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Juan D Duque-Yemail,1 Juan Carlos Avila2 1Psychiatry Resident, Department of Mental Health, Vall d’Hebron University Hospital, Barcelona, Spain; 2Psychiatrist, Mental Health Center, Badalona, SpainCorrespondence: Juan D Duque-Yemail, Vall d’Hebron University Hospital, Department of Mental Health, Antiga Escola d’Infermeria Building, Passeig de la Vall d’Hebron, 119, Barcelona, 08035, Spain, Tel +34 934 89 30 00, Email jduque@vhebron.netAbstract: Despite many available treatments for schizophrenia, several unmet needs persist in treating individuals with this disorder, and the response rate to first-line antipsychotics remains relatively low. Clozapine has shown efficacy in treating schizophrenia patients who failed to respond to previous antipsychotics. However, side effects and the need for routine blood tests have limited its use as a first-line treatment. Cariprazine is a D2/D3 partial agonist antipsychotic with a mechanism of action that differs from other antipsychotics due to its higher affinity for D3 receptors. Several trials have demonstrated the efficacy of cariprazine on positive and negative symptoms of schizophrenia and have shown that it is a well-tolerated treatment. In this series, we present 3 cases of patients diagnosed with schizophrenia who were initially under treatment with clozapine. Despite some initial improvement, the patients showed persisting positive and negative symptoms or developed limiting side effects while in treatment with clozapine. Cariprazine treatment was titrated concurrently with clozapine tapering until its discontinuation. Significant improvement in both positive and negative symptoms was observed up to 14 months after starting cariprazine, and resolution of side effects was reported in all cases. Our case series supports cariprazine as an effective treatment for positive and negative symptoms in patients who failed to adequately respond or poorly tolerated treatment with clozapine, as well as a potential treatment in dual disorders, specifically psychotic disorders and cocaine use disorder.Keywords: schizophrenia, cariprazine, atypical antipsychotics, clozapine, resistant schizophrenia

N-alkanes offer a promising approach for assessing the nutritional contribution of external sources to the diets of laying hens in free-range production systems. However, traditional laboratory methods, involving extraction, purification and gas chromatographic analysis, are both economically burdensome and time-consuming. Near-infrared spectroscopy (NIRS) is emerging as a viable alternative, with varying degrees of accuracy depending on the chemical nature and concentration of the component of interest. In our research, we focus on the accuracy of NIRS in predicting the concentrations of n-alkanes (C25-C33) in excreta under simulated free-range conditions with two different diets: one containing a commercial feed with minimal n-alkane content and another containing 1% alfalfa on top of the commercial feed. Spectra processing and calibration were tailored for each n-alkane, with NIRS performance influenced by diet type. Notably, plant predictions using NIR-generated data were consistent with laboratory results, despite a slight tendency toward overestimation (3.40% using the NIRS-generated C25-C29-C33 combination versus 2.80% using laboratory analysis). This indicates the potential of NIRS as an efficient tool to assess n-alkanes in excreta of laying hens and, consequently, the nutritional contribution of the free-range environment, providing rapid and cost-effective results.

The shift in animal welfare standards towards free-range housing for laying hens in the EU has raised questions about changes in dietary composition. Accurate assessment of outdoor plant material intake is crucial for effective feeding strategies. This study introduces an approach using n-alkanes as markers to determine plant intake in laying hens, involving n-alkane recovery rate assessment, discriminant analysis and linear equation-solving for both qualitative and quantitative assessment, respectively, considering systematic n-alkane combinations. Two diets: a standard commercial diet and a diet incorporating 1% alfalfa were tested. Chemical analyses showed an altered n-alkane profile due to alfalfa inclusion, resulting a recovery rates ranging from 30-44% depending on the n-alkane type and diet. Statistical analysis revealed significant differences in recovery rates among the different alkanes for the same diets and between the diets for the same alkane, together with an interaction between n-alkane carbon chain length and initial concentration in the diet. The method accurately predicted plant inclusion, with a slight overestimation (2.80%) using the combination C25-C29-C33. Accurate qualitative classification of the animals based on fecal n-alkanes profiles was observed. The study successfully demonstrated the utility of n-alkanes for estimating dietary composition, providing a non-invasive approach for future free-range studies.

Single quantum emitters embedded in solid-state hosts are an ideal platform for realizing quantum information processors and quantum network nodes. Among the currently investigated candidates, Er^{3+} ions are particularly appealing due to their 1.5  μm optical transition in the telecom band as well as their long spin coherence times. However, the long lifetimes of the excited state-generally in excess of 1 ms-along with the inhomogeneous broadening of the optical transition result in significant challenges. Photon emission rates are prohibitively small, and different emitters generally create photons with distinct spectra, thereby preventing multiphoton interference-a requirement for building large-scale, multinode quantum networks. Here we solve this challenge by demonstrating for the first time linear Stark tuning of the emission frequency of a single Er^{3+} ion. Our ions are embedded in a lithium niobate crystal and couple evanescently to a silicon nanophotonic crystal cavity that provides a strong increase of the measured decay rate. By applying an electric field along the crystal c axis, we achieve a Stark tuning greater than the ion's linewidth without changing the single-photon emission statistics of the ion. These results are a key step towards rare earth ion-based quantum networks.

Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (β = 2.26, hazard ratio [HR] = 9.54, P = .003), EZH2 (β = 1.12, HR = 3.062, P = .009), NRAS (β = 1.29, HR = 3.63, P = .048), and U2AF1 (β = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.

Study Objective: The objective of the InMEDIATE study was to evaluate the change in intensity of traumatic pain over the first 20 min in adult patients treated with methoxyflurane versus standard analgesic treatment in Spain. This the first randomized, active-controlled, multicenter trial of methoxyflurane in the emergency setting in Europe., Methods: This was a randomized, controlled study that enrolled adult patients with acute moderate to severe (score ≥4 on the 11-point Numeric Rating Scale) trauma-associated pain in 14 Spanish emergency departments. Patients were randomized 1:1 to methoxyflurane (up to 2×3 mL) or standard analgesic treatment. Coprimary endpoints were the change from baseline in Numeric Rating Scale pain intensity score during the first 20 minutes of treatment and time to first pain relief., Results: Three hundred five patients were randomized (methoxyflurane 156; standard analgesic treatment 149). Most patients in the standard analgesic treatment group (70%) received intravenous first-step analgesics and 9.4% of patients were treated with opioids. Mean decrease from baseline in Numeric Rating Scale pain intensity score was greater for methoxyflurane than standard analgesic treatment at all points, with a significant treatment difference overall up to 20 minutes (repeated-measures model 2.47 versus 1.39; treatment difference 1.00; 95% confidence interval 0.84 to 1.32). Median time to first pain relief was significantly shorter for methoxyflurane than standard analgesic treatment (3 versus 10 minutes). Methoxyflurane achieved better patient and clinician ratings for pain control and comfort of treatment than standard analgesic treatment and exceeded patient and clinician expectations of treatment in, respectively, 77% and 72% of cases compared with 38% and 19% for standard analgesic treatment., Conclusion: These results support consideration of methoxyflurane as a nonnarcotic, easy-to-administer, rapid-acting, first-line alternative to currently available analgesic treatments for trauma pain., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Type 2 diabetes mellitus (DM2) is strongly associated with other comorbidities such as obesity, atherosclerosis, and hypertension. Obesity is associated with sustained low-grade inflammatory response due to the production of proinflammatory cytokines. This inflammatory process promotes the differentiation of some myeloid cells, including myeloid-derived suppressor cells (MDSCs). In this study, two groups of individuals were included: DM2 patients and non-DM2 individuals with similar characteristics. Immunolabeling of CD15+ CD14- and CD33+ HLA-DR-/low was performed from whole peripheral blood, and samples were analyzed by flow cytometry, and frequencies of MDSCs and the relationship of these with clinical variables, cytokine profile (measured by cytometric bead array), and anthropometric variables were analyzed. The frequency of CD33+ HLA-DR-/low MDSCs (that produce IL-10 and TGF- β , according to an intracellular detection) is higher in patients with DM2 ( P < 0.05), and there is a positive correlation between the frequency of CD15+ CD14- and CD33+ HLA-DR-/low MDSC phenotypes. DM2 patients have an increased concentration of serum IL-5 ( P < 0.05). Also, a negative correlation between the frequency of CD15+ CD14- MDSCs and LDL cholesterol was found. Our group of DM2 patients have an increased frequency of mononuclear MDSC CD33+ HLA-DR-/low that produce TGF- β and IL-10. These cytokines have been associated with immune modulation and reduced T cell responses. DM2 and non-DM2 subjects show a similar cytokine profile, but the DM2 patients have an increased concentration of IL-5., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Julio C. Fernández-Ruiz et al.)

Objective: The recent advances in technology are opening a new opportunity to remotely evaluate motor features in people with Parkinson's disease (PD). We hypothesized that typing on an electronic device, a habitual behavior facilitated by the nigrostriatal dopaminergic pathway, could allow for objectively and nonobtrusively monitoring parkinsonian features and response to medication in an at-home setting., Methods: We enrolled 31 participants recently diagnosed with PD who were due to start dopaminergic treatment and 30 age-matched controls. We remotely monitored their typing pattern during a 6-month (24 weeks) follow-up period before and while dopaminergic medications were being titrated. The typing data were used to develop a novel algorithm based on recursive neural networks and detect participants' responses to medication. The latter were defined by the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) minimal clinically important difference. Furthermore, we tested the accuracy of the algorithm to predict the final response to medication as early as 21 weeks prior to the final 6-month clinical outcome., Results: The score on the novel algorithm based on recursive neural networks had an overall moderate kappa agreement and fair area under the receiver operating characteristic (ROC) curve with the time-coincident UPDRS-III minimal clinically important difference. The participants classified as responders at the final visit (based on the UPDRS-III minimal clinically important difference) had higher scores on the novel algorithm based on recursive neural networks when compared with the participants with stable UPDRS-III, from the third week of the study onward., Conclusions: This preliminary study suggests that remotely gathered unsupervised typing data allows for the accurate detection and prediction of drug response in PD. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

The original version of this article contains a mistake.

Introduction: Zonisamide is a new-generation anticonvulsant antiepileptic drug metabolized primarily in the liver, with subsequent elimination via the renal route., Objectives: Our objective was to evaluate the utility of pharmacometabolomics in the detection of zonisamide metabolites that could be related to its disposition and therefore, to its efficacy and toxicity., Methods: This study was nested to a bioequivalence clinical trial with 28 healthy volunteers. Each participant received a single dose of zonisamide on two separate occasions (period 1 and period 2), with a washout period between them. Blood samples of zonisamide were obtained from all patients at baseline for each period, before volunteers were administered any medication, for metabolomics analysis., Results: After a Lasso regression was applied, age, height, branched-chain amino acids, steroids, triacylglycerols, diacyl glycerophosphoethanolamine, glycerophospholipids susceptible to methylation, phosphatidylcholines with 20:4 FA (arachidonic acid) and cholesterol ester and lysophosphatidylcholine were obtained in both periods., Conclusion: To our knowledge, this is the only research study to date that has attempted to link basal metabolomic status with pharmacokinetic parameters of zonisamide.

The early establishment of the diagnosis of a syndesmotic injury is essential for treatment selection. However, such injuries may not be apparent radiographically. Previous studies have attempted to describe correlations between medial malleolar fracture geometry and syndesmotic disruption. The main objective of this study was to create predictive models for assessing syndesmotic injuries based on an originally described angle, i.e., the medial crural-focal angle (MCFA). This study included 138 ankle fractures involving the medial malleolus. Any measure from the plain radiograph that could potentially lead to the suspicion of a syndesmotic disruption was recorded, and the newly described MCFA (formed by the main line of the medial malleolus fracture and a line perpendicular to the bearing surface of the tibial plafond) was also recorded. The inter- and intraobserver reliabilities were obtained using Krippendorff's alpha coefficients. To examine the predictive abilities of every parameter, several statistical methods were applied including logistic regression, an ad hoc clinical rule, and discriminant analysis. After variable selection, we obtained the best possible logistic model. The variables that were found to be statistically significant were the MCFA, the tibiofibular clear space (TFCS) and the type of injury in the Lauge-Hansen (L-H) classification. This model was tested by cross validation, which revealed a mean percentage of correctly classified patients of 88%. A simpler and more intuitive alternative model was sought that was based solely on the influences of the MCFA and the TFCS. Our study revealed that an absence of syndesmotic disruptions when the MCFA was under 60 ° , and there were no uninjured patients with tibiofibular clear space values over 6mm. Cross-validation revealed that the mean percentage of patients who were correctly classified with this model was 86%. The application of discriminant analysis to this combination of variables resulted in a function was able to correctly classify a mean of 84% of patients. In conclusion, three models that can predict syndesmotic injury using parameters from preoperative plain radiographs were obtained and validated. The MCFA measurement was in these models and found to be a reliable technique., (© 2017 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the influence of two variants of P450 oxidoreductase (POR), rs2868177 and POR*28, on the stable dosage of acenocoumarol., Patients & Methods: For this observational, cross-sectional study, patients were undergone stable anticoagulant treatment with acenocoumarol. Univariate and multiple regression analyses were performed to assess the influence of POR polymorphisms., Results: About 340 patients were enrolled. Multiple regression had a coefficient of determination (R 2 ) of 51.5% and an Akaike information criterion of 234.22. The inclusion of POR*28 polymorphisms increased the R 2 to 52.0% and reduced the Akaike information criteria to 230.58. The POR*28 heterozygote showed statistical significance in the algorithm., Conclusion: The POR*28 heterozygote appears to be associated with the stable dose of acenocoumarol, but its clinical contribution to the prediction of the dosing of this drug is minimal.

Aim: This study analysed the changes in growth velocity (GV) of preterm infants weighing <1500 g based on different nutritional practices over a 24-year period., Methods: A retrospective study with prospectively collected data was performed in a level three Spanish neonatal intensive care unit. Data on birthweight, gestational age (GA) and GV were collected from 1990 to 2013 and breastfeeding data were gathered from 2000. A generalised linear model corrected by GA and small for gestational age was applied. Multiple mean comparisons between the levels of the variables of interest were performed using the Tukey test., Results: We included 1651 children in the study. The average GA in 1990-1991 was 30.48 ± 2.89 and the average GA in 2012-2013 was 28.79 ± 2.58 (p < 0.01). Significant differences were found when we compared the adjusted GV between the first and last study periods. The most important differences appeared between 1990 and 2013, when the GV increased by 3.27 ± 0.5 g/kg/day (p < 0.01). The breastfeeding rate in 2000-2001 was 47.95% and in 2012-2013 it was 73.58% (p = 0.0002)., Conclusion: Introducing nutritional practices such as the increased use of breastmilk and the breastfeeding rate improved GV over the study period., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Introduction: Bacterial infections represent a serious complication of liver cirrhosis. Traditionally, Gram negative bacteria have been described as the microorganisms responsible for the majority of the infections. However, in the past few years, changes in the microbiological spectrum have been described, and multiresistant bacteria are observed more frequently. , Objective: To assess the proportion of patients with infections caused by multiresistant bacteria admitted to our hospital, and to obtain information about their epidemiology, risk factors and clinical impact. , Materials and Methods: We performed a retrospective evaluation of 294 cirrhotic patients admitted to our unit due to infection between June, 2011, and June, 2013. , Results: We isolated 310 microorganisms from 294 patients; 109 (35.2%) were Gram positive, 167 (53.9%), Gram negative, and 34, fungi (11%). As for the microbiological agents, the most frequent was Escherichia coli (98 isolations). The infection was community-acquired in 22.9% of cases, healthcareassociated in 38.1% and nosocomial in 39%. Worse liver infections and septic shock were more frequent among patients with multiresistant isolates (p=0.05); and intrahospital mortality was also higher among them (p=0.017). Previous hospital admission, antibiotic treatment 60 days before, nosocomial or healthcare-associated acquisition and bacterial isolation in control cultures were identified as possible risk factors for the development of multiresistant infection. , Discussion: The results of our study confirm that important changes have ocurred in the microbiological spectrum of bacterial infections in patients with liver cirrhosis. Multiresistant bacteria are associated with high morbidity and mortality, as well as failure of traditional antibiotic treatment. Successfull control of the infection requires an early identification of patients at risk.

We describe the case of a 23-month-old female infant with a diagnosis of hemolytic uremic syndrome (HUS) and hemorrhagic retinopathy. The patient had a past history of abdominal pain, bloody diarrhea, and acute renal failure. On ophthalmologic examination, indirect ophthalmoscopy revealed extensive areas of flame-shaped hemorrhage, cotton wool spots, macular edema and optic nerve head neovascularization in both eyes. Fluorescein angiography showed severe bilateral retinal ischemia and neovascularization leakage in disk. The patient, who had the visual acuity of 20/1000 in the right eye (OD) and 20/540 in the left eye (OS) at the first examination, was treated with panretinal photocoagulation (PRP) and presented at the end of the 6th month of follow-up improvement to 20/540 in OD and 20/270 in OS. There was also a regression of disc neovascularization, hemorrhages and macular edema. Despite intense retinal ischemia, there were no complications related to angiogenesis such as vitreous hemorrhage and/or neovascular glaucoma. We describe, in this report, the association between hemorrhagic retinopathy with features of Purtscher-like disease and HUS.

In this note, a procedure to partition the genetic trend of a selected population is presented. Each part of the genetic gain accounts for the Mendelian sampling terms of different groups of animals, which can be sometimes assigned to different selection policies. The method is based on a simple transformation of the predicted breeding values. The procedure was illustrated with two simulated examples. In the first example, the genetic trend is partitioned into two pieces, one coming from the selection on sires and the other coming from the selection on dams. The second example shows how the impact of an artificial insemination center in the genetic gain of the whole population can be evaluated.