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Background and Aims: Cell culture is a fundamental experimental tool for understanding cell physiology. However, translating these findings to in vivo settings has proven challenging. Replicating donor tissue conditions, including oxygen levels, is crucial for achieving meaningful results. Nevertheless, oxygen culture conditions are often overlooked, particularly in the context of chemotherapy-induced neurotoxicity., Methods: In this study, we investigated the role of oxygen levels in primary neuronal cultures by comparing neuronal performance under cisplatin exposure (1 μg/mL) in supraphysiological normoxia (representing atmospheric conditions in a standard incubator; 18.5% O 2 ) and physioxia (representing physiologic oxygen conditions in nervous tissue; 5% O 2 ). Experiments were also conducted to assess survival, neurite development, senescence marker expression, and proinflammatory cytokine secretion., Results: Under control conditions, both oxygen concentration conditions exhibited similar behaviors. However, after cisplatin administration, sensory neurons cultured under supraphysiological normoxic conditions show higher mortality, exhibit an evolutionarily proinflammatory cytokine profile over time, and activate apoptotic-regulated neuron death markers. In contrast, under physiological conditions, neurons treated with cisplatin exhibited senescence marker expression and an attenuated inflammatory secretome., Interpretation: These results underscore the critical role of oxygen in neuronal culture, particularly in studying compounds where neuronal damage is mechanistically linked to oxidative stress. Even at identical doses of evaluated neurotoxic drugs, distinct cellular phenotypic fates can emerge, impacting translatability to the in vivo setting., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Purpose: To develop Mexico's first methodologically rigorous clinical practice guideline for the management of adult overweight and obesity. The target audiences are interdisciplinary healthcare professionals across healthcare systems who are the first point of contact for patients with obesity in Mexico, patients, and health system decision makers., Recent Findings: A review of recent international obesity clinical practice guidelines and an expert consensus process identified: i) common recommendations appropriate for implementation in Mexico and ii) knowledge gaps requiring the formulation of new recommendations. In all, 20 new recommendations and 20 good practice statements were developed using the GRADE Evidence-to-Decision Framework and expert consensus. Overweight and obesity negatively impact the health and well-being of individuals and populations in Mexico. This guideline aims to establish a new evidence-based, patient-centered, non-stigmatizing, and practical treatment and management framework, based on the fundamental principles of chronic disease prevention and management., (© 2024. The Author(s).)

Aggregation-induced emission luminogens (AIEgens) that respond to mechanical force are increasingly used as force probes, memory devices, and advanced security systems. Most of the known mechanisms to modulate mechanoresponsive AIEgens have been based on changes in aggregation states, involving only physical alterations. Instances that employ covalent bond cleavage are still rare. We have developed a novel mechanochemical uncaging strategy to unveil AIEgens with diverse emission characteristics using engineered norborn-2-en-7-one (NEO) mechanophores. These NEO mechanophores were covalently integrated into polymer molecules and activated in both the solution and solid states. This activation resulted in highly tunable fluorescence upon immobilization through solidification or aggregation, producing blue, green, yellow, and orange-red emissions. By designing the caged and uncaged forms as donor-acceptor pairs for Förster resonance energy transfer (FRET), we achieved multicolor mechanofluorescence, effectively broadening the color spectrum to include white emission. Additionally, we computationally explored the electronic structures of activated NEOs, providing insights into the observed regiochemical effects of the substituents. This understanding, together with the novel luminogenic characteristics of the caged and activated species, provides a highly tunable reporter that traces progress with continuous color evolution. This advancement paves the way for future applications of mechanoresponsive materials in areas like damage detection and bioimaging.

Antimicrobial peptides (AMPs) are regarded as a promising alternative to traditional antibiotics in the face of ever-increasing resistance. However, many AMPs fail to progress into clinics due to unexpected difficulties found in preclinical in vivo phases. Our research has focused on crotalicidin (Ctn), an AMP from snake venom, and a fragment thereof, Ctn[15-34], with improved in vitro antimicrobial and anticancer activities and remarkable serum stability. As the retroenantio versions of both AMPs maintained favorable profiles, in this work, we evaluate the in vivo efficacy of both the native-sequence AMPs and their retroenantio counterparts in a murine infection model with Acinetobacter baumannii . A significant reduction in bacterial levels is found in the mice treated with Ctn[15-34]. However, contrary to expectations, the retroenantio analogs either exhibit toxicity or lack efficacy when administered to mice. Our findings underscore the critical importance of in vivo infection model evaluation to fully calibrate the therapeutic potential of AMPs.

Alaska contains over 600 formerly used defense (FUD) sites, many of which serve as point sources of pollution. These sites are often co-located with rural communities that depend upon traditional subsistence foods, especially lipid-rich animals that bioaccumulate and biomagnify persistent organic pollutants (POPs). Many POPs are carcinogenic and endocrine-disrupting compounds that are associated with adverse health outcomes. Therefore, elevated exposure to POPs from point sources of pollution may contribute to disproportionate incidence of disease in arctic communities. We investigated PCB concentrations and the health implications of POP exposure in sentinel fishes collected near the Northeast Cape FUD site on Sivuqaq (St. Lawrence Island), Alaska. Sivuqaq residents are almost exclusively Yupik and rely on subsistence foods. At the request of the Sivuqaq community, we examined differential gene expression and developmental pathologies associated with exposure to POPs originating at the Northeast Cape FUD site. We found significantly higher levels of PCBs in Alaska blackfish (Dallia pectoralis) collected from contaminated sites downstream of the FUD site compared to fish collected from upstream reference sites. We compared transcriptomic profiles and histopathologies of these same blackfish. Blackfish from contaminated sites overexpressed genes involved in ribosomal and FoxO signaling pathways compared to blackfish from reference sites. Contaminated blackfish also had significantly fewer thyroid follicles and smaller pigmented macrophage aggregates. Conversely, we found that ninespine stickleback (Pungitius pungitius) from contaminated sites exhibited thyroid follicle hyperplasia. Despite our previous research reporting transcriptomic and endocrine differences in stickleback from contaminated vs. reference sites, we did not find significant differences in kidney or gonadal histomorphologies. Our results demonstrate that contaminants from the Northeast Cape FUD site are associated with altered gene expression and thyroid development in native fishes. These results are consistent with our prior work demonstrating disruption of the thyroid hormone axis in Sivuqaq residents., 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 Elsevier Ltd. All rights reserved.)

Background: The design of reverse shoulder arthroplasty (RSA) implants has evolved significantly over the past 50 years. Today there are many options available that differ in design of the glenoid and humeral components, fixation methods, sizes, and modularity. With respect to the humeral component, the literature has generally focused on the differences between inlay and onlay designs and the potential impact on outcomes. However, inlay and onlay design represents only one factor of many., Methods: It is our hypothesis that separating onlay and inlay designs into 2 distinct entities is an oversimplification as there can be a wide overlap of the 2 designs, depending on surgical technique and the implant selected. As such, the differences between inlay and onlay designs should be measured in absolute terms-meaning combined distalization and lateralization., Results: By reviewing the many factors that can contribute to the glenosphere-humerus relationship, the role of inlay and onlay humeral designs as an important distinguishing feature is shown to be limited. Preliminary studies suggest that the amount of distalization and lateralization of the construct may be the most accurate method of describing the differences in the constructs., Conclusions: Inlay and onlay humeral component design represents only one factor of many that may impact outcomes. A more accurate method of defining specific design and technique factors in RSA is the degree of lateralization and distalization., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

The formation and analysis of amyloid fibers by two β-glucosidases, BglA and BglB, belonging to the GH1 enzyme family, are reported. Both proteins have the (β/α) 8 TIM-barrel fold, which is characteristic of this family and is also the most common protein structure. BglA is an octamer, whereas BglB is a monomer. Amyloid fibrillation using pH and temperature as perturbing agents was investigated using fluorescence spectroscopy as a preliminary approach and corroborated using wide-field optical microscopy, confocal microscopy, and field-emission scanning electron microscopy. These analyses showed that both enzymes fibrillate at a wide range of acidic and alkaline conditions and at several temperature conditions, particularly at acidic pH (3-4) and at temperatures between 45 and 65 °C. Circular dichroism spectroscopy corroborated the transition from an α-helix to a β-sheet secondary structure of both proteins in conditions where fibrillation was observed. Overall, our results suggest that fibrillation is a rather common phenomenon caused by protein misfolding, driven by a transition from an α-helix to a β-sheet secondary structure, that many proteins can undergo if subjected to conditions that disturb their native conformation.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, which makes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Castillo, Ramírez, Ramos, Martinez-Arribas, Domingo-Contreras, Mackenzie, Peña-Varas, Lindemann, Montero, Annang, Vicente, Genilloud, González-Pacanowska and Fernandez-Godino.)

Background and Purpose: The aim of this study was to determine the diagnostic value of fractional plasma volume derived from dynamic contrast-enhanced perfusion MR imaging versus ADC, obtained from DWI in differentiating between grade 2 (low-grade) and grade 3 (high-grade) intracranial ependymomas., Materials and Methods: A hospital database was created for the period from January 2013 through June 2022, including patients with histologically-proved ependymoma diagnosis with available dynamic contrast-enhanced MR imaging. Both dynamic contrast-enhanced perfusion and DWI were performed on each patient using 1.5T and 3T scanners. Fractional plasma volume maps and ADC maps were calculated. ROIs were defined by a senior neuroradiologist manually by including the enhancing tumor on every section and conforming a VOI to obtain the maximum value of fractional plasma volume (Vp max ) and the minimum value of ADC (ADC min ). A Mann-Whitney U test at a significance level of corrected P  = .01 was used to evaluate the differences. Additionally, receiver operating characteristic curve analysis was applied to assess the sensitivity and specificity of Vp max and ADC min values., Results: A total of 20 patients with ependymomas (10 grade 2 tumors and 10 grade 3 tumors) were included. Vp max values for grade 3 ependymomas were significantly higher ( P  < .002) than those for grade 2. ADC min values were overall lower in high-grade lesions. However, no statistically significant differences were found ( P  = .12114)., Conclusions: As a dynamic contrast-enhanced perfusion MR imaging metric, fractional plasma volume can be used as an indicator to differentiate grade 2 and grade 3 ependymomas. Dynamic contrast-enhanced perfusion MR imaging plays an important role with high diagnostic value in differentiating low- and high-grade ependymoma., (© 2024 by American Journal of Neuroradiology.)

Background and Purpose: Distinguishing treatment-induced imaging changes from progressive disease has important implications for avoiding inappropriate discontinuation of a treatment. Our goal in this study is to evaluate the utility of dynamic contrast-enhanced (DCE) perfusion MRI as a biomarker for the early detection of progression. We hypothesize that DCE-MRI may have the potential as an early predictor for the progression of disease in GBM patients when compared to the current standard of conventional MRI. Methods: We identified 26 patients from 2011 to 2023 with newly diagnosed primary glioblastoma by histopathology and gross or subtotal resection of the tumor. Then, we classified them into two groups: patients with progression of disease (POD) confirmed by pathology or change in chemotherapy and patients with stable disease without evidence of progression or need for therapy change. Finally, at least three DCE-MRI scans were performed prior to POD for the progression cohort, and three consecutive DCE-MRI scans were performed for those with stable disease. The volume of interest (VOI) was delineated by a neuroradiologist to measure the maximum values for Ktrans and plasma volume (Vp). A Friedman test was conducted to evaluate the statistical significance of the parameter changes between scans. Results: The mean interval between subsequent scans was 57.94 days, with POD-1 representing the first scan prior to POD and POD-3 representing the third scan. The normalized maximum Vp values for POD-3, POD-2, and POD-1 are 1.40, 1.86, and 3.24, respectively (FS = 18.00, p = 0.0001). It demonstrates that Vp max values are progressively increasing in the three scans prior to POD when measured by routine MRI scans. The normalized maximum Ktrans values for POD-1, POD-2, and POD-3 are 0.51, 0.09, and 0.51, respectively (FS = 1.13, p < 0.57). Conclusions: Our analysis of the longitudinal scans leading up to POD significantly correlated with increasing plasma volume (Vp). A longitudinal study for tumor perfusion change demonstrated that DCE perfusion could be utilized as an early predictor of tumor progression.

Light has myriad impacts on behavior, health, and physiology. These signals originate in the retina and are relayed to the brain by more than 40 types of retinal ganglion cells (RGCs). Despite a growing appreciation for the diversity of RGCs, how these diverse channels of light information are ultimately integrated by the ~50 retinorecipient brain targets to drive these light-evoked effects is a major open question. This gap in understanding primarily stems from a lack of genetic tools that specifically label, manipulate, or ablate specific RGC types. Here, we report the generation and characterization of a new mouse line (Opn4 FlpO ), in which FlpO is expressed from the Opn4 locus, to manipulate the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells. We find that the Opn4 FlpO line, when crossed to multiple reporters, drives expression that is confined to ipRGCs and primarily labels the M1-M3 subtypes. Labeled cells in this mouse line show the expected intrinsic, melanopsin-based light response and morphological features consistent with the M1-M3 subtypes. In alignment with the morphological and physiological findings, we see strong innervation of non-image forming brain targets by ipRGC axons, and weaker innervation of image forming targets in Opn4 FlpO mice labeled using AAV-based and FlpO-reporter lines. Consistent with the FlpO insertion disrupting the endogenous Opn4 transcript, we find that Opn4 FlpO/FlpO mice show deficits in the pupillary light reflex, demonstrating their utility for behavioral research in future experiments. Overall, the Opn4 FlpO mouse line drives Flp-recombinase expression that is confined to ipRGCs and most effectively drives recombination in M1-M3 ipRGCs. This mouse line will be of broad use to those interested in manipulating ipRGCs through a Flp-based recombinase for intersectional studies or in combination with other, non-Opn4 Cre driver lines.

The PD-1/PD-L1 protein-protein interaction (PPI) controls an adaptive immune resistance mechanism exerted by tumor cells to evade immune responses. The large-molecule nature of current commercial monoclonal antibodies against this PPI hampers their effectiveness by limiting tumor penetration and inducing severe immune-related side effects. Synthetic small-molecule inhibitors may overcome such limitations and have demonstrated promising clinical translation, but their design is challenging. Microbial natural products (NPs) are a source of small molecules with vast chemical diversity that have proved anti-tumoral activities, but which immunotherapeutic properties as PD-1/PD-L1 inhibitors had remained uncharacterized so far. Here, we have developed the first cell-based PD-1/PD-L1 blockade reporter assay to screen NPs libraries. In this study, 6000 microbial extracts of maximum biosynthetic diversity were screened. A secondary metabolite called alpha-cyclopiazonic acid (α-CPA) of a bioactive fungal extract was confirmed as a new PD-1/PD-L1 inhibitor with low micromolar range in the cellular assay and in an additional cell-free competitive assay. Thermal denaturation experiments with PD-1 confirmed that the mechanism of inhibition is based on its stabilization upon binding to α-CPA. The identification of α-CPA as a novel PD-1 stabilizer proves the unprecedented resolution of this methodology at capturing specific PD-1/PD-L1 PPI inhibitors from chemically diverse NP libraries., 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 B.V. All rights reserved.)

Peripheral nerve damage results in the loss of sensorimotor and autonomic functions, which is a significant burden to patients. Furthermore, nerve injuries greater than the limiting gap length require surgical repair. Although autografts are the preferred clinical choice, their usage is impeded by their limited availability, dimensional mismatch, and the sacrifice of another functional donor nerve. Accordingly, nerve guidance conduits, which are tubular scaffolds engineered to provide a biomimetic environment for nerve regeneration, have emerged as alternatives to autografts. Consequently, a few nerve guidance conduits have received clinical approval for the repair of short-mid nerve gaps but failed to regenerate limiting gap damage, which represents the bottleneck of this technology. Thus, it is still necessary to optimize the morphology and constituent materials of conduits. This review summarizes the recent advances in nerve conduit technology. Several manufacturing techniques and conduit designs are discussed, with emphasis on the structural improvement of simple hollow tubes, additive manufacturing techniques, and decellularized grafts. The main objective of this review is to provide a critical overview of nerve guidance conduit technology to support regeneration in long nerve defects, promote future developments, and speed up its clinical translation as a reliable alternative to autografts.

Growing resistance to current antiparasitic medications, both in livestock and in zoological species under human care, makes it imperative to evaluate available drugs on the market, such as eprinomectin. In this prospective study, five males and one female of reticulated ( Giraffa reticulata ; n = 2), Masai ( Giraffa tippelskirchii ; n = 1), Nubian ( Giraffa camelopardalis ; n = 2), and hybrid subspecies ( n = 1) of giraffe, received 1.5 mg/kg eprinomectin topically along the dorsum. Using high-performance liquid chromatography, concentrations of eprinomectin in plasma samples collected at 0, 4, 24, and 48 h, and 7, 14, 21, and 28 d were evaluated following drug administration. Complete blood cell counts and biochemistry panels were performed before ( n = 6) and after ( n = 3) eprinomectin administration. Samples for modified double centrifugal fecal flotation ( n = 6) were evaluated prior to eprinomectin administration to evaluate for endoparasites and were repeated after the study ( n = 5). Noncompartmental pharmacokinetic analysis was applied to the data. The observed maximum plasma concentration was 11.45 ng/ml and the time of observed maximum concentration was 2.67 d. The mean terminal half-life was 5.16 d. No adverse effects were observed related to eprinomectin administration and no blood work changes were observed. Parasite loads decreased ( n = 3) or did not change ( n = 2) after eprinomectin administration. The mean peak plasma concentration of eprinomectin in giraffe was similar to that achieved in cattle, despite using three times the dose.

Key Message: NOI10 and NOI11 are two RIN4-like/NOI proteins that participate in the immune response of the Arabidopsis plant and affect the RIN4-regulated mechanisms involving the R-proteins RPM1 and RPS2. The immune response in plants depends on the regulation of signaling pathways triggered by pathogens and herbivores. RIN4, a protein of the RIN4-like/NOI family, is considered to be a central immune signal in the interactions of plants and pathogens. In Arabidopsis thaliana, four of the 15 members of the RIN4-like/NOI family (NOI3, NOI5, NOI10, and NOI11) were induced in response to the plant herbivore Tetranychus urticae. While overexpressing NOI10 and NOI11 plants did not affect mite performance, opposite callose accumulation patterns were observed when compared to RIN4 overexpressing plants. In vitro and in vivo analyses demonstrated the interaction of NOI10 and NOI11 with the RIN4 interactors RPM1, RPS2, and RIPK, suggesting a role in the context of the RIN4-regulated immune response. Transient expression experiments in Nicotiana benthamiana evidenced that NOI10 and NOI11 differed from RIN4 in their functionality. Furthermore, overexpressing NOI10 and NOI11 plants had significant differences in susceptibility with WT and overexpressing RIN4 plants when challenged with Pseudomonas syringae bacteria expressing the AvrRpt2 or the AvrRpm1 effectors. These results demonstrate the participation of NOI10 and NOI11 in the RIN4-mediated pathway. Whereas RIN4 is considered a guardee protein, NOI10 and NOI11 could act as decoys to modulate the concerted activity of effectors and R-proteins., (© 2024. The Author(s).)

Objective: To assess safety, urinary symptoms, and feasibility of JJ stent removal with exteriorized threads through the percutaneous tract after percutaneous nephrolithotomy (PCNL)., Materials and Methods: Prospective, transversal, comparative, experimental, randomized 1-to-1 cohort study in 52 patients who underwent "tubeless" PCNL from October 2020 to November 2022. Group A with threads through the urethra and Group B through the percutaneous tract. The validated USSQ (Ureteral Stent Symptom Questionnaire) was applied in the Urology office a week after the procedure, and the JJ stent was withdrawn by pulling the threads. Hemoglobin and urine culture, and pre- and post-surgery were evaluated., Results: There is a statistically significant difference in favor of group B when comparing urinary symptoms (p = 0.008), body pain (p = 0.009), and general condition (p = 0.042), mainly for non-urgency incontinence, frequency of analgesic use, and dysuria. There were significant differences between groups (p = 0.028, p = 0.026, p = 0.027, respectively). There is no association with urinary infections (p = 0.603) nor an increased risk of bleeding (p = 0.321)., Conclusion: The removal of the JJ stent with exteriorized threads through the percutaneous tract after PCNL in the office is a feasible and safe procedure if it is removed before 8 days and has better tolerance regarding the urinary symptoms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High amounts of phosphorus (P) in rivers come mainly from two sources: fertilizers washed off from agricultural and urban areas by runoff water (non-point sources) and urban and industrial development which are translated in P discharges from wastewater treatment plants (WWTP). This work analyses the content of P in water for nearly 40 years inquiring into the origin of the sources, based on the hypothesis of runoff generation from the detection of river streamflow increases during the P contribution episode and the previous precipitation. For this purpose, the Guadaira River, which is located in the South of Spain and has a drainage surface of 1524 km 2 , was selected. In this watershed agricultural land use converges with numerous human activities resulting in high pressures on water quality. We found 40% of the P contribution episodes found seem to come from the runoff generated after the heaviest rainfall events, which normally occur between November and May. The remaining 60% of the P contribution episodes were found to be linked to point sources, which become more relevant from June to September, reaching the highest concentration values (6-17 mg/L). The results highlight that the target phosphate concentration value of 0.34 mg PO 4 /L imposed by the national legislation for a good state following the Water Framework Directive 2000/60/EC is exceeded by 96% of the measurements during the period from 1981 to 2022. On a monthly basis, PO 4 loads showed a linear relationship with river streamflow (R 2  = 0.94). However, on field measurements scale, a potential relationship between both variables was found, which changed according to the improvement in the wastewater treatment and facilities for 1982-1994, 1995-2017 and 2018-2022. In these three periods, different significant decreasing trends of the P content were found, mainly marked by the setup of each individual WWTP., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: The efficacy of COVID-19 convalescent plasma (CP) associates with high titres of antibodies. ConPlas-19 clinical trial showed that CP reduces the risk of progression to severe COVID-19 at 28 days. Here, we aim to study ConPlas-19 donors and characteristics that associate with high anti-SARS-CoV-2 antibody levels., Materials and Methods: Four-hundred donors were enrolled in ConPlas-19. The presence and titres of anti-SARS-CoV-2 antibodies were evaluated by EUROIMMUN anti-SARS-CoV-2 S1 IgG ELISA., Results: A majority of 80.3% of ConPlas-19 donor candidates had positive EUROIMMUN test results (ratio ≥1.1), and of these, 51.4% had high antibody titres (ratio ≥3.5). Antibody levels decline over time, but nevertheless, out of 37 donors tested for an intended second CP donation, over 90% were still EUROIMMUN positive, and nearly 75% of those with high titres maintained high titres in the second sample. Donors with a greater probability of developing high titres of anti-SARS-CoV-2 antibodies include those older than 40 years of age (RR 2.06; 95% CI 1.24-3.42), with more than 7 days of COVID-19 symptoms (RR 1.89; 95% CI 1.05-3.43) and collected within 4 months from infection (RR 2.61; 95% CI 1.16-5.90). Male donors had a trend towards higher titres compared with women (RR 1.67; 95% CI 0.91-3.06)., Conclusion: SARS-CoV-2 CP candidate donors' age, duration of COVID-19 symptoms and time from infection to donation associate with the collection of CP with high antibody levels. Beyond COVID-19, these data are relevant to inform decisions to optimize the CP donor selection process in potential future outbreaks., (© 2023 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Persistent organic pollutants (POPs) are lipophilic compounds that bioaccumulate in animals and biomagnify within food webs. Many POPs are endocrine disrupting compounds that impact vertebrate development. POPs accumulate in the Arctic via global distillation and thereby impact high trophic level vertebrates as well as people who live a subsistence lifestyle. The Arctic also contains thousands of point sources of pollution, such as formerly used defense (FUD) sites. Sivuqaq (St. Lawrence Island), Alaska was used by the U.S. military during the Cold War and FUD sites on the island remain point sources of POP contamination. We examined the effects of POP exposure on ninespine stickleback (Pungitius pungitius) collected from Troutman Lake in the village of Gambell as a model for human exposure and disease. During the Cold War, Troutman Lake was used as a dump site by the U.S. military. We found that PCB concentrations in stickleback exceeded the U.S. Environmental Protection Agency's guideline for unlimited consumption despite these fish being low trophic level organisms. We examined effects at three levels of biological organization: gene expression, endocrinology, and histomorphology. We found that ninespine stickleback from Troutman Lake exhibited suppressed gonadal development compared to threespine stickleback (Gasterosteus aculeatus) studied elsewhere. Troutman Lake stickleback also displayed two distinct hepatic phenotypes, one with lipid accumulation and one with glycogen-type vacuolation. We compared the transcriptomic profiles of these liver phenotypes using RNA sequencing and found significant upregulation of genes involved in ribosomal and metabolic pathways in the lipid accumulation group. Additionally, stickleback displaying liver lipid accumulation had significantly fewer thyroid follicles than the vacuolated phenotype. Our study and previous work highlight health concerns for people and wildlife due to pollution hotspots in the Arctic, and the need for health-protective remediation., 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 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular disease (CVD) represents the primary cause of death and disability globally, with elevated cholesterol as one of the leading risk factors for CVD. We describe the clinical characteristics, treatment patterns, and effectiveness of evolocumab in treating hyperlipidemia., Methods: Observational study conducted through a chart review of patients with hyperlipidemia receiving evolocumab as part of clinical management in Colombia., Results: This study included 115 patients treated with evolocumab. A total of 101 patients (87.8%) had a history of CVD, 13 (11.3%) familial hypercholesterolemia (FH), and 23 (20%) type 2 diabetes. Thirty-nine patients reported intolerance to any statin (33.9%). The median value of LDL-C before initiation of evolocumab was 147mg/dL (IQR: 122.5-183.7mg/dL). Within the first 3 months of treatment, LDL-C value dropped to a median value of 53mg/dL (IQR: 34.0-95.5mg/dL), showing a reduction of 63.9%. The median LDL-C values remained below 45mg/dL until the end of follow-up. Among the patients with available data, up to 61% achieved an LDL-C level below 55mg/dL at the 10-12-month follow-up. A total of 72% of patients were persistent with treatment. Safety results showed a low frequency of hospitalizations (≤2%) and treatment-emergent adverse drug reactions (5.2%). No serious adverse events were reported., Conclusions: Evolocumab was associated with reductions in LDL-C levels, with a relative decrease of 63.9% within the first 3 months of treatment. Low rates of interruptions due to adverse events and adequate medication persistence was reported., (Copyright © 2023 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Phase-type distributions (PHDs), which are defined as the distribution of the lifetime up to the absorption in an absorbent Markov chain, are an appropriate candidate to model the lifetime of any system, since any non-negative probability distribution can be approximated by a PHD with sufficient precision. Despite PHD potential, friendly statistical programs do not have a module implemented in their interfaces to handle PHD. Thus, researchers must consider others statistical software such as R, Matlab or Python that work with the compilation of code chunks and functions. This fact might be an important handicap for those researchers who do not have sufficient knowledge in programming environments. In this paper, a new interactive web application developed with shiny is introduced in order to adjust PHD to an experimental dataset. This open access app does not require any kind of knowledge about programming or major mathematical concepts. Users can easily compare the graphic fit of several PHDs while estimating their parameters and assess the goodness of fit with just several clicks. All these functionalities are exhibited by means of a numerical simulation and modeling the time to live since the diagnostic in primary breast cancer patients.

Background and Objectives: Peripheral nerve injuries resulting in a nerve defect require surgical repair. The gold standard of autograft (AG) has several limitations, and therefore, new alternatives must be developed. The main objective of this study was to assess nerve regeneration through a long gap nerve injury (50 mm) in the peroneal nerve of sheep with a decellularized nerve allograft (DCA)., Methods: A 5-cm long nerve gap was made in the peroneal nerve of sheep and repaired using an AG or using a DCA. Functional tests were performed once a month and electrophysiology and echography evaluations at 6.5 and 9 months postsurgery. Nerve grafts were harvested at 9 months for immunohistochemical and morphological analyses., Results: The decellularization protocol completely eliminated the cells while preserving the extracellular matrix of the nerve. No significant differences were observed in functional tests of locomotion and pain response. Reinnervation of the tibialis anterior muscles occurred in all animals, with some delay in the DCA group compared with the AG group. Histology showed a preserved fascicular structure in both AG and DCA; however, the number of axons distal to the nerve graft was higher in AG than in DCA., Conclusion: The decellularized graft assayed supported effective axonal regeneration when used to repair a 5-cm long gap in the sheep. As expected, a delay in functional recovery was observed compared with the AG because of the lack of Schwann cells., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Objective: Untreated mental disorders are important among low- and middle-income country (LMIC) university students in Latin America, where barriers to treatment are high. Scalable interventions are needed. This study compared transdiagnostic self-guided and guided internet-delivered cognitive behavioral therapy (i-CBT) with treatment as usual (TAU) for clinically significant anxiety and depression among undergraduates in Colombia and Mexico., Method: 1,319 anxious, as determined by the Generalized Anxiety Disorder-7 (GAD-7) = 10+ and/or depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) = 10+, undergraduates (mean [SD] age = 21.4 [3.2]); 78.7% female; 55.9% first-generation university student) from seven universities in Colombia and Mexico were randomized to culturally adapted versions of self-guided i-CBT (n = 439), guided i-CBT (n = 445), or treatment as usual (TAU; n = 435). All randomized participants were reassessed 3 months after randomization. The primary outcome was remission of both anxiety (GAD-7 = 0-4) and depression (PHQ-9 = 0-4). We hypothesized that remission would be higher with guided i-CBT than with the other interventions., Results: Intent-to-treat analysis found significantly higher adjusted (for university and loss to follow-up) remission rates (ARD) among participants randomized to guided i-CBT than either self-guided i-CBT (ARD = 13.1%, χ12 = 10.4, p = .001) or TAU (ARD = 11.2%, χ12 = 8.4, p = .004), but no significant difference between self-guided i-CBT and TAU (ARD = -1.9%, χ12 = 0.2, p = .63). Per-protocol sensitivity analyses and analyses of dimensional outcomes yielded similar results., Conclusions: Significant reductions in anxiety and depression among LMIC university students could be achieved with guided i-CBT, although further research is needed to determine which students would most likely benefit from this intervention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The characterization of non-point source pollution at the watershed scale difficult owing to its distributed nature combined with the lack of suitable measurements for validation. This study proposes the classification of land within a Mediterranean watershed according to its potential source of non-point pollution, considering interannual precipitation variability and dam regulation effects. For this purpose, the potential non-point pollution index (PNPI) developed by the Italian Environmental Protection Agency was modified to include annual local precipitation behavior, named local annual PNPI (APNPI). PNPI and APNPI were computed for the Guadalquivir River (Spain), which has a drainage surface of 57,500 km 2 and is highly regulated by >60 reservoirs. The results reflect the vulnerability along the Guadalquivir River in terms of the spatially variable non-point pollutant nature of its contributing watersheds. The annual average nitrate concentration values on the southern side exceeded the average value on the northern side by almost five times and showed a statistically significant power fit with the PNPI, with an R 2 of 0.65. Long-term available nitrate data (1981/82-2006/07) on a monthly scale at the outlets of some watersheds allowed us to rank priority pollutant source areas within the watershed. The power fits between the annual average nitrate loads and the APNPI (R 2  = 0.51-0.99) were statistically significant, which validated the utility of adding the variability of precipitation at an annual scale as a dynamic factor in the index. The APNPI can constitute a simple dynamic classification index for assessing the relative risk of non-point source pollution across a large area, especially in data-scarce situations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maria Jose Polo reports financial support was provided by European Funding for Rural Development (FEDER) and the Office for Economy, Knowledge, Enterprises and University of the Andalusian Regional Government., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: This study characterizes patients receiving evolocumab in clinical practice and assesses treatment effectiveness, safety and persistence outcomes across five countries., Methods: This retrospective and prospective observational study enrolled patients initiated on evolocumab during August 2017 to July 2019 at 49 sites across Canada, Mexico, Colombia, Saudi Arabia and Kuwait. Medical records data were extracted within 6 months prior to (baseline) and every 3 months for 12 months post evolocumab initiation and reported as available., Results: A total of 578 patients were enrolled (40.1% female, median age 60 [interquartile range (IQR) 51-68] years); 83.7% had atherosclerotic cardiovascular disease and/or familial hypercholesterolemia. Median low-density lipoprotein cholesterol (LDL-C) at baseline was 3.4 (IQR 2.7-4.2) mmol/L (131.5 [IQR 104.4-162.4] mg/dL), with 75.6% of patients receiving a statin (59.2% high intensity). Compared to baseline, the median lowest LDL-C was reduced by 70.2% and remained stable over 12 months of treatment. Guideline-recommended LDL-C thresholds < 1.8, < 1.4 and < 1.0 mmol/L (< 70, < 55 and < 40 mg/dL) were achieved by 75.3%, 63.6% and 47.4% of patients. LDL-C outcomes were consistent across high- and very high-risk patients. Background lipid-lowering therapy remained relatively stable. No serious treatment-emergent adverse events were reported, and persistence to evolocumab was 90.2% at 12 months., Conclusion: These findings provide real-world evidence that evolocumab use is in accordance with its international guideline-recommended place in dyslipidemia therapy, as well as confirmation of its effectiveness and safety in a heterogeneous population. Evolocumab can address a healthcare gap in the management of dyslipidemia by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk., (© 2023. The Author(s).)

In the pursuit of enhanced athletic prowess in different disciplines, athletes constantly look for strategies to increase their physical performance, encompassing technical skills and dietary components, which inevitably, in most cases, include the incorporation of sports supplements. In recent years, there has been an increase in the number of athletes using ergogenic aids. In this context, scientific evidence must play a prominent role in either endorsing or warning against the use of these products, ensuring the preservation of health while promoting the theoretically established positive benefits. In this vein, beetroot juice (BJ) stands out as a key supplement as an ergogenic aid to improve sports performance, given its demonstrated influence on both aerobic and anaerobic exercise. However, despite widespread global demand, there remains a lack of understanding regarding the potential synergistic effects of combining BJ with other supplements. Consequently, our study aims to determine whether the combination of BJ with another nutritional supplement can enhance its beneficial effects and, therefore, optimize physical performance in humans. A comprehensive literature search was conducted in two major databases-Web of Science and PubMed-from 1 January 2018 to 29 January 2023, using specific keywords. After the exclusion criteria, six articles were selected for analysis. Therefore, our study shows that the effectiveness of combining BJ with another supplement mainly depends on the duration of the chronic intervention, which is where the greatest benefits have been observed.

Heavy metals can act as selective agents in the development and proliferation of antibiotic-resistant bacteria through a process called coselection. In the year 2050, an estimated 10 million deaths will be caused by antibiotic-resistant bacteria; therefore, the presence of heavy metals in bodies of water represents an environmental and sanitary threat that requires efficient treatment processes and/or materials for their removal. In the present study, the effect of the hydroxyapatite coating on the adsorbent capacity of cadmium in alumina spheres was evaluated. The hydroxyapatite coating on the alumina sphere increased the surface area from 0.66 to 0.96 m 2 /g and the number of acid sites from 0.064 to 0.306 meq/g and displaced the IEP of hydroxyapatite from 5.37 to 4.2, increasing the Cd 2+ adsorbing capacity from 59.87 mg/g to 89.37 mg/g and promoting adsorption by surface complexation. Alumina-hydroxyapatite spheres stand out for their improved adsorbent properties and easy handling, which positioned this material as a potential alternative in adsorption processes., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Melanopsin signaling within intrinsically photosensitive retinal ganglion cell (ipRGC) subtypes impacts a broad range of behaviors from circadian photoentrainment to conscious visual perception. Yet, how melanopsin phototransduction within M1-M6 ipRGC subtypes impacts cellular signaling to drive diverse behaviors is still largely unresolved. The identity of the phototransduction channels in each subtype is key to understanding this central question but has remained controversial. In this study, we resolve two opposing models of M4 phototransduction, demonstrating that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dispensable for this process and providing support for a pathway involving melanopsin-dependent potassium channel closure and canonical transient receptor potential (TRPC) channel opening. Surprisingly, we find that HCN channels are likewise dispensable for M2 phototransduction, contradicting the current model. We instead show that M2 phototransduction requires TRPC channels in conjunction with T-type voltage-gated calcium channels, identifying a novel melanopsin phototransduction target. Collectively, this work resolves key discrepancies in our understanding of ipRGC phototransduction pathways in multiple subtypes and adds to mounting evidence that ipRGC subtypes employ diverse phototransduction cascades to fine-tune cellular responses for downstream behaviors., Competing Interests: EC, JB, TS, LB, TS No competing interests declared

Chenopodium quinoa Willd. (quinoa), a member of the Amaranthaceae family, is an allotetraploid annual plant, endemic to South America. The plant of C. quinoa presents significant ecological plasticity with exceptional adaptability to several environmental stresses, including salinity. The resilience of quinoa to several abiotic stresses, as well as its nutritional attributes, have led to significant shifts in quinoa cultivation worldwide over the past century. This work first defines germination sensu stricto in quinoa where the breakage of the pericarp and the testa is followed by endosperm rupture (ER). Transcriptomic changes in early seed germination stages lead to unstable expression levels in commonly used reference genes that are typically stable in vegetative tissues. Noteworthy, no suitable reference genes have been previously identified specifically for quinoa seed germination under salt stress conditions. This work aims to identify these genes as a prerequisite step for normalizing qPCR data. To this end, germinating seeds from UDEC2 and UDEC4 accessions, with different tolerance to salt, have been analyzed under conditions of absence (0 mM NaCl) and in the presence (250 mM NaCl) of sodium chloride. Based on the relevant literature, six candidate reference genes, Glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ), Monensin sensitivity1 ( MON1 ), Polypyrimidine tract-binding protein ( PTB ), Actin-7 ( ACT7 ), Ubiquitin-conjugating enzyme ( UBC ), and 18S ribosomal RNA ( 18S ), were selected and assessed for stability using the RefFinder Tool encompassing the statistical algorithms geNorm , NormFinder , BestKeeper , and ΔCt in the evaluation. The data presented support the suitability of CqACT7 and CqUBC as reference genes for normalizing gene expression during seed germination under salinity stress. These recommended reference genes can be valuable tools for consistent qPCR studies on quinoa seeds.

Leucoptera sinuella (Reutti) (Lepidoptera: Lyonetiidae) is a leaf miner specialist on Salicaceae recently introduced to Chile and Argentina, where it is causing economic damage to poplar plantations. We report a field survey in a poplar nursery naturally infested showing that regardless of the poplar hybrid taxon, high variability in resistance was observed among clones within families for oviposition and leaf-mining damage. A group of susceptible and resistant hybrid poplar clones was then selected for a laboratory evaluation of oviposition (antixenosis) and leaf-mining damage (antibiosis) on potted, rooted shoot cuttings. The concentration of condensed tannins (CTs) and salicinoid phenolic glucosides (SPGs) of the leaves of the selected clones from the laboratory study was also measured. Total oviposited eggs were positively correlated with leaf area, with the lowest oviposition on TMxT 11372 clone. The lowest percentage of mined leaf area was obtained for clones TMxT 11372, TMxT 11463, and TDxD 17574, but surprisingly no correlation between the percentage of mined leaf area and concentration of CTs and SPGs was found. Resistant poplar hybrids of our study could be suitable for breeding programs aimed for L. sinuella integrated pest management., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The role of the tumor microenvironment (TME) in immuno-oncology has driven demand for technologies that deliver in situ, or spatial, molecular information. Compartmentalized heterogeneity that traditional methods miss is becoming key to predicting both acquired drug resistance to targeted therapies and patient response to immunotherapy. Here, we describe a novel method for assay-agnostic spatial profiling and demonstrate its ability to detect immune microenvironment signatures in breast cancer patients that are unresolved by the immunohistochemical (IHC) assessment of programmed cell death ligand-1 (PD-L1) on immune cells, which represents the only FDA microenvironment-based companion diagnostic test that has been approved for triple-negative breast cancer (TNBC). Two distinct physiological states were found that are uncorrelated to tumor mutational burden (TMB), microsatellite instability (MSI), PD-L1 expression, and intrinsic cancer subtypes., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Antibodies and helper T cells play important roles in SARS-CoV-2 infection and vaccination. We sequenced B- and T-cell receptor repertoires (BCR/TCR) from the blood of 251 infectees, vaccinees, and controls to investigate whether features of these repertoires could predict subjects' SARS-CoV-2 neutralizing antibody titer (NAbs), as measured by enzyme-linked immunosorbent assay (ELISA). We sequenced recombined immunoglobulin heavy-chain (IGH), TCRβ (TRB), and TCRδ (TRD) genes in parallel from all subjects, including select B- and T-cell subsets in most cases, with a focus on their hypervariable CDR3 regions, and correlated this AIRRseq data with demographics and clinical findings from subjects' electronic health records. We found that age affected NAb levels in vaccinees but not infectees. Intriguingly, we found that vaccination, but not infection, has a substantial effect on non-productively recombined IGHs, suggesting a vaccine effect that precedes clonal selection. We found that repertoires' binding capacity to known SARS-CoV-2-specific CD4+ TRBs performs as well as the best hand-tuned fuzzy matching at predicting a protective level of NAbs, while also being more robust to repertoire sample size and not requiring hand-tuning. The overall conclusion from this large, unbiased, clinically well annotated dataset is that B- and T-cell adaptive responses to SARS-CoV-2 infection and vaccination are surprising, subtle, and diffuse. We discuss methodological and statistical challenges faced in attempting to define and quantify such strong-but-diffuse repertoire signatures and present tools and strategies for addressing these challenges.

Background: Indacaterol acetate (IND), a long-acting β 2 -agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma., Methods: In this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥ 6 to < 12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler ® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV 1 ) after two weeks of treatment., Results: In total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV 1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV 1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 μg group and 25% patients in IND 150 μg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥ 0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile., Conclusions: Once-daily IND 75 μg and IND 150 μg via Breezhaler ® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 μg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma., Trial Registration: ClinicalTrials.gov (NCT02892019; 08-Sep-2016)., (© 2023. The Author(s).)

The development of several vaccines against the SARS-CoV2 virus and their application in millions of people have shown efficacy and safety in the transfer of genes to muscle turning this tissue into a protein-producing factory. Established advanced liver fibrosis, is characterized by replacement of hepatic parenchyma by tissue scar, mostly collagen type I, with increased profibrogenic and proinflammatory molecules gene expression. Matrix metalloproteinase 8 (MMP-8) is an interstitial collagen-degrading proenzyme acting preferentially on collagen type I when activated. This study was carried out to elucidate the effect of an intramuscularly delivered adenoviral vector containing proMMP-8 gene cDNA (AdhMMP8) in male Wistar rats with experimental advanced liver fibrosis induced by thioacetamide. Therapeutic effects were monitored after 1, 2, or 3 weeks of a single dose (3 × 10 11 vp/kg) of AdhMMP8. Circulating and liver concentration of MMP-8 protein remained constant; hepatic fibrosis decreased up to 48%; proinflammatory and profibrogenic genes expression diminished: TNF-α 2.28-fold, IL-1 1.95-fold, Col 1A1 4-fold, TGF-β1 3-fold and CTGF 2-fold; and antifibrogenic genes expression raised, MMP-9 2.8-fold and MMP-1 10-fold. Our data proposes that the administration of AdhMMP8 in muscle is safe and effective in achieving liver fibrosis regression at a comparable extent as when the adenoviral vector is delivered systemically to reach the liver, using a minimally invasive procedure.

Desert shrubs are keystone species for plant diversity and ecosystem function. Atriplex clivicola and Atriplex deserticola (Amaranthaceae) are native shrubs from the Atacama Desert that show contrasting altitudinal distribution ( A. clivicola : 0-700 m.a.s.l.; A. deserticola : 1500-3000 m.a.s.l.). Both species possess a C4 photosynthetic pathway and Kranz anatomy, traits adaptive to high temperatures. Historical records and projections for the near future show trends in increasing air temperature and frequency of heat wave events in these species' habitats. Besides sharing a C4 pathway, it is not clear how their leaf-level physiological traits associated with photosynthesis and water relations respond to heat stress. We studied their physiological traits (gas exchange, chlorophyll fluorescence, water status) before and after a simulated heat wave (HW). Both species enhanced their intrinsic water use efficiency after HW but via different mechanisms. A. clivicola , which has a higher LMA than A. deserticola , enhances water saving by closing stomata and maintaining RWC (%) and leaf Ψ md potential at similar values to those measured before HW. After HW, A. deserticola showed an increase of A max without concurrent changes in g s and a significant reduction of RWC and Ψ md . A. deserticola showed higher values of Chl a fluorescence after HW. Thus, under heat stress, A. clivicola maximizes water saving, whilst A. deserticola enhances its photosynthetic performance. These contrasting (eco)physiological strategies are consistent with the adaptation of each species to their local environmental conditions at different altitudes.

In patients with glycogen storage disease type Ib (GSD Ib), quality of life is severely hampered by neutropenia and neutropenia-associated symptoms. SGLT2 inhibitors are a new treatment option and have shown improved medical outcomes in more than 120 patients so far. The aim of this international questionnaire study was to assess patient-reported outcomes of this new treatment in GSD Ib patients. Patients and caregivers of pediatric patients were invited to complete a web-based questionnaire. This was designed to evaluate treatment effects of the SGLT2 inhibitor empagliflozin on clinical symptoms and important aspects of daily life including physical performance, sleep, social and work life, traveling, socioeconomic aspects, and quality of life. The questionnaire was completed by 73 respondents from 17 different countries. The mean duration of treatment was 15 months, the cumulative treatment time was 94.8 years. More than 80% of patients reported an improved quality of life. The number of hospitalizations was reduced (66% of patients), as well as the number of days absent from school or work. Granulocyte colony-stimulating factor (G-CSF) treatment could be stopped in 49% of patients and reduced in another 42%. Clear improvement of neutropenia and all neutropenia-associated symptoms was reported by the majority of patients. Additionally, patients or caregivers reported positive effects on appetite (63%), level of activity (75%), overall well-being (96%), and sleep (63%). Empagliflozin positively impacts many aspects of daily life including work and social life and thereby significantly improves quality of life of patients and caregivers., Competing Interests: The authors declare that they have no competing interests concerning the content of this manuscript., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Optic neuritis (ON) can be an initial manifestation of neuromyelitis optica spectrum disorder (NMOSD) associated with aquaporin 4-antibody (AQP4-Ab) or myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease (MOGAD). Additionally, both diseases may have overlapping paraclinical and radiological features. These diseases may have different outcomes and prognoses. We aimed to compare clinical outcomes and prognostic features of patients with NMOSD and MOGAD presenting ON as first attack, from different ethnic groups in Latin America., Methods: We conducted a retrospective observational multicenter study in patients from Argentina (n = 61), Chile (n = 18), Ecuador (n = 27), Brazil (n = 30), Venezuela (n = 10) and Mexico (n = 49) with MOGAD or NMOSD related ON. Predictors of disability outcomes at last follow-up, namely visual disability (Visual Functional System Score ≥4), motor disability (permanent inability to walk further than 100 m unaided) and wheelchair dependence based on EDSS score were evaluated., Results: After a mean disease duration of 42.7 (±40.2) months in NMOSD and 19.7 (±23.6) in MOGAD, 55% and 22% (p>0.001) experienced permanent severe visual disability (visual acuity from 20/100 to 20/200), 22% and 6% (p = 0.01) permanent motor disability and 11% and 0% (p = 0.04) had become wheelchair dependent, respectively. Older age at disease onset was a predictor of severe visual disability (OR=1,03 CI95%1.01-1.05, p = 0.03); older age at disease onset (OR=1,04 CI95%1.01-1.07, p = 0.01), higher number of relapses (OR=1,32 CI95%1.02-1.71, p = 0.03) and rituximab treatment (OR=0,36 CI95%0.14-0.90, p = 0.02) were predictors of permanent motor disability, whereas ON associated with myelitis at disease onset was a predictor of wheelchair dependency (OR=4,16, CI95%1.23-14.08, p = 0,02) in NMOSD patients. No differences were found when evaluating distinct ethnic groups (Mixed vs. Caucasian vs. Afro-descendant) CONCLUSIONS: NMOSD was associated with poorer clinical outcomes than MOGAD. Ethnicity was not associated with prognostic factors. Distinct predictors of permanent visual and motor disability and wheelchair dependency in NMOSD patients were found., Competing Interests: Declaration of Competing Interest None of the authors have any potential financial conflict of interest relating to this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In response to sensory stimulation, the cortex exhibits an early transient response followed by late and slower activation. Recent studies suggest that the early component represents features of the stimulus while the late component is associated with stimulus perception. Although very informative, these studies only focus on the amplitude of the evoked responses to study its relationship with sensory perception. In this work, we expand upon the study of how patterns of evoked and spontaneous activity are modified by experience at the mesoscale level using voltage and extracellular glutamate transient recordings over widespread regions of mouse dorsal neocortex. We find that repeated tactile or auditory stimulation selectively modifies the spatiotemporal patterns of cortical activity, mainly of the late evoked response in anesthetized mice injected with amphetamine and also in awake mice. This modification lasted up to 60 min and results in an increase in the amplitude of the late response after repeated stimulation and in an increase in the similarity between the spatiotemporal patterns of the late early evoked response. This similarity increase occurs only for the evoked responses of the sensory modality that received the repeated stimulation. Thus, this selective long-lasting spatiotemporal modification of the cortical activity patterns might provide evidence that evoked responses are a cortex-wide phenomenon. This work opens new questions about how perception-related cortical activity changes with sensory experience across the cortex., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This study describes the therapeutic strategies in NMOSD and MOGAD adopted by neurologists to treat both conditions in Latin America (LATAM) with main focus on rituximab (RTX) and the disease outcome., Methods: retrospective study in a cohort of NMOSD and MOGAD patients followed in specialized MS/NMOSD centers from eight countries and 14 LATAM reference centers. Demographics and clinical characteristics were collected. RTX strategies on naïve (for rituximab) patients were summarized as follows: scheme A: two 1000 mg infusions 15 days apart and repeated every 6 months; scheme B: four 375 mg/m2 infusions every week for 4 weeks and repeated every 6 months; scheme C: one 1000 mg infusions and repeated every 6 months; scheme D: other scheme used. Relapse rate and adverse events during follow-up were analyzed considering the different RTX schemes. Poisson and logistic regression analysis were used to assess baseline aspects and disease activity during follow-up., Results: A total of 217 patients were included. 197 were NMOSD patients (164, 83.2% AQP4-IgG seropositive and 16.7% seronegative) and 20 were MOGAD patients. The most frequent long-term treatment was RTX in both groups (48.2% and 65% for NMOSD and MOGAD patients, respectively). The most common RTX regimen used in 79 (83.1%) patients was two 1000 mg infusions 15 days apart and repeat every 6 months. Relapses under RTX treatment were observed in 21 (22.1%) patients. Relapses after RTX treatment were associated with higher EDSS (OR 1.75, 95%CI 1.44-2.34, p = 0.03) and higher ARR pre-RTX (OR = 2.17, 95% CI 1.72-3.12, p = 0.002) but not with RTX regimen (OR = 1.10, 95% CI 0.89-1.21, p = 0.60)., Conclusion: the most strategy used in LATAM was RTX with two 1000 mg infusions 15 days apart. Relapses during follow up were not associated with RTX regimen used., Competing Interests: Declaration of Competing Interest JIR has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Biogen, Genzyme, Merck, Novartis. TA has received consulting fees, lecture honoraria and Travel Support from Biogen, Merck, Roche and Teva. PAL has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Biogen, Genzyme, Merck, Novartis and Roche. JF has received consulting fees from Biogen, Novartis and Genzyme, as a lecturer from Merck Serono, Novartis and Biogen, and collaboration for attendance to national and international congresses from Biogen, Novartis, Merck Serono, Bayer and Gador. FG has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Biogen, Genzyme, Merck, Novartis, Bayer. CN has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Stendhal, Roche, Biogen, Genzyme, Merck, Novartis, Biopas. LP has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Biogen, Genzyme, Merck, Novartis. EC has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Biogen, Genzyme, Merck, Novartis. ECC has received reimbursement for developing educational presentations, educational and research grants, consultations fees and travel stipends from Bayer, Biogen, Ipsen, Merck, Novartis, Roche, Sanofi, Teva. The rest of the authors declares not conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Despite advances in microsurgery, full functional recovery of severe peripheral nerve injuries is not commonly attained. The sheep appears as a good preclinical model since it presents nerves with similar characteristics to humans. In this study, we induced 5 or 7 cm resection in the peroneal nerve and repaired with an autograft. Functional evaluation was performed monthly. Electromyographic and ultrasound tests were performed at 6.5 and 9 months postoperation (mpo). No significant differences were found between groups with respect to functional tests, although slow improvements were seen from 5 mpo. Electrophysiological tests showed compound muscle action potentials (CMAP) of small amplitude at 6.5 mpo that increased at 9 mpo, although they were significantly lower than the contralateral side. Ultrasound tests showed significantly reduced size of tibialis anterior (TA) muscle at 6.5 mpo and partially recovered size at 9 mpo. Histological evaluation of the grafts showed good axonal regeneration in all except one sheep from autograft 7 cm (AG7) group, while distal to the graft there was a higher number of axons than in control nerves. The results indicate that sheep nerve repair is a useful model for investigating long-gap peripheral nerve injuries.

Introduction: COVID-19 is a worldwide public health threat. Diagnosis by RT-PCR has been employed as the standard method to confirm viral infection. Sample pooling testing can optimize the resources by reducing the workload and reagents shortage, and be useful in laboratories and countries with limited resources. This study aims to evaluate SARS-CoV-2 detection by sample pooling testing in comparison with individual sample testing., Materials and Methods: We created 210 pools out of 245 samples, varying from 4 to 10 samples per pool, each containing a positive sample. We conducted detection of SARS-CoV-2-specific RdRp/E target sites., Results: Pooling of three samples for SARS-CoV-2 detection might be an efficient strategy to perform without losing RT-PCR sensitivity., Conclusions: Considering the positivity rate in Dominican Republic and that larger sample pools have higher probabilities of obtaining false negative results, the optimal sample size to perform a pooling strategy shall be three samples., (© 2021 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

The purpose of the study was to evaluate the production of lignin-modifying enzyme extracts and delignified biomass from agro-industrial wastes using white rot fungi ( Inonotus sp. Sp2, Stereum hirsutum Ru-104, Bjerkandera sp. BOS55 , Pleurotus eryngii IJFM 169 and Phanerochaete chrysosporium BKM-F-1767). These were screened based on their adaptability and colonization ability on different substrates, as well as by the Laccase, Manganese peroxidase, and Lignin peroxidase enzymatic production. Native strains ( Inonotus sp. Sp2 and S. hirsutum Ru-104) showed the highest growth kinetics under the solid-substrate fermentation conditions and the growth rate parameters of the kinetic logistic model for the different substrates were between 0.39-0.81 (1/d) and 0.42-0.83 (1/d), respectively; the determination coefficients were ≥0.99. Inonotus sp. Sp2 was subsequently cultured in static flasks to produce crude enzyme extracts, obtaining manganese peroxidase activity levels of 18.5 and 31.3 (U/g) when growing in corn cob husk and spent tea leaves, respectively. Besides, it was to establish that the best conditions for lignin-modifying enzymes production using corn cob husk are 70% of initial moisture and 2.12 mm of particle size; reaching after 30 incubation days a manganese peroxidase activity of 21 ± 6 (U/g) under these conditions; enzyme that showed a suitable thermostability.

Introduction: COVID-19 is a worldwide public health threat. Diagnosis by RT-PCR has been employed as the standard method to confirm viral infection. Sample pooling testing can optimize the resources by reducing the workload and reagents shortage, and be useful in laboratories and countries with limited resources. This study aims to evaluate SARS-CoV-2 detection by sample pooling testing in comparison with individual sample testing., Materials and Methods: We created 210 pools out of 245 samples, varying from 4 to 10 samples per pool, each containing a positive sample. We conducted detection of SARS-CoV-2-specific RdRp/E target sites., Results: Pooling of three samples for SARS-CoV-2 detection might be an efficient strategy to perform without losing RT-PCR sensitivity., Conclusions: Considering the positivity rate in Dominican Republic and that larger sample pools have higher probabilities of obtaining false negative results, the optimal sample size to perform a pooling strategy shall be three samples., (Copyright © 2021 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Decellularized nerve allografts (DC) are an alternative to autografts (AG) for repairing severe peripheral nerve injuries. We have assessed a new DC provided by VERIGRAFT. The decellularization procedure completely removed cellularity while preserving the extracellular matrix. We first assessed the DC in a 15 mm gap in the sciatic nerve of rats, showing slightly delayed but effective regeneration. Then, we assayed the DC in a 70 mm gap in the peroneal nerve of sheep compared with AG. Evaluation of nerve regeneration and functional recovery was performed by clinical, electrophysiology and ultrasound tests. No significant differences were found in functional recovery between groups of sheep. Histology showed a preserved fascicular structure in the AG while in the DC grafts regenerated axons were grouped in small units. In conclusion, the DC was permissive for axonal regeneration and allowed to repair a 70 mm long gap in the sheep nerve.

Background: Research is scarce on the prospective predictors of first onset suicidal thoughts and behaviors (STB) and the accuracy of these predictors in university students, particularly in low-and-middle income countries. Therefore, we assessed the 1-year incidence of STB among first-year students, a broad range of prospective predictors of STB incidence, and evaluated the prediction accuracy of a baseline multivariate risk prediction model to identify students at highest risk for STB onset over the subsequent 12 months., Methods: Students (n = 3238) from 13 universities in Mexico completed an online survey developed for the World Mental Health International College Student Surveys in their first year and again 12 months after. We ran generalized linear models and receiver operator curves., Results: The 1-year incidence of suicidal ideation, plan and attempt was 8.53%, 3.75%, and 1.16%, respectively. Predictors in final models were female sex (ideation only), minority sexual orientation (ideation only), depression, eating disorders, ADHD (ideation and plan), ongoing arguments or breakup with a romantic partner (ideation only), emotional abuse (ideation only), parental death (ideation, plan), not Catholic/Christian (ideation, plan), not having someone to rely on, psychotic experiences (plan only), and insufficient sleep (attempt only). Prediction accuracy for ideation, plan and attempt was area under the curve = 0.76, 0.81 and 0.78, respectively. Targeting the top 10% of students at highest risk could reduce STB in the subsequent year up to 36%., Conclusions: By assessing these risk/protective factors in incoming students we identified students at greatest risk for developing STB to whom suicide prevention strategies could be targeted., (© 2022 Wiley Periodicals LLC.)