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BACKGROUND: Latent left ventricular outflow tract obstruction (LVOTO) is an important cause of symptoms in patients with hypertrophic cardiomyopathy (HCM) but can be challenging to provoke. OBJECTIVES AND METHODS: To examine the value of postprandial resting and stress echocardiography and utilization of invasive or enhanced drug therapies (surgical myectomy, alcohol septal ablation, disopyramide, and mavacamten) in patients with postprandial LVOTO. Consecutive HCM patients without LVOTO underwent routine and postprandial echocardiography at rest, with provocation (Valsalva and standing) and after symptom-limited treadmill stress. RESULTS: Among 252 patients (mean age, 58 years, 39% women), postprandial LVOT gradients were higher compared with routine echocardiography at rest (median, 9.0 [0-38.0] vs 0 [0-14.0] mm Hg; P < .0001) and with provocation (18.5 [0-70.3] vs 1.5 [0-41.0] mm Hg; P < .0001). Postprandial exercise stress echocardiogram (PPXSE) gradients were higher in a subset of 44 patients who underwent both postprandial and fasting stress echocardiography (47.0 [5.3-81.0] vs 17.5 [0-46.0] mm Hg; P < .0001). In total, 49 (19.5%) patients achieved the ≥50 mm Hg threshold under routine conditions (rest/provocation); 90 (35.7%) additional patients achieved postprandial gradients ≥50 mm Hg (rest/provocation/exercise), 38 (15.1%) with PPXSE alone. A total of 71 patients were treated with 91 invasive or enhanced drug therapies, 32 (45.1%) of whom had gradients ≥50 mm Hg only after eating (rest/provocation) and 8 (11.3%) only with PPXSE, with symptom relief in the majority. CONCLUSIONS: Postprandial echocardiography was useful at unmasking LVOTO in more than one-third of patients who did not have high gradients otherwise. Eating before echocardiography is a powerful provocative tool in the evaluation of patients with HCM.
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OBJECTIVE: To compare whole-body kinematics, leg muscle activity, and discomfort while performing a 10-min carrying task with and without a passive upper-body exoskeleton (CarrySuitâ), for both males and females. BACKGROUND: Diverse commercial passive exoskeletons have appeared on the market claiming to assist lifting or carrying task. However, evidence of their impact on kinematics, muscle activity, and discomfort while performing these tasks are necessary to determine their benefits and/or limitations. METHOD: Sixteen females and fourteen males carried a 15kg load with and without a passive exoskeleton during 10-min over a round trip route, in two non-consecutive days. Whole-body kinematics and leg muscle activity were evaluated for each condition. In addition, leg discomfort ratings were quantified before and immediately after the task. RESULTS: The gastrocnemius and vastus lateralis muscle activity remained constant over the task with the exoskeleton. Without the exoskeleton a small decrease of gastrocnemius median activation was observed regardless of sex, and a small increase in static vastus lateralis activation was observed only for females. Several differences in sagittal, frontal, and transverse movements' ranges of motion were found between conditions and over the task. With the exoskeleton, ROM in the sagittal plane increased over time for the right ankle and pelvis for both sexes, and knees for males only. Thorax ROMs in the three planes were higher for females only when using the exoskeleton. Leg discomfort was lower with the exoskeleton than without. CONCLUSION: The results revealed a positive impact on range of motion, leg muscle activity, and discomfort of the tested exoskeleton.
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Dispositivo Exoesqueleto , Pierna , Músculo Esquelético , Humanos , Masculino , Femenino , Fenómenos Biomecánicos , Adulto , Músculo Esquelético/fisiología , Pierna/fisiología , Adulto Joven , Rango del Movimiento Articular/fisiología , Electromiografía , Soporte de Peso/fisiologíaRESUMEN
INTRODUCTION: After 17 years on the market, biosimilar medicines have contributed significantly to the sustainability of healthcare in Spain, providing cost-effective treatment options and savings of more than 1 billion by 2022 alone. To fully exploit this potential and meet the European pharmaceutical strategy's objectives of increased access and a resilient supply chain, Member States need to optimize their biosimilars policies. AREAS COVERED: We conducted an exhaustive review of biosimilar medicines in Spain, first describing their regulatory framework. Biosimilar policies at both national and regional level have been collected and updated figures on the biosimilars market are provided based on official data. Knowledge and acceptance of biosimilar medicines among patients and medical societies based on biosimilar positioning documents is reviewed. National evidence on the contribution of biosimilars to savings and sustainability is also included in this study. EXPERT OPINION: In Spain, there is a need to further build confidence in biosimilars, develop a strong national biosimilars policy and address regional variability, improve public procurement and adapt clinical practice guidelines following the commercialization of biosimilars. By implementing a holistic and evidence-based policy, Spain can fully exploit the benefits of biosimilar medicines and ensure better and equitable access across the healthcare system.
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Biosimilares Farmacéuticos , Biosimilares Farmacéuticos/economía , Biosimilares Farmacéuticos/uso terapéutico , España , Humanos , Política de SaludRESUMEN
Itraconazole is a drug used in veterinary medicine for the treatment of different varieties of dermatophytosis at doses between 3-5 mg/kg/day in cats. Nevertheless, in Spain, it is only available in the market as a 52 mL suspension at 10 mg/mL. The lack of alternative formulations, which provide sufficient formulation to cover the treatment of large animals or allow the treatment of a group of them, can be overcome with compounding. For this purpose, it has to be considered that itraconazole is a weak base, class II compound, according to the Biopharmaceutics Classification System, that can precipitate when reaching the duodenum. The aim of this work is to develop alternative oral formulations of itraconazole for the treatment of dermatophytosis. Several oral compounds of itraconazole were prepared and compared, in terms of dissolution rate, permeability, and stability, in order to provide alternatives to the medicine commercialized. The most promising formulation contained hydroxypropyl methylcellulose and ß-cyclodextrin. This combination of excipients was capable of dissolving the same concentration as the reference product and delaying the precipitation of itraconazole upon leaving the stomach. Moreover, the intestinal permeability of itraconazole was increased more than two-fold.
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BACKGROUND: The identification of low-frequency haplotypes, never observed in homozygous state in a population, is considered informative on the presence of potentially harmful alleles (candidate alleles), putatively involved in inbreeding depression. Although identification of candidate alleles is challenging, studies analyzing the dynamics of potentially harmful alleles are lacking. A pedigree of the highly endangered Gochu Asturcelta pig breed, including 471 individuals belonging to 51 different families with at least 5 offspring each, was genotyped using the Axiom PigHDv1 Array (658,692 SNPs). Analyses were carried out on four different cohorts defined according to pedigree depth and at the whole population (WP) level. RESULTS: The 4,470 Linkage Blocks (LB) identified in the Base Population (10 individuals), gathered a total of 16,981 alleles in the WP. Up to 5,466 (32%) haplotypes were statistically considered candidate alleles, 3,995 of them (73%) having one copy only. The number of alleles and candidate alleles varied across cohorts according to sample size. Up to 4,610 of the alleles identified in the WP (27% of the total) were present in one cohort only. Parentage analysis identified a total of 67,742 parent-offspring incompatibilities. The number of mismatches varied according to family size. Parent-offspring inconsistencies were identified in 98.2% of the candidate alleles and 100% of the LB in which they were located. Segregation analyses informed that most potential candidate alleles appeared de novo in the pedigree. Only 17 candidate alleles were identified in the boar, sow, and paternal and maternal grandparents and were considered segregants. CONCLUSIONS: Our results suggest that neither mutation nor recombination are the major forces causing the apparition of candidate alleles. Their occurrence is more likely caused by Allele-Drop-In events due to SNP calling errors. New alleles appear when wrongly called SNPs are used to construct haplotypes. The presence of candidate alleles in either parents or grandparents of the carrier individuals does not ensure that they are true alleles. Minimum Allele Frequency thresholds may remove informative alleles. Only fully segregant candidate alleles should be considered potentially harmful alleles. A set of 16 candidate genes, potentially involved in inbreeding depression, is described.
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Alelos , Haplotipos , Linaje , Polimorfismo de Nucleótido Simple , Animales , Porcinos/genética , Dinámica Poblacional , Femenino , Masculino , Frecuencia de los GenesRESUMEN
BACKGROUND: Patients with limited health literacy have difficulty understanding their injuries and postoperative treatment, which can negatively affect their outcomes. MATERIALS AND METHODS: This cross-sectional questionnaire-based study of 103 adult patients sought to quantify patients' health literacy at a single county hospital's orthopedic trauma clinic and to examine their ability to understand injuries and treatment plans. Demographics, Newest Vital Sign (NVS) health literacy assessment, and knowledge scores were used to assess patients' comprehension of their injuries and treatment plan. Patients were grouped by NVS score (NVS <4: limited health literacy). Fisher's exact tests and t tests were used to compare demographic and comprehension scores. Multivariate logistic regression analysis was used to examine the association among low health literacy, sociodemographic variables, and knowledge scores. RESULTS: Of the 103 patients, 75% were determined to have limited health literacy. Patients younger than 30 years were more likely to have adequate literacy (50% vs 23%, P=.01). Patients who spoke Spanish as their primary language were 8.77 times more likely to have limited health literacy with respect to sociodemographic factors (odds ratio, 8.77; 95% CI, 1.03-76.92; P=.04). Low health literacy was 3.52 and 4.14 times more likely to predict discordance in answers to specific bone fractures and the narcotics prescribed (P=.04 and P=.02, respectively). CONCLUSION: Spanish-speaking patients have demonstrated limited health literacy and difficulty understanding their injuries and postoperative treatment plans compared with English-speaking patients. Patients with low health literacy are more likely to be unsure regarding which bone they fractured or their prescribed opiates. [Orthopedics. 2024;47(4):249-255.].
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Alfabetización en Salud , Hospitales de Condado , Humanos , Alfabetización en Salud/estadística & datos numéricos , Estudios Transversales , Masculino , Femenino , Adulto , Persona de Mediana Edad , Hospitales de Condado/estadística & datos numéricos , Encuestas y Cuestionarios , Procedimientos Ortopédicos/estadística & datos numéricos , Anciano , Adulto Joven , Heridas y Lesiones/cirugía , Cirugía de Cuidados IntensivosRESUMEN
The use of visible photon fluxes to influence catalytic reactions on metal nanoparticle surfaces has attracted attention based on observations of reaction mechanisms and selectivity not observed under equilibrium heating. These observations suggest that photon fluxes can selectively impact the rates of certain elementary steps, creating nonequilibrium energy distributions among various reaction pathways. However, quantitative studies validating these hypotheses on metal nanoparticle surfaces are lacking. We examine the influence of continuous wave visible photon fluxes on the CO desorption rates from 1 to 2 nm diameter Pt and Pd nanoparticle surfaces supported on γ-Al2O3. Temperature-programmed desorption measurements quantified via diffuse reflectance infrared Fourier transform spectroscopy demonstrate that visible photon fluxes significantly enhanced the rate of CO desorption from Pt nanoparticles in a wavelength-dependent manner. 440 nm photons most efficiently promoted CO desorption from Pt nanoparticle surfaces, aligning with the excitation energy for the interfacial electronic transition within the Pt-CO bond. Conversely, visible photon fluxes had no measurable influence on CO desorption rates from Pd nanoparticle surfaces after accounting for photon-induced heating. Density functional theory calculations demonstrate that the Pt-CO bond exhibits a narrower LUMO resonance, stronger coupling between the photoexcitation and forces induced on the metal-C bond, and vibrational energy dissipation that more effectively couples to desorption as compared to Pd-CO. These results demonstrate the specificity photons provide in facilitating chemical reactions on metal nanoparticle surfaces and substantiate the idea that photon fluxes can steer processes and outcomes of catalytic reactions in ways not achievable by equilibrium heating.
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Many scientific societies have issued guidelines to introduce population-based cervical cancer screening with HPV testing. The Vitro HPV Screening assay is a fully automatic multiplex real-time PCR test targeting the L1 GP5+/GP6+ region of HPV genome. The assay detects 14 high risk (HR) HPV genotypes, identifying individual HPV16 and HPV18 genotypes, and the HPV-positive samples for the other 12 HR HPV types are subsequently genotyped with the HPV Direct Flow Chip test. Following international guidelines, the aim of this study was to validate the clinical accuracy of the Vitro HPV Screening test on ThinPrep-collected samples for its use as primary cervical cancer screening, using as comparator the validated cobas® 4800 HPV test. The non-inferiority analysis showed that the clinical sensitivity and specificity of the Vitro HPV Screening assay for a diagnosis of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) were not inferior to those of cobas® 4800 HPV (p = 0.0049 and p < 0.001 respectively). The assay has demonstrated a high intra- and inter-laboratory reproducibility, also among the individual genotypes. The Vitro HPV Screening assay is valid for cervical cancer screening and it provides genotyping information on HPV-positive samples without further sample processing in a fully automated workflow.
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The well-being of people is a key aspect of the field of psychology. Hence, it is important to analyse the variables that are related to life satisfaction and happiness as perceived by individuals and that, therefore, increase their overall well-being. The main objective of this study was to analyse the predictive capacity of emotional intelligence and perceived social support on both the level of life satisfaction and perceived happiness. A total of 380 psychology students completed the Trait Meta Mood Scale, the Multidimensional Scale of Perceived Social Support, the Satisfaction with Life Scale, and the Subjective Happiness Scale. The results show that both emotional intelligence and social support are related to and predictive of subjective happiness and life satisfaction. The importance of developing the components of emotional intelligence and promoting an adequate social network in young people is highlighted.
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The purpose of this study was to predict the in vivo bioequivalence (BE) outcome of valsartan (VALS, BCS class IV) from three oral-fixed combination products with hydrochlorothiazide (HCTZ, BCS class III) (Co-Diovan® Forte as reference and two generic formulations in development) by conducting in vivo predictive dissolution with a gastrointestinal simulator (GIS) and a physiologically based biopharmaceutic model (PBBM). In the first BE study, the HCTZ failed, but the VALS 90% CI of Cmax and the AUC were within the acceptance limits, while, in the second BE study, the HCTZ 90% CI of Cmax and the AUC were within the acceptance limits, but the VALS failed. As both drugs belong to different BCS classes, their limiting factors for absorption are different. On the other hand, the gastrointestinal variables affected by the formulation excipients have a distinct impact on their in vivo exposures. Dissolution tests of the three products were performed in a GIS, and a PBBM was constructed for VALS by incorporating in the mathematical model of the in vitro-in vivo correlation (IVIVC) the gastrointestinal variables affected by the excipients, namely, VALS permeability and GI transit time. VALS permeability in presence of the formulation excipients was characterized using the in situ perfusion method in rats, and the impact of the excipients on the GI transit times was estimated from the HCTZ's in vivo results. The model was able to fit the in vivo BE results with a good prediction error. This study contributes to the field by showing the usefulness of PBBM in establishing in vitro-in vivo relationships incorporating not only dissolution data but also other gastrointestinal critical variables that affect drug exposure in BCS class IV compounds.
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BACKGROUND: Patients often mention distress, anxiety, or claustrophobia related to MRI, resulting in no-shows, disturbances of the workflow, and lasting psychological effects. Patients' experience varies and is moderated by socio-demographic aspects alongside the clinical condition. While qualitative studies help understand individuals' experiences, to date a systematic review and aggregation of MRI individuals' experience is lacking. PURPOSE: To investigate how adult patients experience MRI, and the characterizing factors. STUDY TYPE: Systematic review with meta-aggregation and meta-synthesis. POPULATION: 220 patients' reported experience of adults undergoing clinical MRI and 144 quotes from eight qualitative studies. ASSESSMENT: Systematic search in PubMed, Scopus, Web of Science, and PsycInfo databases according to the PRISMA guidelines. For quality appraisal, the Joanna Briggs Institute (JBI) tools were used. Convergent segregated approach was undertaken. DATA ANALYSIS: Participant recruitment, setting of exploration, type of interview, and analysis extracted through Joana Briggs Qualitative Assessment and Review Instrument (JBI QARI) tool. Meta-synthesis was supported by a concept map. For meta-aggregation, direct patient quotes were extracted, findings grouped, themes and characterizing factors at each stage abstracted, and categories coded in two cycles. Frequency of statements was quantified. Interviews' raw data unavailability impeded computer-aided analysis. RESULTS: Eight articles out of 12,755 initial studies, 220 patients, were included. Meta-aggregation of 144 patient quotes answered: (1) experiences before, at the scanning table, during, and after an MRI, (2) differences based on clinical condition, and (3) characterizing factors, including coping strategies, look-and-feel of medical technology, interaction with professionals, and information. Seven publications lack participants' health literacy level, occupation, and eight studies lack developmental conditions, ethnicity, or country of origin. Six studies were conducted in university hospitals. DATA CONCLUSION: Aggregation of patients' quotes provide a foundational description of adult patients' MRI experience across the stages of an MRI process. Insufficient raw data of individual quotes and limited socio-demographic diversity may constrain the understanding of individual experience and characterizing factors. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.
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BACKGROUND: Involving patient and community stakeholders in clinical trials adds value by ensuring research prioritizes patient goals both in conduct of the study and application of the research. The use of stakeholder committees and their impact on the conduct of a multicenter clinical trial have been underreported clinically and academically. The aim of this study is to describe how Study Advisory Committee (SAC) recommendations were implemented throughout the Emergency Medicine Palliative Care Access (EMPallA) trial. EMPallA is a multi-center, pragmatic two-arm randomized controlled trial (RCT) comparing the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. METHODS: A SAC consisting of 18 individuals, including patients with palliative care experience, members of healthcare organizations, and payers was convened for the EMPallA trial. The SAC engaged in community-based participatory research and assisted in all aspects from study design to dissemination. The SAC met with the research team quarterly and annually from project inception to dissemination. Using meeting notes and recordings we completed a qualitative thematic analysis using an iterative process to develop themes and subthemes to summarize SAC recommendations throughout the project's duration. RESULTS: The SAC convened 16 times between 2017 and 2020. Over the course of the project, the SAC provided 41 unique recommendations. Twenty-six of the 41 (63%) recommendations were adapted into formal Institutional Review Board (IRB) study modifications. Recommendations were coded into four major themes: Scientific, Pragmatic, Resource and Dissemination. A majority of the recommendations were related to either the Scientific (46%) or Pragmatic (29%) themes. Recommendations were not mutually exclusive across three study phases: Preparatory, execution and translational. A vast majority (94%) of the recommendations made were related to the execution phase. Major IRB study modifications were made based on their recommendations including data collection of novel dependent variables and expanding recruitment to Spanish-speaking patients. CONCLUSIONS: Our study provides an example of successful integration of a SAC in the conduct of a pragmatic, multi-center RCT. Future trials should engage with SACs in all study phases to ensure trials are relevant, inclusive, patient-focused, and attentive to gaps between health care and patient and family needs. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03325985, 10/30/2017.
Clinical research should involve patient and community stakeholder perspectives to make sure the study addresses questions important to the studied population. One way to do this is by creating a group of stakeholders who can advise on the conduct of a study. We assembled a Study Advisory Committee (SAC) for the Emergency Medicine Palliative Care Access (EMPallA) trial. The purpose of this clinical trial is to compare the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. This paper describes how the SACs involvement translated into direct impacts on the EMPallA trial. The trial research team held regular meetings with the SAC throughout the trial process. Their involvement led to many significant changes in the trial, such as expanding recruitment inclusion criteria (Spanish-speaking patients), and including survey instruments to measure lonelines and caregiver burden. The SAC also devised strategies to overcome patient and caregiver recruitment and retention challenges, including the creation of patient-friendly materials and training for research coordinators. This study provides a successful example of how actively engaging patient and community stakeholders, through committee engagement, can promote patient priorities in all phases of a trial while facilitating patient recruitment and retention.
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BACKGROUND: MRI is generally well-tolerated although it may induce physiological stress responses and anxiety in patients. PURPOSE: Investigate the psychological, physiological, and behavioral responses of patients to MRI, their evolution over time, and influencing factors. STUDY TYPE: Systematic review with meta-analysis. POPULATION: 181,371 adult patients from 44 studies undergoing clinical MRI. ASSESSMENT: Pubmed, PsycInfo, Web of Science, and Scopus were systematically searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Quality appraisal was conducted with the Joanna Briggs Institute critical appraisal tools. Meta-analysis was conducted via Meta-Essentials workbooks when five studies were available for an outcome. Psychological and behavioral outcomes could be analyzed. Psychological outcomes were anxiety (State-Trait-Anxiety Inventory, STAI-S; 37) and willingness to undergo MRI again. Behavioral outcomes included unexpected behaviors: No shows, sedation, failed scans, and motion artifacts. Year of publication, sex, age, and positioning were examined as moderators. STATISTICAL TESTS: Meta-analysis, Hedge's g. A P value <0.05 was considered to indicate statistical significance. RESULTS: Of 12,755 initial studies, 104 studies were included in methodological review and 44 (181,371 patients) in meta-analysis. Anxiety did not significantly reduce from pre- to post-MRI (Hedge's g = -0.20, P = 0.051). Pooled values of STAI-S (37) were 44.93 (pre-MRI) and 40.36 (post-MRI). Of all patients, 3.9% reported unwillingness to undergo MRI again. Pooled prevalence of unexpected patient behavior was 11.4%; rates for singular behaviors were: Failed scans, 2.1%; no-shows, 11.5%; sedation, 3.3%; motion artifacts, 12.2%. Year of publication was not a significant moderator (all P > 0.169); that is, the patients' response was not improved in recent vs. older studies. Meta-analysis of physiological responses was not feasible since preconditions were not met for any outcome. DATA CONCLUSION: Advancements of MRI technology alone may not be sufficient to eliminate anxiety in patients undergoing MRI and related unexpected behaviors. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.
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Ansiedad , Imagen por Resonancia Magnética , Adulto , Humanos , Imagen por Resonancia Magnética/psicología , Pacientes no Presentados , Cooperación del PacienteRESUMEN
Background: Glioblastoma is the most common and lethal brain cancer. New treatments are needed. However, the presence of the blood-brain barrier is limiting the development of new treatments directed toward the brain, as it restricts the access and distribution of drugs to the CNS. Materials & methods: In this work, two different nanoparticles (i.e., mesoporous silica nanoparticles and magnetic mesoporous silica nanoparticles) loaded with ponatinib were prepared. Results & conclusion: Both particles were characterized and tested in vitro and in vivo, proving that they are not toxic for blood-brain barrier cells and they increase the amount of drug reaching the brain when administered intranasally in comparison with the results obtained for the free drug.
This article presents a couple of promising nanoparticles for the treatment of brain cancer. This research is interesting because the brain and spinal cord are protected by a membrane that prevents toxic substances from reaching them but also hinders the access of drugs. One type of particle has a magnet in its core, so it can be driven with another external magnet until it reaches target; the other type does not have a magnet but has a small size, which would allow it to cross the membrane mentioned above. These particles have been proven to be able to kill cancer cells and to reach the brain after been administered through the nose in a better way than the free drug.
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Portadores de Fármacos , Nanopartículas , Administración Intranasal , Encéfalo , Dióxido de Silicio , Sistemas de Liberación de Medicamentos/métodos , PorosidadRESUMEN
BACKGROUND: In spite of the availability of single nucleotide polymorphism (SNP) array data, differentiation between observed homozygosity and that caused by mating between relatives (autozygosity) introduces major difficulties. Homozygosity estimators show large variation due to different causes, namely, Mendelian sampling, population structure, and differences among chromosomes. Therefore, the ascertainment of how inbreeding is reflected in the genome is still an issue. The aim of this research was to study the usefulness of genomic information for the assessment of genetic diversity in the highly endangered Gochu Asturcelta pig breed. Pedigree depth varied from 0 (founders) to 4 equivalent discrete generations (t). Four homozygosity parameters (runs of homozygosity, FROH; heterozygosity-rich regions, FHRR; Li and Horvitz's, FLH; and Yang and colleague's FYAN) were computed for each individual, adjusted for the variability in the base population (BP; six individuals) and further jackknifed over autosomes. Individual increases in homozygosity (depending on t) and increases in pairwise homozygosity (i.e., increase in the parents' mean) were computed for each individual in the pedigree, and effective population size (Ne) was computed for five subpopulations (cohorts). Genealogical parameters (individual inbreeding, individual increase in inbreeding, and Ne) were used for comparisons. RESULTS: The mean F was 0.120 ± 0.074 and the mean BP-adjusted homozygosity ranged from 0.099 ± 0.081 (FLH) to 0.152 ± 0.075 (FYAN). After jackknifing, the mean values were slightly lower. The increase in pairwise homozygosity tended to be twofold higher than the corresponding individual increase in homozygosity values. When compared with genealogical estimates, estimates of Ne obtained using FYAN tended to have low root-mean-squared errors. However, Ne estimates based on increases in pairwise homozygosity using both FROH and FHRR estimates of genomic inbreeding had lower root-mean-squared errors. CONCLUSIONS: Parameters characterizing homozygosity may not accurately depict losses of variability in small populations in which breeding policy prohibits matings between close relatives. After BP adjustment, the performance of FROH and FHRR was highly consistent. Assuming that an increase in homozygosity depends only on pedigree depth can lead to underestimating it in populations with shallow pedigrees. An increase in pairwise homozygosity computed from either FROH or FHRR is a promising approach for characterizing autozygosity.
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Endogamia , Polimorfismo de Nucleótido Simple , Humanos , Porcinos , Animales , Linaje , Homocigoto , Genoma , GenotipoRESUMEN
Copy number variations regions (CNVRs) can be classified either as segregating, when found in both parents, and offspring, or non-segregating. A total of 65 segregating and 31 non-segregating CNVRs identified in at least 10 individuals within a dense pedigree of the Gochu Asturcelta pig breed was subjected to enrichment and functional annotation analyses to ascertain their functional independence and importance. Enrichment analyses allowed us to annotate 1018 and 351 candidate genes within the bounds of the segregating and non-segregating CNVRs, respectively. The information retrieved suggested that the candidate genes spanned by segregating and non-segregating CNVRs were functionally independent. Functional annotation analyses allowed us to identify nine different significantly enriched functional annotation clusters (ACs) in segregating CNVR candidate genes mainly involved in immunity and regulation of the cell cycle. Up to five significantly enriched ACs, mainly involved in reproduction and meat quality, were identified in non-segregating CNVRs. The current analysis fits with previous reports suggesting that segregating CNVRs would explain performance at the population level, whereas non-segregating CNVRs could explain between-individuals differences in performance.
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PURPOSE: The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib. METHODS: HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1-3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR). RESULTS: A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003-10 (210), and GEICAM-2006-10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%. CONCLUSIONS: This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted. TRIAL REGISTRATION: ClinTrials.gov: GEICAM/9906: NCT00129922; GEICAM/ 2003-10: NCT00129935 and GEICAM/ 2006-10: NCT00543127.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Aminopiridinas/uso terapéutico , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor ErbB-2/genéticaRESUMEN
OBJECTIVE: The goal of this study was to compare erector spinae muscle fatigue, upper limb muscle activity, body areas discomfort, and heart rate during a 10-min carrying task with and without a passive upper-body exoskeleton (CarrySuitâ) while considering sex influences. BACKGROUND: Passive exoskeletons are commercially available to assist lifting or carrying task. However, evidence of their impact on muscle activity, fatigue, heart rate and discomfort are scarce and/or do not concur during carrying tasks. METHOD: Thirty participants (16 females and 14 male) performed a 10-min, 15kg load-carrying task with and without the exoskeleton in two non-consecutive days. Heart rate, and erector spinae, deltoid, biceps and brachioradialis muscle activity were recorded during the carrying tasks. In addition, erector spinae electromyography during an isometric hold test and discomfort ratings were measured before and after the task. RESULTS: While without the exoskeleton upper limb muscle activity increased or remained constant during the carrying task and showing high peak activation for both males and females, a significant activity reduction was observed with the exoskeleton. Low back peak activation, heart rate and discomfort were lower with than without the exoskeleton. In males muscle activation was significantly asymmetric without the exoskeleton and more symmetric with the exoskeleton. CONCLUSION: The tested passive exoskeleton appears to alleviate the physical workload and impact of carrying heavy loads on the upper limbs and lower back for both males and females.
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Dispositivo Exoesqueleto , Femenino , Humanos , Masculino , Frecuencia Cardíaca , Músculo Esquelético/fisiología , Electromiografía , Dorso/fisiología , Músculos Paraespinales , Fenómenos BiomecánicosRESUMEN
Neuroinflammation plays a crucial role in the progression of Alzheimer's disease and other neurodegenerative disorders. Overactivated microglia cause neurotoxicity and prolong the inflammatory response in many neuropathologies. In this study, we have synthesised a series of isatin derivatives to evaluate their anti-neuroinflammatory potential using lipopolysaccharide activated microglia as a cell model. We explored four different substitutions of the isatin moiety by testing their anti-neuroinflammatory activity on BV2 microglia cells. Based on the low cytotoxicity and the activity in reducing the release of nitric oxide, pro-inflammatory interleukin 6 and tumour necrosis factor α by microglial cells, the N1-alkylated compound 10 and the chlorinated 20 showed the best results at 25 µM. Taken together, the data suggest that 10 and 20 are promising lead compounds for developing new neuroprotective agents.
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Isatina , Fármacos Neuroprotectores , Humanos , Antiinflamatorios/farmacología , Microglía/metabolismo , Isatina/farmacología , Enfermedades Neuroinflamatorias , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Óxido Nítrico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fármacos Neuroprotectores/farmacologíaRESUMEN
BACKGROUND: Mitral valve (MV) elongation is a primary hypertrophic cardiomyopathy (HCM) phenotype and contributes to obstruction. The residual MV leaflet that protrudes past the coaptation point is especially susceptible to flow-drag and systolic anterior motion. Histopathological features of MVs in obstructive hypertrophic cardiomyopathy (OHCM), and of residual leaflets specifically, are unknown. OBJECTIVES: The purpose of this study was to characterize gross, structural, and cellular histopathologic features of MV residual leaflets in OHCM. On a cellular-level, we assessed for developmental dysregulation of epicardium-derived cell (EPDC) differentiation, adaptive endocardial-to-mesenchymal transition and valvular interstitial cell proliferation, and genetically-driven persistence of cardiomyocytes in the valve. METHODS: Structural and immunohistochemical staining were performed on 22 residual leaflets excised as ancillary procedures during myectomy, and compared with 11 control leaflets from deceased patients with normal hearts. Structural components were assessed with hematoxylin and eosin, trichrome, and elastic stains. We stained for EPDCs, EPDC paracrine signaling, valvular interstitial cells, endocardial-to-mesenchymal transition, and cardiomyocytes. RESULTS: The residual leaflet was always at A2 segment and attached by slack, elongated and curlicued, myxoid chords. MV residual leaflets in OHCM were structurally disorganized, with expanded spongiosa and increased, fragmented elastic fibers compared with control leading edges. The internal collagenous fibrosa was attenuated and there was collagenous tissue overlying valve surfaces in HCM, with an overall trend toward decreased leaflet thickness (1.09 vs 1.47 mm, P = 0.08). No markers of primary cellular processes were identified. CONCLUSIONS: MV residual leaflets in HCM were characterized by histologic findings that were likely secondary to chronic hemodynamic stress and may further increase susceptibility to systolic anterior motion.