnc80 and AAV3B, the best transduction levels were achieved when the vector was administered after IgG digestion products were cleared from circulation. However, for AAV8 we only observed a modest and transient inhibition of transduction by IdeS cleavage products., Conclusion: Preconditioning with IdeS represents a unique treatment opportunity for patients primarily excluded from participation in gene therapy clinical trials because of elevated circulating anti-AAV NAb levels. However, careful determination of the optimal IdeS dose and timing for the administration of each AAV serotype is essential for optimal transduction., Competing Interests: The following authors are employees of Vivet Therapeutics: IRG, LTM, BT, AD, JPC, BB, VF and GGA., (© 2022 Vivet Therapeutics SAS. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background and Objective: The assessment of dependence in older adults currently requires a manual collection of data taken from questionnaires. This process is time consuming for the clinicians and intrudes the daily life of the elderly. This paper aims to semi-automate the acquisition and analysis of health data to assess and predict the dependence in older adults while executing one instrumental activity of daily living (IADL)., Methods: In a mobile-health (m-health) scenario, we analyze whether the acquisition of data through wearables during the performance of IADLs, and with the help of machine learning techniques could replace the traditional questionnaires to evaluate dependence. To that end, we collected data from wearables, while older adults do the shopping activity. A trial supervisor (TS) labelled the different shopping stages (SS) in the collected data. We performed data pre-processing techniques over those SS and analyzed them with three machine learning algorithms: k-Nearest Neighbors (k-NN), Random Forest (RF) and Support Vector Machines (SVM)., Results: Our results confirm that it is possible to replace the traditional questionnaires with wearable data. In particular, the best learning algorithm we tried reported an accuracy of 97% in the assessment of dependence. We tuned the hyperparameters of this algorithm and used embedded feature selection technique to get the best performance with a subset of only 10 features out of the initial 85. This model considers only features extracted from four sensors of a single wearable: accelerometer, heart rate, electrodermal activity and temperature. Although these features are not observational, our current proposal is semi-automatic, because it needs a TS labelling the SS (with a smartphone application). In the future, this labelling process could be automatic as well., Conclusions: Our method can semi-automatically assess the dependence, without disturbing daily activities of elderly people. This method can save clinicians' time in the evaluation of dependence in older adults and reduce healthcare costs., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Limited information is available on incidence and outcomes of COVID-19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS-CoV-2 infection and COVID-19-related outcomes in patients with MS, and compared these with the general population., Methods: A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID-19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020., Results: Two-hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID-19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70-0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76-6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying treatment and hospitalization risk., Conclusions: Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue disease-modifying treatment should be based on a careful risk-benefit assessment., (© 2021 European Academy of Neurology.)

Background: Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2'3'-cyclic GMP-AMP (2'3'-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism., Methods: Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2'3'-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed., Results: Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy. In this setting, the CART/STING-L combination, but not the monotherapy with CART cells or STING-L, restrained tumor progression and enhanced overall survival, showing abscopal effects on distal STING-L-non-treated tumors. Interestingly, a secondary immune response against non-chimeric antigen receptor-targeted Ags (epitope spreading), as determined by major histocompatibility complex-I-tetramer staining, was fostered and its intensity correlated with the efficacy of the combination. This was consistent with the oligoclonal expansion of host T cells, as revealed by in-depth T-cell receptor repertoire analysis. Moreover, only in the combination group did the activation of endogenous T cells translate into a systemic antitumor response. Importantly, the epitope spreading and the antitumor effects of the combination were fully dependent on host STING signaling and Batf3-dependent DCs, and were partially dependent on Perf release by CART cells. Interestingly, the efficacy of the CART/STING-L treatment also depended on STING signaling in CART cells., Conclusions: Our data show that 2'3'-cGAMP is a suitable adjuvant to combine with CART-cell therapy, allowing the induction of an endogenous T-cell response that prevents the outgrowth of Ag-loss tumor variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited., Objective: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting., Methods: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated., Results: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy., Conclusions: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.