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Background: Metformin is the first-line antidiabetic therapy for type 2 diabetes in Mexico, despite recent recommendations highlighting alternatives like GLP-1 receptor agonists for individuals with obesity. Metformin elimination is reliant on liver and kidney function, and variants in transport proteins such as Multidrug and Toxin Extrusion Protein 1 (MATE1), MATE2, and Organic Cation Transporter 2 (OCT2) can influence its pharmacokinetics. Understanding these variants' frequencies in the Mexican population is crucial for tailoring personalized treatment strategies., Objective: This study aimed to determine the genotypic and allelic frequencies of key variants in metformin transporters within a Mexican population, addressing the interindividual variability in drug response., Methodology: Genetic analysis was conducted on 101 healthy, unrelated Mexican subjects who were genotyped for the MATE1, MATE2, and OCT2 variants using allele-specific real-time PCR assays., Results: The allele frequencies were 0.07 for OCT2, 0.23 for MATE1, and 0.67 for MATE2. The g.-66T→C variant was found only in wild-type and heterozygous forms. Comparative analysis indicated significant differences in allele frequencies between this Mexican population and other ethnic groups, highlighting potential implications for metformin efficacy and safety., Conclusion: This study provides crucial insights into the genetic variability of metformin transporter genes in a Mexican population, offering a foundation for personalized therapeutic approaches in type 2 diabetes management., 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., (Copyright © 2024 Chávez-Arreola, Lazalde, López-López, Ortega-Vázquez and Torres-Salazar.)

The goal of this work is to investigate if the synergistic antifungal activity between cyclosporine A, CsA, and voriconazole, VRZ, increases when both drugs are encapsulated in a nanocarrier as compared when they are free. The preparation and characterization of blank and VRZ and CsA loaded polymeric based PLGA nanoparticles (PLGA, PLGA-PEG, and PLGA+PEG) was a necessary previous step. Using the more suitable NPs, those of PLGA, the antifungal susceptibility tests performed with VRZ-loaded PLGA NPs, show no significant increase of the antifungal activity in comparison to that of free VRZ. However, the synergistic behavior found for the (VRZ+CsA)-loaded PLGA NPs was fourfold stronger than that observed for the two free drugs together. On the other hand, the investigation into the suppression of C. albicans biofilm formation showed that blank PLGA NPs inhibit the biofilm formation at high NPs concentrations. However, a minor effect or even a slight biofilm increase formation was observed at low and moderate NPs concentrations. Therefore, the enhancement of the biofilm inhibition found for the three tested treatments (CsA alone, VRZ alone, and VRZ+CsA) when comparing free and encapsulated drugs, within the therapeutic window, can be attributed to the drug encapsulation approach. Indeed, polymeric PLGA NPs loaded with CsA, VRZ, or VRZ+CsA are more effective at inhibiting the C. albicans biofilm growth than their free counterparts., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: The Coronal Plane Alignment of the Knee (CPAK) classification is a pragmatic distribution of nine phenotypes for coronal knee alignment that can be used on healthy and arthritic knees. Our study aimed to describe the CPAK distributions in a Spanish southeast osteoarthritic population and compare them to other populations' published alignment distributions. Method and Materials: Full-leg standing X-rays of the lower limb from 528 cases originating from the so-called Vega Alta del Segura (southeast of the Iberian Peninsula) were retrospectively analysed. We measured the mechanical hip-knee-ankle, lateral distal femoral, and medial proximal tibial angles. We calculated the arithmetic hip-knee-ankle angle and the joint line obliquity to classify each case according to the criteria of the CPAK classification. Results: Based on the aHKA result, 59.1% of the cases were varus (less than -2°), 32.7% were neutral (0° ± 2°), and 8.2% were valgus (greater than +2°). Based on the JLO result, 56.7% of the cases had a distal apex (less than 177°), 39.9% had a neutral apex (180° ± 3°), and 3.4% had a proximal apex (greater than 183°). The most common CPAK distribution in our Spanish southeast osteoarthritic population was type I (30.7%), followed by type IV (25.9%), type II (21%), type V (11.2%), type III (5%), type VI (2.8%), type VII (2.4%), type VIII (0.6%), and type IX (0.4%). Conclusions: We described the distribution according to the CPAK classification in a sample of the osteoarthritic population from southeastern Spain. In our sample, more than 75% of the patients were classified as type I, II, and IV.

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk.

The HIV attacks the immune system provoking an infection that is considered a global health challenge. Despite antiretroviral treatments being effective in reducing the plasma viral load in the blood to undetectable levels in people living with HIV (PLWH), the disease is not cured and has become chronic. This happens because of the existence of anatomical and cellular viral reservoirs, mainly located in the lymph nodes and gastrointestinal tract, which are composed of infected CD4+ T cells with a resting memory phenotype and inaccessible to antiretroviral therapy. Herein, a new therapeutic strategy based on nanotechnology is presented. Different combinations of antiretroviral drugs (bictegravir/tenofovir/emtricitabine and nevirapine/tenofovir/emtricitabine) and toll-like receptor agonists were encapsulated into metal-organic frameworks (MOFs) PCN-224 and ZIF-8. The encapsulation efficiencies of all the drugs, as well as their release rate from the carriers, were measured. In vitro studies about the cell viability, the hemocompatibility, and the platelet aggregation of the MOFs were carried out. Epifluorescence microscopy assays confirmed the ability of ZIF-8 to target a carboxyfluorescein probe inside HeLa cell lines and PBMCs. These results pave the way for the use of these structures to eliminate latent HIV reservoirs from anatomical compartments through the activation of innate immune cells, and a higher efficacy of the triplet combinations of antiretroviral drugs.

Tomato fruit is susceptible to chilling injury (CI) during its postharvest handling at low temperature. The symptoms caused by this physiological disorder have been commonly evaluated by visual inspection at a macro-observation scale on fruit surface; however, the structure at deeper scales is also affected by CI. This work aimed to propose a descriptive model of the CI development in tomato tissue under the micro-scale, micro-nano-scale and nano-scale approaches using fractal analysis. For that, quality and fractal parameters were determined. In this sense, light microscopy, Environmental Scanning Electron Microscopy (ESEM) and Atomic Force Microscopy (AFM) were applied to analyse micro-, micro-nano- and nano-scales, respectively. Results showed that the morphology of tomato tissue at the micro-scale level was properly described by the multifractal behaviour. Also, generalised fractal dimension (D q=0 ) and texture fractal dimension (FD) of CI-damaged pericarp and cuticle were higher (1.659, 1.601 and 1.746, respectively) in comparison to non-chilled samples (1.606, 1.578 and 1.644, respectively); however, FD was unsuitable to detect morphological changes at the nano-scale. On the other hand, lacunarity represented an appropriate fractal parameter to detect CI symptoms at the nano-scale due to differences observed between damaged and regular ripe tissue (0.044 and 0.025, respectively). The proposed multi-scale approach could improve the understanding of CI as a complex disorder to the development of novel techniques to avoid this postharvest issue at different observation scales., 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.)

Parkinson's disease (PD) pathophysiology includes mitochondrial dysfunction, neuroinflammation, and aging as its biggest risk factors. Mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) are biological aging markers with inconclusive results regarding their association with PD. A case-control study was used to measure TL and mtDNA-CN using qPCR in PBMCs. PD patients were naive at baseline (T0) and followed-up at one (T1) and two (T2) years after the dopaminergic treatment (DRT). Plasmatic cytokines were determined by ELISA in all participants, along with clinical parameters of patients at T0. While TL was shorter in patients vs. controls at all time points evaluated ( p < 0.01), mtDNA-CN showed no differences. An increase in mtDNA-CN and TL was observed in treated patients vs. naive ones ( p < 0.001). Our statistical model analyzed both aging markers with covariates, showing a strong correlation between them (r = 0.57, p < 0.01), and IL-17A levels positively correlating with mtDNA-CN only in untreated patients (r = 0.45, p < 0.05). TL and mtDNA-CN could be useful markers for monitoring inflammation progression or treatment response in PD. DRT might modulate TL and mtDNA-CN, reflecting a compensatory mechanism to counteract mitochondrial dysfunction in PD, but this needs further investigation.

Recent advances allow the use of Augmented Reality (AR) for many medical procedures. AR via optical navigators to aid various knee surgery techniques (e.g., femoral and tibial osteotomies, ligament reconstructions or menisci transplants) is becoming increasingly frequent. Accuracy in these procedures is essential, but evaluations of this technology still need to be made. Our study aimed to evaluate the system's accuracy using an in vitro protocol. We hypothesised that the system's accuracy was equal to or less than 1 mm and 1° for distance and angular measurements, respectively. Our research was an in vitro laboratory with a 316 L steel model. Absolute reliability was assessed according to the Hopkins criteria by seven independent evaluators. Each observer measured the thirty palpation points and the trademarks to acquire direct angular measurements on three occasions separated by at least two weeks. The system's accuracy in assessing distances had a mean error of 1.203 mm and an uncertainty of 2.062, and for the angular values, a mean error of 0.778° and an uncertainty of 1.438. The intraclass correlation coefficient was for all intra-observer and inter-observers, almost perfect or perfect. The mean error for the distance's determination was statistically larger than 1 mm (1.203 mm) but with a trivial effect size. The mean error assessing angular values was statistically less than 1°. Our results are similar to those published by other authors in accuracy analyses of AR systems.

We report a 49-year-old patient suffering from spastic paraplegia with a novel heterozygous mutation and analyzed the levels of heat shock proteins (hsp)-27, dopamine (DA), and its metabolites in their cerebrospinal fluid (CSF). The hsp27 protein concentration in the patient's CSF was assayed by an ELISA kit, while DA levels and its metabolites in the CSF, 3,4-dihydroxyphenylacetic acid (DOPAC), Cys-DA, and Cys-DOPA were measured by HPLC. Whole exome sequencing demonstrated SPG-11 c.1951C>T and novel SYNJ1 c.2614G>T mutations, both heterozygous recessive. The patient's DA and DOPAC levels in their CSF were significantly decreased (53.0 ± 6.92 and 473.3 ± 72.19, p < 0.05, respectively) while no differences were found in their Cys-DA. Nonetheless, Cys-DA/DOPAC ratio (0.213 ± 0.024, p < 0.05) and hsp27 levels (1073.0 ± 136.4, p < 0.05) were significantly higher. To the best of our knowledge, the c.2614G>T SYNJ1 mutation has not been previously reported. Our patient does not produce fully functional spatacsin and synaptojanin-1 proteins. In this line, our results showed decreased DA and DOPAC levels in the patient's CSF, indicating loss of DAergic neurons. Many factors have been described as being responsible for the increased cys-DA/DOPAC ratio, such as MAO inhibition and decreased antioxidant activity in DAergic neurons which would increase catecholquinones and consequently cysteinyl-catechols. In conclusion, haploinsufficiency of spatacsin and synaptojanin-1 proteins might be the underlying cause of neurodegeneration produced by protein trafficking defects, DA vesicle trafficking/recycling processes, autophagy dysfunction, and cell death leading to hsp27 upregulation as a cellular mechanism of protection and/or to balance impaired protein trafficking.

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

Objective: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls., Methods: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model., Results: GSH levels were significantly reduced and, conversely, GPx activity was higher in PD patients compared to controls. GCLC&#95;GAG-7/9 genotype (OR=4.3, CI95=1.40-14.31, p=0.019) and hetero-/homozygous genotypes of GCLC&#95;rs761142 (OR=6.09, CI95=1.93-22.59, p=0.003) were found as risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or to metabolic ratio., Conclusions: GCLC variants were associated with the oxidative stress profile of PD patients raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal., Competing Interests: The authors report no conflicts of interest.

Computer technologies play a crucial role in orthopaedic surgery and are essential in personalising different treatments. Recent advances allow the usage of augmented reality (AR) for many orthopaedic procedures, which include different types of knee surgery. AR assigns the interaction between virtual environments and the physical world, allowing both to intermingle (AR superimposes information on real objects in real-time) through an optical device and allows personalising different processes for each patient. This article aims to describe the integration of fiducial markers in planning knee surgeries and to perform a narrative description of the latest publications on AR applications in knee surgery. Augmented reality-assisted knee surgery is an emerging set of techniques that can increase accuracy, efficiency, and safety and decrease the radiation exposure (in some surgical procedures, such as osteotomies) of other conventional methods. Initial clinical experience with AR projection based on ArUco-type artificial marker sensors has shown promising results and received positive operator feedback. Once initial clinical safety and efficacy have been demonstrated, the continued experience should be studied to validate this technology and generate further innovation in this rapidly evolving field.

The design and preparation of new vectors to transport genetic material and increase the transfection efficiency continue being an important research line. Here, a novel biocompatible sugar-based polymer derived from D-mannitol has been synthesized to be used as a gene material nanocarrier in human (gene transfection) and microalga cells (transformation process). Its low toxicity allows its use in processes with both medical and industrial applications. A multidisciplinary study about the formation of polymer/p-DNA polyplexes has been carried out using techniques such as gel electrophoresis, zeta potential, dynamic light scattering, atomic force microscopy, and circular dichroism spectroscopy. The nucleic acids used were the eukaryotic expression plasmid pEGFP-C1 and the microalgal expression plasmid Phyco69, which showed different behaviors. The importance of DNA supercoiling in both transfection and transformation processes was demonstrated. Better results were obtained in microalga cells nuclear transformation than in human cells gene transfection. This was related to the plasmid's conformational changes, in particular to their superhelical structure. It is noteworthy that the same nanocarrier has been used with eukaryotic cells from both human and microalga., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lactoferrin (LF) is a first-line defense protein with a pleiotropic functional pattern that includes anti-inflammatory, immunomodulatory, antiviral, antibacterial, and antitumoral properties. Remarkably, this iron-binding glycoprotein promotes iron retention, restricting free radical production and avoiding oxidative damage and inflammation. On the ocular surface, LF is released from corneal epithelial cells and lacrimal glands, representing a significant percentage of the total tear fluid proteins. Due to its multifunctionality, the availability of LF may be limited in several ocular disorders. Consequently, to reinforce the action of this highly beneficial glycoprotein on the ocular surface, LF has been proposed for the treatment of different conditions such as dry eye, keratoconus, conjunctivitis, and viral or bacterial ocular infections, among others. In this review, we outline the structure and the biological functions of LF, its relevant role at the ocular surface, its implication in LF-related ocular surface disorders, and its potential for biomedical applications.

The research on flavonoids has exponentially grown since their first therapeutic evidence, in 1937. They are effective in vitro in a wide range of human diseases, particularly those mediated by free radicals, such as cancer, atherosclerosis, AIDS, or neuronal diseases. However, their applications have been reduced due to their low solubility, poor absorption, and rapid metabolism. Flavonoid encapsulation in nanocarriers significantly improves their oral absorption, protects the drug against degradation, decreases the first-pass hepatic effect, and makes absorption through the lymphatic system easier. In this work, carbon nanotubes were used as nanocarriers of 7-hydroxyflavone, 7-HF. The encapsulation of 7-HF into pristine single- and multi-walled carbon nanotubes, and into -COOH functionalized single-walled carbon nanotubes has been investigated. The equilibrium association constants were estimated. The structural backbone of 7-HF, two benzene rings linked through three carbon atoms that form a pyran heterocyclic ring containing a keto group, seems to play a key role in the 7-HF/CNT interactions, although other types of interactions are also at work. The in vitro release of 7-HF was studied at three pHs, 2.0, 7.4, and 9.2, mimicking the different biological barriers of the human organism.

Keratoconus (KC) is a corneal disorder whose etiology shares a close relationship with Lactoferrin (LTF) dysregulation and Toll-like Receptors 2 (TLR2) overexpression. This study shows how these two important biomarkers are clinically and molecularly interrelated, increasing knowledge about KC pathophysiology, and opening the door to future therapies. In this prospective clinical study, serum and tear LTF concentrations were quantified in 90 KC patients and 60 controls. A correlation analysis with multiple blood and tear immunoinflammatory mediators, and KC-associated tomographic parameters, was performed. An in vitro study using HEK-BlueTMhTLR2 cell cultures was also conducted to determine the expression and functionality of TLR2 under the influence of LTF treatment. As a result, a LTF decreased was observed in KC patients compared to controls (p < 0.0001), evidencing the strong correlation with TLR2 overexpression at systemic and ocular surface level, with inflammatory mediator upregulation and with KC severity. In stimulated cell cultures, TLR2 expression was decreased using 2 mg/mL of LTF. The levels of secreted embryonic alkaline phosphatase (SEAP) and interleukin-8 (IL-8) were also reduced in supernatants after LTF treatment. As conclusions, the dysregulation of LTF and TLR2 in the ocular surface of KC patients contributes to KC severity by maintaining a detrimental chronic immune−inflammatory state. The immunomodulatory properties of LTF on TLR2 expression suggest its potential as a therapeutic approach for KC.

Pseudomonas aeruginosa has a high adaptive capacity, favoring the selection of antibiotic-resistant strains, which are currently considered a global health problem. The purpose of this work was to investigate the rate and distribution of extensively drug-resistant (XDR) P. aeruginosa in pediatric patients with cystic fibrosis (CF) with recurrent infections and to distinguish the current efficacy of antibiotics commonly used in eradication therapy at a Mexican institute focused on children. A total of 118 P. aeruginosa isolates from 25 children with CF (2015-2019) underwent molecular identification, antimicrobial sensitivity tests, and Random Amplified Polymorphic DNA genotyping (RAPD-PCR). The bacterial isolates were grouped in 84 RAPD profiles, revealing a cross-infection between two sisters, whose resistance profile remained unchanged for more than 2 years. Furthermore, 77.1% (91/118) and 51.7% (61/118) of isolates showed in vitro susceptibility to ceftazidime and amikacin, respectively, antibiotics often used in eradication therapy at our institution. As well, 42.4% (50/118) were categorized as multi-drug resistant (MDR) and 12.7% (15/118) were XDR. Of these resistant isolates, 84.6% (55/65) were identified from patients with recurrent infections. The high frequency of XDR strains in children with CF should be considered a caution mark, as such resistance patterns are more commonly found in adult patients. Additionally, amikacin may soon prove ineffective. Careful use of available antibiotics is crucial before therapeutic possibilities are reduced and "antibiotic resistance crisis" worsens., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Almost all countries have developed measures to ensure that children do not suffer from violence in their families. However, the legal framework, definitions of maltreatment, and institutional structures differ. Whereas in other areas of social policy comparative research is very common, child protection research falls behind., Research Questions: The article examines the differences between cases referred to local child and youth welfare authorities due to concerns about abuse or neglect in Germany, England and the Netherlands, comparing the characteristics of the child, the family, the person reporting the suspected maltreatment, and the type of maltreatment., Method: 1207 case files on children investigated due to suspected child maltreatment from the Netherlands, England, and Germany were analyzed using a standardized coding scheme., Results: The family backgrounds of the children reported differed substantially, with more lone parents in England and more children living in two households in the Netherlands. The persons and institutions reporting their concerns to the local child and youth welfare authorities also differed, with more reports from children and family members in Germany and more from health services in England. In England, physical abuse, sexual abuse, and sexual exploitation were more frequently the reason for referral than in the Netherlands and Germany., Discussion: Differences between countries can partially be explained based on differences in policies and relations of other systems to the child protection system., (Copyright © 2022. Published by Elsevier Ltd.)

The posterior condylar offset (PCO) has been proposed as a determinant of a postoperative range of motion after total knee arthroplasty, although there is no consensus. This study aimed to demonstrate the error introduced by forcing the femoral rotation to overlap both condyles for the "true" lateral X-ray projection for the PCO measurement. We hypothesize that the angular discrepancy between the posterior femoral cortical reference plane and the posterior condylar axis plane due to rotation invalidates the acquisition of reliable measurements on X-rays. We have measured the PCO in 50 "true" lateral X-rays and compared it with the medial and lateral condyles PCO's assessed on a computed tomography-scan-based three-dimensional (3D) model of each knee. PCO based on the 3D imaging differed significantly between the medial (25.8 ± 3.67 mm) and lateral (16.59 ± 2.92 mm) condyle. Three-dimensional PCO values differ significantly from those determined in the radiographic studies. Also, the mean values of the medial and lateral condyle PCO measurements differed significantly (p < 0.001) with all PCO measurements on radiographs. We have identified a difference between the posterior cortical plane and the posterior condylar axis projections, both on the axial plane with a mean value of 11.23° ± 3.64°. Our data show an interplane discrepancy angle between the posterior femoral diaphyseal cortical and the posterior condylar axis plane (due to the femur's necessary rotation to overlap both condyles) may invalidate the 2D X-ray PCO assessment as a reliable measurement., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: School textbooks have a significant role in transferring knowledge to the students and changing their behavior. This work aims to analyze school textbooks to find the representation of natural hazards in Iran, which is vital for supporting children in disaster situations., Methods: In this study, a qualitative content analysis was used. Data were analyzed qualitatively by using MAXQDA 2018 software. For the 2019-2020 school year, 300 Iranian school textbooks in Persian language were collected., Results: Findings of this work show that students receive information about disaster risk reduction (DRR) education through the primary and secondary grade levels in all 12 grades. The educational content covers various types of natural hazards, including geophysical, hydrological, climatological, meteorological, and biological disasters. In addition, the textbooks contain discussions about local hazards, causes and effects of disasters, and the disaster management cycle., Conclusions: The coverage of DRR and the relevant contents in school textbooks reveals that the discourse of natural hazards is important for Iranian authorities, especially in the education system. This study helps decision-makers and practitioners design more effective interventions to prepare children for disasters.

In this paper, a dual-band graphene coplanar waveguide antenna is designed for smart cities and internet of things applications. A graphene film is chosen as the conductive material for the radiation patches and ground plane with a thickness of 240 μm and an electric conductivity of 3.5 × 10 5 S/m. The dielectric is glass with a dielectric permittivity of 6 and a thickness of 2 mm. The implementation of the antenna on glass permits the integration of the antenna in smart cities and IoT applications. This antenna is based on two trapezoidal patches that generate the dual-band behavior. The overall dimensions of the antenna are 30 mm × 30 mm × 2 mm. The reflection coefficient, gain, and radiation patterns were measured and compared with the simulations. The antenna covers two frequency bands; the lower band covers the 2.45 GHz ISM band, and the upper band range covers from 4 to 7 GHz.

Schools have a significant role in disaster education to children. This study investigates the research works about school-based education programs in order to discover challenges and best practices. We conducted a systematic review of English language papers published in peer-review journals.The search identified 2577 publications and 61 articles meeting selection criteria and included in the review. Reviewed studies indicated that disaster education in schools is effective but yet insufficient in many countries. Lack of equipment, financial resources, policy gaps, and teachers' knowledge are common problems in programs. Main outcomes of this systematic review are showing methods used for health emergency preparedness of children of different ages and gender differences in school-based disaster preparedness, as well as the difference in their lifesaving skills in disasters.This study shows that some disaster education programs reported in the papers reviewed were not high-quality enough, which may lead to insufficient preparedness of children in disasters and consequently may put their health at risk, considering the increasing number of natural hazards.

Introduction: Patient-specific instrumentation (PSI) for total knee arthroplasty (TKA) surgery was initially developed to increase accuracy. The potential PSI benefits have expanded in the last decade, and other advantages have been published. However, different authors are critical of PSI and argue that the advantages are not such and do not compensate for the extra cost. This article aims to describe the recently published advantages and disadvantages of PSI., Areas Covered: Narrative description of the latest publications related to PSI in accuracy, clinical and functional outcomes, operative time, efficiency, and other benefits., Expert Opinion: We have published high accuracy of the system, with a not clinically relevant loss of accuracy, significantly higher precision with PSI than with conventional instruments, and a high percentage of cases in the optimal range and similar to that obtained with computer-assisted navigation, greater imprecision for tibial slope, a significant blood loss reduction, and time consumption, an acceptable and non-significant increase in the cost per procedure, and no difference in complications during hospital admission and at 90 days. We think that PSI will not follow the Scott Parabola and that it will continue to be a valuable type of device in some instances of TKA surgery.

Background: Cognitive impairment in schizophrenia (SCZ) is a core feature, relevant for the disease prognosis and functional capacity of the patients. It has also been identified as an endophenotype and proposed as a genetic mechanism of risk for schizophrenia., Aim of the Study: We aimed to evaluate the association of genetic variants in COMT, PRODH, and DISC1 with the cognitive performance of Mexican-Mestizo adult patients with SCZ in order to identify endophenotypes., Subjects and Methods: The association of seven variants in COMT, 15 in PRODH, and three in DISC1 was evaluated in 150 patients and 150 control volunteers. The MATRICS Consensus Cognitive Battery was administered to a subset of 44 patients and 42 controls., Results: COMT rs4633 was related to MATRICS global assessment, while in the multi-phenotype analysis, PRODH rs2870984 was associated with processing speed, working memory, verbal learning, and social cognition. In addition, the association of variants in COMT and PRODH with the risk for SCZ was also found in Mexican-Mestizo patients., Conclusion: COMT might be a potential biomarker of cognitive impairment in Mexican-Mestizo patients with SCZ, supporting the relevance of this gene for drug design., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Long-term studies have shown significantly lower mortality rates in patients with continuous clozapine (CLZ) treatment than other antipsychotics. We aimed to evaluate epigenetic age and DNA methylome differences between CLZ-treated patients and those without psychopharmacological treatment. The DNA methylome was analyzed using the Infinium MethylationEPIC BeadChip in 31 CLZ-treated patients with psychotic disorders and 56 patients with psychiatric disorders naive to psychopharmacological treatment. Delta age (Δage) was calculated as the difference between predicted epigenetic age and chronological age. CLZ-treated patients were stratified by sex, age, and years of treatment. Differential methylation sites between both groups were determined using linear regression models. The Δage in CLZ-treated patients was on average lower compared with drug-naive patients for the three clocks analyzed; however, after data-stratification, this difference remained only in male patients. Additional differences were observed in Hannum and Horvath clocks when comparing chronological age and years of CLZ treatment. We identified 44,716 differentially methylated sites, of which 87.7% were hypomethylated in CLZ-treated patients, and enriched in the longevity pathway genes. Moreover, by protein-protein interaction, AMPK and insulin signaling pathways were found enriched. CLZ could promote a lower Δage in individuals with long-term treatment and modify the DNA methylome of the longevity-regulating pathways genes., 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., (Copyright © 2022 Pérez-Aldana, Martínez-Magaña, Mayén-Lobo, Dávila-Ortiz de Montellano, Aviña-Cervantes, Ortega-Vázquez, Genis-Mendoza, Sarmiento, Soto-Reyes, Juárez-Rojop, Tovilla-Zarate, González-Castro, Nicolini, López-López and Monroy-Jaramillo.)

Purpose: The qualitative approach followed in this study aims to obtain an extensive view of the keratoconus (KC) tear proteome, which could highlight proteins previously undetected and enlarge our knowledge of the disease's pathophysiology., Methods: Twenty-five patients diagnosed with KC and 25 control subjects were studied in a prospective, cross-sectional study. KC screening examinations, including clinical and tomographic examinations, were performed on all participants. Tear samples were collected using Schirmer strips and analyzed by liquid chromatography-tandem mass spectrometry in a data-dependent workflow. A spectral count was used as a semiquantification tool. The tear proteomes of both groups were identified and profiled, and the functional interactions and biological characterization of differential proteins were analyzed using in silico tools., Results: We identified a total of 232 proteins, of whom 133 were expressed in both groups' samples; 41 were observed only in control samples and 58 were identified just in tears of patients with KC. A semiquantitative analysis showed the dysregulation of 17 proteins in the KC samples. An in silico analysis linked proteins only expressed in KC samples to oxidative stress, skin development, and apoptosis. The dysregulation of proteins involved in iron transport, inflammation, oxidative stress, and protease inhibition was observed in the semiquantitative results., Conclusions: A shotgun analysis showed that the tear proteome of patients with KC differed from controls by more than one-third of the total proteins identified, highlighting the relationship of the proteins only expressed in KC tears with processes of cell death, oxidative damage, and inflammation. The underexpression of proteins involved in iron pathways might support the iron imbalance as a contributing factor to cellular damage and death in KC disease.

Introduction: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response., Development: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial., Conclusions: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging., (Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response., Development: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial., Conclusions: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing., (Copyright © 2018 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: A wide range of studies have revealed racial/ethnic and gender disparities in child protection decision-making., Objective: This study investigated whether disparities are mediated by stereotypes that professionals may hold, by applying the Stereotype Content Model (SCM) which suggests that stereotypes are formed by perceptions of sociability, morality, and competence., Participants and Setting: 258 professionals (133 current staff and 125 trainees) from Colorado participated in the study., Methods: The study applied a 2 × 3 randomized experimental vignette design. Participants read a case in which the gender of the parent responsible for maltreatment (mother or father) and race/ethnicity of the family (white, Black, or Latinx) varied., Results: A SEM model (CFI = .94, RMSEA = .05) with free parameters for trainees and current staff was estimated. No significant association between stereotypes and race/ethnicity and gender appeared. However, evidence for disparities emerged. In the trainee group, scores to decide for a supervision order were higher for white fathers, Black mothers, Latinx mothers, and Latinx fathers (β = 0.18 to 0.25) compared to white mothers. Current staff provided larger risk scores for Black mothers and both Latinx parents (β = 0.20 to 0.22) compared to the white mother, resulting in increased inclinations to decide for a supervision order (β = 0.26). Lastly, negative perceptions of morality increased supervision order scores (β = -0.55 to -0.36)., Conclusions: Evidence for disparities in decision-making appeared, but the study could not confirm that these disparities were mediated by stereotypes. Furthermore, perceptions of morality seemed to impact decision-making processes., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: the present work describes the preparation, characterization and optimization of eight types of PLGA-based nanosystems (nanospheres and nanocapsules) as innovative mucoadhesive drug delivery systems of lactoferrin, in order to achieve a preclinical consistent base as an alternative pharmacological treatment to different ocular syndromes and diseases., Methods: All different nanoparticles were prepared via two modified nanoprecipitation techniques, using a three-component mixture of drug/polymer/surfactant (Lf/PLGA/Poloxamer), as a way to overcome the inherent limitations of conventional PLGA NPs. These modified polymeric nanocarriers, intended for topical ophthalmic administration, were subjected to in vitro characterization, surface modification and in vitro and in vivo assessments., Results: An appropriate size range, uniform size distribution and negative ζ potential values were obtained for all types of formulations. Lactoferrin could be effectively included into all types of nanoparticles with appropriate encapsulation efficiency and loading capacity values. A greater, extended, and controlled delivery of Lf from the polymeric matrix was observed through the in vitro release studies. No instability or cytotoxicity was proved for all the formulations by means of organotypic models. Additionally, mucoadhesive in vitro and in vivo experiments show a significant increase in the residence time of the nanoparticles in the eye surface., Conclusions: all types of prepared PLGA nanoparticles might be a potential alternative for the topical ophthalmic administration of lactoferrin.

Patient-specific instrumentation (PSI) has been introduced to simplify and make total knee arthroplasty (TKA) surgery more precise, effective, and efficient. We performed this study to determine whether the postoperative coronal alignment is related to preoperative deformity when computed tomography (CT)-based PSI is used for TKA surgery, and how the PSI approach compares with deformity correction obtained with conventional instrumentation. We analyzed pre- and post-operative full length standing hip-knee-ankle (HKA) X-rays of the lower limb in both groups using a convention > 180 degrees for valgus alignment and < 180 degrees for varus alignment. For the PSI group, the mean (± SD) pre-operative HKA angle was 172.09 degrees varus (± 6.69 degrees) with a maximum varus alignment of 21.5 degrees (HKA 158.5) and a maximum valgus alignment of 14.0 degrees. The mean post-operative HKA was 179.43 degrees varus (± 2.32 degrees) with a maximum varus alignment of seven degrees and a maximum valgus alignment of six degrees. There has been a weak correlation among the values of the pre- and post-operative HKA angle. The adjusted odds ratio (aOR) of postoperative alignment outside the range of 180 ± 3 degrees was significantly higher with a preoperative varus misalignment of 15 degrees or more (aOR: 4.18; 95% confidence interval: 1.35-12.96; p  = 0.013). In the control group (conventional instrumentation), this loss of accuracy occurs with preoperative misalignment of 10 degrees. Preoperative misalignment below 15 degrees appears to present minimal influence on postoperative alignment when a CT-based PSI system is used. The CT-based PSI tends to lose accuracy with preoperative varus misalignment over 15 degrees., Competing Interests: V. L. M. reports board membership Sociedad Española de la Rodilla (SEROD); expert testimony from Medacta International; payment for the development of educational presentations including service on speakers’ bureaus from Medacta International; and travel/accommodations expenses covered or reimbursed by Medacta International. The rest of the authors do not declare any conflict of interest., (Thieme. All rights reserved.)

Background and Objectives: A worldwide objective in the area of health is to offer high-quality services supported by certification strategies that contribute to improving standards for processes commonly used in medicine. However, few pulmonary function test laboratories (PFTLs) follow official standards in their daily operations or are organized around an integrated total quality management system (ITQMS) focused on their established processes. The aim was to determine the feasibility of implementing an ITQMS to accredit the International Organization for Standardization (ISO) 9001:2015 standard in a high-demand PFTL where 13 respiratory function tests are routinely performed together with teaching and research activities., Methods: This project was conducted at the PFTL of the Instituto Nacional de Enfermedades Respiratorias in Mexico City from November 2014 to August 2017 and involved the implementation of an ITQMS guided by ISO 9001:2015 in 5 phases: (1) the establishment of a work team; (2) the elaboration of situational diagnoses; (3) the development of guidelines for the ITQMS; (4) the implementation of the ITQMS model; and (5) the evaluation of the ITQMS., Results: Upon completing the 5 phases, an evaluation of the system by an internal audit identified 3 minor cases of nonconformity (NC), while additional observations and an external audit found 5 minor cases of NC. These issues were addressed through a root-cause analysis to establish an action plan for each one. At the end of the process, the institution was granted the ISO 9001:2015 certification for its 3 processes: medical attention in support of diagnoses, teaching, and research., Conclusions: It is possible to implement an ISO quality management system as a routine operating methodology in a high-demand PFTL., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics. CYP1A2*1F, *1C  and other alleles not yet discovered could support a precision medicine approach for better therapeutic effects and fewer CLZ ADRs. CLZ monitoring systems should be amended and include alcohol intake to protect patients from severe CLZ ADRs.

Nanostructured lipid carriers (NLC) are novel lipidic nanosystems that provide significant improvements in terms of high drug loading capacity and controlled drug release. The purpose of the present work was based on the design, development, and physicochemical characterization of lactoferrin-loaded NLCs as a new therapeutic alternative for the keratoconus treatment. Lactoferrin-loaded NLCs were successfully prepared by a double emulsion/solvent evaporation method. The resultant NLC were assessed in terms of particle size, size distribution, surface charge, morphology, encapsulation efficiency (EE), loading capacity (LC), stability, cytotoxicity, in vitro release, and ocular surface retention. Resulting data showed a size of 119.45 ± 11.44 nm, a 0.151 ± 0.045 PDI value and a surface charge of -17.50 ± 2.53 mV. Besides, high EE and LC values were obtained (up to 75%). The in vitro release study demonstrated a lactoferrin controlled release pattern. NLCs were also stable, non-toxic and show mucoadhesive properties. Thus, a consistent preclinical base was obtained, where NLC may be considered as a potential controlled release novel drug delivery system of lactoferrin for the keratoconus treatment., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Alzheimer's Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it is urgent to find biomarkers to allow for early diagnosis of the disease. There is increasing scientific evidence highlighting the similarities between the eye and other structures of the CNS, suggesting that knowledge acquired in eye research could be useful for research and diagnosis of AD. For example, the retina and optic nerve are considered part of the central nervous system, and their damage can result in retrograde and anterograde axon degeneration, as well as abnormal protein aggregation. In the anterior eye segment, the aqueous humor and tear film may be comparable to the cerebrospinal fluid. Both fluids are enriched with molecules that can be potential neurodegenerative biomarkers. Indeed, the pathophysiology of AD, characterized by cerebral deposits of amyloid-beta (Aβ) and tau protein, is also present in the eyes of AD patients, besides numerous structural and functional changes observed in the structure of the eyes. Therefore, all this evidence suggests that ocular changes have the potential to be used as either predictive values for AD assessment or as diagnostic tools.

This study explains how qualitative content analysis was applied to investigate natural hazards in textbooks for children with intellectual disabilities in Iran. Qualitative content analysis of textbooks is one of the ways for understanding the priorities of Iranian education system with regard to natural hazards. Data samples included whole textbooks for children with intellectual disabilities in all grades during school year 2020-2021 in Iran. Data were collected by transferring textbooks to MAXQDA 2018 software and coding themes with the software. A narrative format was used for analyzing qualitative data. Examples were presented along with tables and quotations in the study. Peer checking and expert check were employed to ensure trustworthiness of the study. The above research design showed the strengths and weaknesses of information provided in Iranian textbooks on natural hazards and disasters management. Iran is a disaster-prone country and various natural hazards happen in Iran every year including earthquake, flood, drought, and extreme weather. Children are a vulnerable population in disasters. One of the most important issues for children's health is disaster preparedness. Intersection of age with other social determinants such as disability, gender, and ethnicity can increase vulnerability. This method was recommended to researchers investigating representation of natural hazards in textbooks of children in different countries, grades, and textbooks. Furthermore, it is possible to use this method for a comparative analysis of information in two or more countries, or different school years in a country.•Explicit and implicit information on natural hazards in textbooks could be investigated with qualitative content analysis.•This method could facilitate cross-country comparisons by providing a framework to investigate the content of textbooks for children without disabilities and/or with disabilities.•It is a valuable method for evaluation of disaster programs for children in local, national, and global levels., Competing Interests: There was no conflict of interest among the authors. All authors read the final manuscript and approved of it. 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., (© 2021 The Author(s).)

Aim: We evaluated the potential influence of genetic ( CYP3A5 , EPHX1 , NR1I2 , HNF4A , ABCC2 , RALBP1 , SCN1A , SCN2A and GABRA1 ) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan ® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2 -rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2 -rs3814055 and EPHX1 -rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2 , EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.

The formation of calixarene-based liposomes was investigated, and the characterization of these nanostructures was carried out using several techniques. Four amphiphilic calixarenes were used. The length of the hydrophobic chains attached to the lower rim as well as the nature of the polar group present in the upper rim of the calixarenes were varied. The lipid bilayer was formed with one calixarene and with the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, DOPE. The cytotoxicity of the liposomes for various cell lines was also studied. From the results obtained, the liposomes formed with the least cytotoxic calixarene, (TEAC 12 ) 4 , were used as nanocarriers of both nucleic acids and the antineoplastic drug doxorubicin, DOX. Results showed that (TEAC 12 ) 4 /DOPE/p-EGFP-C1 lipoplexes, of a given composition, can transfect the genetic material, although the transfection efficiency substantially increases in the presence of an additional amount of DOPE as coadjuvant. On the other hand, the (TEAC 12 ) 4 /DOPE liposomes present a high doxorubicin encapsulation efficiency, and a slow controlled release, which could diminish the side effects of the drug.

Purpose: To elucidate dysregulated proteins in keratoconus (KC) to provide a better understanding of the molecular mechanisms that lead to the development of the disease using sequential window acquisition of all theoretical mass spectra (SWATH-MS) as a protein quantification tool of the tear proteomic profile., Methods: Prospective cross-sectional study that includes 25 keratoconic eyes and 25 healthy eyes. All participants underwent a clinical, tomographic, and aberrometric exam. Tear sample was collected using Schirmer strips and analyzed by liquid chromatography with tandem mass spectrometry. SWATH-MS was used as a quantification tool of the tear proteomic profile. The expression of the quantified proteins was compared between groups, and the biological and molecular functions of the dysregulated proteins as well as their functional relationships were studied by in silico analysis., Results: A total of 203 proteins were quantified in tear samples of patients with KC and control participants, of which 18 showed differential expression between groups (P < 0.05). An increase in the expression of 7 proteins and a decrease in the expression of 11 proteins were observed. Protein-protein interactions and gene ontology analysis showed the involvement of these dysregulated proteins in structural, inflammatory-immune, iron homeostasis, oxidative stress, and extracellular matrix proteolysis processes., Conclusions: Tear protein quantification has revealed the dysregulation of proteins involved in biological processes previously associated with KC. Among them, iron homeostasis should be highlighted as a relevant pathway in the KC pathophysiology, and it should be taken into account in the development of therapeutic targets to cope with tissue damage derived from iron accumulation and toxicity.

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI 95  = 1.041-12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI 95  = 1.473-42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples., (© 2020 Wiley Periodicals, LLC.)

The interaction between calf-thymus DNA, ctDNA, and various single-chained surfactants with different functional groups at the end of hydrophobic tail was studied with the goal of investigating the influence of the functional group nature on surfactant DNA compacting efficiency. The surfactants investigated were dodecyltriethylammonium bromide (DTEABr), triethyl(1-phenoxydodecyl)ammonium bromide (12PhBr), triethyl(2-naphthoxydodecyl)ammonium bromide (12NBr) and 11-(isonicotinoyloxy)- N , N , N -triethyl-1-undecanaminium bromide (11PyBr). Results made evident that the surfactants' tendencies to self-aggregation is the key factor determining their efficiency to compact the nucleic acid. Subsequently, DOPE/12NBr/pEGFP-C1 lipoplexes, with different cationic surfactant molar fractions (α) and mass ratios (L/D), were prepared and characterized. DOPE is a zwitterionic phospholipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, and the plasmid pEGFP-C1 carries a GFP coding sequence with the necessary regulatory elements for constitutive expression of the gene in human cells. 12NBr was chosen because it was the most efficient DNA compacting agent among the surfactants investigated. Finally, the cytotoxicity and transfection efficiency (TE) of DOPE/12NBr/pDNA lipoplexes, with different compositions, were investigated.

Individualized pre-operative assessment of the patterns of the lower extremity anatomy and deformities in patients undergoing total knee arthroplasty seems essential for a successful surgery. In the present study, we investigated the relationship among the coronal alignment and the rotational profile of the lower extremities in the Caucasian population with end-stage knee osteoarthritis. We conducted a prospective study of 385 knees that underwent a pre-operative three-dimensional computed tomography-based model. The lower extremity alignment was determined (mechanical tibiofemoral or hip-knee-ankle angle, supplementary angle of the femoral lateral distal angle, and proximal medial tibial angle). For each case, the femoral distal rotation (condylar twist angle), the femoral proximal version, and the tibial torsion were determined. As the coronal alignment changed from varus to valgus, the femoral external rotation increased (r = 0.217; p < 0.0005). As the coronal alignment changed from varus to valgus, the external tibial torsion increased (r = 0.248; p < 0.0005). No correlation was found between the global coronal alignment and the femoral version. The present study demonstrates a linear relationship between the coronal alignment and the rotational geometry of the distal femur. This correlation also occurs with the tibial torsion. Perhaps outcomes of total knee arthroplasty surgery might be improved by addressing these deformities as well.

Background: We aimed to analyze the impact of two different types of surgical instrumentation (conventional manual instrumentation (CI) and patient-specific instrumentation (PSI)) on length of stay (LOS) and objectify differences in cost. We hypothesized that there are no differences in the LOS and cost due to the instrumentation system used., Research Design and Methods: LOS was registered using inpatient admission data provided by the Institutional Management Control Department. We recorded the costs associated with each procedure that could be influenced by the use of one system or another during the in-hospital stay. We conducted a prospectively single-center cohort study of 305 TKAs. Surgery was performed with conventional CI in 122 cases and with PSI in 183 cases., Results: The mean LOS for the CI group was 4.29 days (SD 1.65) and 4.22 days (SD 1.26), for the PSI group. No significant difference among both instrumentation systems was obtained. When comparing global costs, the mean cost was slightly higher (without a significant difference) for the PSI cases (€3110.24 vs. €2852.7 for the CI cases)., Conclusions: LOS and overall cost, in hospitals with a low annual TKA surgery volume, are unrelated to conventional or patient-specific instrumentation.

There have been remarkable advances in knee replacement surgery over the last few decades. One of the concerns continues to be the accuracy in achieving the desired alignment. Patient-specific instrumentation (PSI) was developed to increase component placement accuracy, but the available evidence is not conclusive. Our study aimed to determine a PSI system's three-dimensional accuracy on 3D virtual models obtained by post-operative computed tomography. We compared the angular placement values of 35 total knee arthroplasties (TKAs) operated within a year obtained with the planned ones, and we analyzed the possible relationships between alignment and patient-reported outcomes. The mean (SD) discrepancies measured by two experienced engineers to the planned values observed were 1.64° (1.3°) for the hip-knee-ankle angle, 1.45° (1.06°) for the supplementary angle of the femoral lateral distal angle, 1.44° (0.97°) for the proximal medial tibial angle, 2.28° (1.78°) for tibial slope, 0.64° (1.09°) for femoral sagittal flexion, and 1.42° (1.06°) for femoral rotation. Neither variables related to post-operative alignment nor the proportion of change between pre-and post-operative alignment influenced the patient-reported outcomes. The evaluated PSI system's three-dimensional alignment analysis showed a statistically significant difference between the angular values planned and those obtained. However, we did not find a relevant effect size, and this slight discrepancy did not impact the clinical outcome.

A vast amount of evidence indicates that bisphenol A (BPA) and phthalates are widely distributed in the environment since these compounds are mass-produced for the manufacture of plastics and plasticizers. These compounds belong to a large group of substances termed endocrine-disrupting chemicals (EDC). It is well known that humans and living organisms are unavoidably and unintentionally exposed to BPA and phthalates from food packaging materials and many other everyday products. BPA and phthalates exert their effect by interfering with hormone synthesis, bioavailability, and action, thereby altering cellular proliferation and differentiation, tissue development, and the regulation of several physiological processes. In fact, these EDC can alter fetal programming at an epigenetic level, which can be transgenerational transmitted and may be involved in the development of various chronic pathologies later in the adulthood, including metabolic, reproductive and degenerative diseases, and certain types of cancer. In this review, we describe the most recent proposed mechanisms of action of these EDC and offer a compelling selection of experimental, epidemiological and clinical studies, which show evidence of how exposure to these pollutants affects our health during development, and their association with a wide range of reproductive, metabolic and neurological diseases, as well as hormone-related cancers. We stress the importance of concern in the general population and the urgent need for the medical health care system to closely monitor EDC levels in the population due to unavoidable and involuntary exposure to these pollutants and their impact on human health., 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 © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Clozapine (CLZ) is the only antipsychotic drug that has been proven to be effective in patients with refractory psychosis, but it has also been proposed as an effective mood stabilizer; however, the complex mechanisms of action of CLZ are not yet fully known. To find predictors of CLZ-associated phenotypes (i.e., the metabolic ratio, dosage, and response), we explore the genomic and epigenomic characteristics of 44 patients with refractory psychosis who receive CLZ treatment based on the integration of polygenic risk score (PRS) analyses in simultaneous methylome profiles. Surprisingly, the PRS for bipolar disorder (BD-PRS) was associated with the CLZ metabolic ratio (pseudo-R 2 = 0.2080, adjusted p -value = 0.0189). To better explain our findings in a biological context, we assess the protein-protein interactions between gene products with high impact variants in the top enriched pathways and those exhibiting differentially methylated sites. The GABAergic synapse pathway was found to be enriched in BD-PRS and was associated with the CLZ metabolic ratio. Such interplay supports the use of CLZ as a mood stabilizer and not just as an antipsychotic. Future studies with larger sample sizes should be pursued to confirm the findings of this study.

Purpose: The innate immune toll-like receptors 2 (TLR2) and 4 (TLR4) may play a key role in the physiopathology of keratoconus (KC). Therefore, the aim of this study was to compare TLR2/TLR4 expression in corneal and conjunctival epithelial cells between healthy first-degree relatives of patients with KC and healthy controls as well as KC patients., Methods: Case-control study in 72 healthy eyes of 36 control subjects, 53 eyes of 27 first-degree relatives, and 109 eyes with KC (60 patients). All participants were subjected to a clinical, topographic, aberrometric, and tomographic examination with extraction of corneal and conjunctival epithelial cells through scraping. TLR2/TLR4 expression was measured by flow cytometry, and was compared among controls, first-degree relatives, and KC patients. The relationship between TLR expression and epidemiological-clinical variables or topographic-aberrometric-tomographic parameters was also analyzed., Results: Mean TLR2/TLR4 expression showed a significant gradual increase among groups: controls < first-degree relatives < KC patients. Mean expression of TLR2 in corneal epithelial cells and both TLR2/TLR4 in conjunctival epithelial cells were significantly higher in relatives than in controls (p = 0.026, p < 0.001, and p = 0.031, respectively). Sex, age, allergic disease, eye itching, rubbing, and topographic-aberrometric-tomographic parameters were not associated to TLR2/TLR4 expression in relatives. TLR2 conjunctival expression was independently associated to relatives (OR 1.001; CI 95% 1.000-1.002, p = 0.043) after adjustment by sex, age, and rubbing., Conclusion: TLR2 and TLR4 are overexpressed in corneal and conjunctival epithelial cells of KC relatives compared with controls. Both biomarkers may monitor early ocular changes in first-degree relatives who not show any abnormal clinical-topographic-aberrometric-tomographic parameters.