[Reference levels of thyroid hormones in pregnant woman from Guadalajara]. / Valores de referencia de hormonas tiroideas en la población de gestantes de Guadalajara.

INTRODUCTION: Thyroid dysfunction during gestation impacts on maternal-fetal health and may influence the neurocognitive development of the child. Thyroid physiology changes during pregnancy and requires the establishment of specific reference levels per trimester and for each population and method. The objectives of our study were to analyse thyroid function throughout pregnancy and to establish reference levels for TSH and T4L in each trimester for our population and methodology. MATERIAL AND METHODS: Prospective analytical study of 598 pregnant women from March 2018 to October 2020. TSH, T4L, T3L, ATPO and ATG were determined in all of them. A total of 151 pregnant women were excluded due to positive thyroid immunity, previous thyroid disease in treatment with levothyroxine, twin pregnancy, diagnosis of hypothyroidism and hyperthyroidism in the request or absence of some of the parameters studied, with a reference population of 447 pregnant women. RESULTS: The reference levels for TSH were 0.07-3.14mIU/L for the first, 0.66-3.21mIU/L for the second and 0.52-2.97mIU/L for the third trimester. Reference levels for T4L were 0.81-1.19ng/dL for the first, 0.71-1.07ng/dL for the second and 0.69-1.06ng/dL for the third trimester. CONCLUSIONS: The reference levels for TSH and T4L obtained in this study differ from those used for the general population, which may have led to misclassification errors and unnecessary treatment in pregnant women.

Allergy to cypress and olive pollen: Clinical phenotypes and allergen recognition.

BACKGROUND AND OBJECTIVES: Cypress and olive pollen are the most prevalent sensitizer trees in the Mediterranean area. Some patients exhibit a dual sensitization which has not been well documented yet. To identify the allergens involved in the dual cypress and olive allergy (C+O) and study the relationship between phenotype and allergen sensitization. METHODS: C+O patients were selected. Monosensitized subjects to olive or cypress were used as reference. Specific IgE to whole extracts and purified allergens from olive and cypress were performed. Immunoblotting was done to analyze IgG and IgE-binding using olive polyclonal antibodies and patients' sera, respectively. Mutual immunoblotting inhibition of olive and cypress extracts, and inhibition of cypress extract immunoblotting with olive allergens were performed. Multiple correspondence analysis and hierarchical cluster classifications were conducted to analyze the relationships between C+O clinical presentation (symptoms, seasonality) and allergen profile. RESULTS: C+O patients were clustered in 4 phenotypes. The most frequent one (58.4%) was rhinoconjunctivitis in winter (February) and spring (May), with asthma in 38% of subjects. Ole e 1 and Cup s 1 were the major allergens. Homologous proteins to Ole e 1, Ole e 9 and Ole e 11 in cypress pollen were identified and these olive allergens inhibit IgE-binding to cypress extract. CONCLUSIONS: The exclusive C+O allergy results from co-sensitization to Cup s 1 and Ole e 1, and to cross-reactivity due to Ole e 1-like, Ole e 9-like and Ole e 11-like allergens not described previously, and translates into 4 clinical phenotypes of winter and/or spring or perennial rhinoconjunctivitis with and without asthma.

Cytomegalovirus reactivation in patients diagnosed with severe COVID-19: A point prevalence study in a general hospital.

OBJECTIVE: To determine the prevalence of CMV reactivation in a population admitted for severe COVID-19 to a general hospital. METHODS: Point prevalence study in all hospitalized patients with severe COVID-19 (admitted either to general wards or ICU). Determination of the presence of CMV DNA in circulating blood. COVID-19 was confirmed in patients with compatible clinical manifestations, usually with pneumonia and a positive nasopharyngeal PCR test. RESULTS: We included 140 hospitalized patients with COVID-19 who consented to participate. A total of 16 patients (11.42%), had circulating CMV-DNA in peripheral blood at the time of the study. Patients with positive CMV viral load were mainly ICU patients (11/37 -29,7%) and only 5/103 cases (4,85%) were hospitalized into general wards. The accumulated doses of corticosteroids (prednisone equivalents) in the study day were (median and IQR) 987.50 mg (396.87-2,454.68) and 187.50 mg (75.00-818.12) respectively in CMV positive and negative patients (p < 0.001). A significant proportion of CMV positive patients were discovered because of the study and were clinically unsuspected by their physicians. The coinfected COVID-CMV positive population had a higher risk of accumulated secondary nosocomially-acquired infections and a worse prognosis. CONCLUSIONS: CMV reactivation should be systematically searched in patients in COVID-19 cases admitted to the ICU.

Transient high-grade second-degree atrioventricular block secondary to transvenous atrial septal defect occlusion in a dog.

A 1.2-year-old male-intact Standard Poodle underwent transvenous placement of an Amplazter™ atrial septal occluder for correction of a large secundum atrial septal defect. Thirty-six hours post-operatively, the dog developed high-grade Mobitz type II second-degree atrioventricular block, which resolved with time and corticosteroid administration by 12 days after the procedure. This case report outlines the observation, treatment, and resolution of high-grade Mobitz type II second-degree atrioventricular block, a known complication of atrial septal occluder placement in humans, not previously reported in veterinary literature.

Effect of antibiotics on mechanical properties of Bordetella pertussis examined by atomic force microscopy.

In recent years, the coevolution of microorganisms with current antibiotics has increased the mechanisms of bacterial resistance, generating a major health problem worldwide. Bordetella pertussis is a bacterium that causes whooping cough and is capable of adopting different states of virulence, i.e. virulent or avirulent states. In this study, we explored the nanomechanical properties of both virulent and avirulent B. pertussis as exposed to various antibiotics. The nanomechanical studies highlighted that only virulent B. pertussis cells undergo a decrease in their cell elastic modulus and height upon antimicrobial exposure, whereas their avirulent counterparts remain unaffected. This study also permitted to highlight different mechanical properties of individual cells as compared to those growing in close contact with other individuals. In addition, we analyzed the presence on the bacterial cell wall of Filamentous hemagglutinin adhesin (FHA), the major attachment factor produced by virulent Bordetella spp., under different virulence conditions by Force Spectroscopy.

Association Between the Seed Storage Proteins 2S Albumin and 11S Globulin and Severe Allergic Reaction After Flaxseed Intake.

BACKGROUND: Given the increased popularity of flaxseed in meals, several cases of allergy to these seeds have been reported. Little is known about the allergens implicated in hypersensitivity reactions to flaxseed. The present study aimed to identify the allergens involved in IgE-mediated reactions in 5 patients with a clinical history of severe systemic symptoms after flaxseed consumption. METHODS: Proteins that were potential allergens with IgE-binding capacity were purified from flaxseed extract using chromatography and identified via MALDI-TOF mass spectrometry. Immunoassays were performed using the 5 allergic patients' sera tested individually and as a pool. RESULTS: Immunoblotting of the flaxseed extract revealed a low-molecular-mass protein (around 13 kDa) in 4 of the 5 patients, while a protein of approximately 55 kDa was detected in 2 patients. The proteins were identified by mass spectrometry as flaxseed 2S albumin, which is included in the WHO/IUIS allergen nomenclature as Lin u 1, and 11S globulin. Inhibition assays revealed in vitro IgE-mediated cross-reactivity between Lin u 1 and peanut and cashew nut proteins, while IgE-mediated recognition of 11S globulin by patients' sera was partially inhibited by several plant-derived sources. CONCLUSIONS: Seed storage proteins from flaxseed were involved in the development of severe symptoms in the 5 patients studied and exhibited cross-reactivity with other allergenic sources. Besides the severity of flaxseed allergy in patients sensitized to 2S albumin, this is the first time that 11S globulin has been identified as a potential allergen. Taking these data into account should ensure a more accurate diagnosis.

Unraveling the Diagnosis of Kiwifruit Allergy: Usefulness of Current Diagnostic Tests.

OBJECTIVES: To determine the usefulness of the in vitro and in vivo methods used in the diagnosis of kiwifruit allergy and to specifically assess the impact of seed proteins on sensitivity. METHODS: We performed skin prick tests (SPTs) using various commercial extracts, homemade pulp, and seed extracts and prick-prick tests with kiwifruit on 36 allergic patients. The presence of specific IgE (sIgE) was assessed using the ImmunoCAP (kiwifruit extract), ELISA (Act d 1, Act d 2), ISAC, and FABER assays. Immunoblotting of seed extract was carried out, and a single-blind oral food challenge was performed with whole seeds in seed-sensitized individuals. RESULTS: The prick prick test with kiwifruit demonstrated the highest diagnostic capacity (81.8% sensitivity and 94.1% specificity) among the in vivo tests. The sIgE levels measured using ImmunoCAP (kiwifruit extract) showed a similar sensitivity to that of global ISAC and FABER (63.9%, 59.5%, and 58.3%, respectively). Act d 1 was the major allergen. Sensitization to Act d 1 was associated with positive sIgE results to whole kiwifruit extract detected by ImmunoCAP (P<.000). A positive SPT result to kiwifruit seeds was associated with severe symptoms induced by kiwifruit (P=.019) as a marker of advanced disease, but not with clinically relevant sensitization. Challenge testing with kiwifruit seeds performed on 8 seed-sensitized patients yielded negative results. CONCLUSION: Sensitization to Act d 1 is associated with a positive result in conventional diagnostic techniques, whereas kiwifruit seed sensitization does not increase the sensitivity of the diagnostic techniques evaluated.

Association Between the Seed Storage Proteins 2S Albumin and 11S Globulin and Severe Allergic Reaction After Flaxseed Intake

Background: Given the increased popularity of flaxseed in meals, several cases of allergy to these seeds have been reported. Little is known about the allergens implicated in hypersensitivity reactions to flaxseed. The present study aimed to identify the allergens involved in IgE-mediated reactions in 5 patients with a clinical history of severe systemic symptoms after flaxseed consumption. Methods: Proteins that were potential allergens with IgE-binding capacity were purified from flaxseed extract using chromatography and identified via MALDI-TOF mass spectrometry. Immunoassays were performed using the 5 allergic patients’ sera tested individually and as a pool. Results: Immunoblotting of the flaxseed extract revealed a low-molecular-mass protein (around 13 kDa) in 4 of the 5 patients, while a protein of approximately 55 kDa was detected in 2 patients. The proteins were identified by mass spectrometry as flaxseed 2S albumin, which is included in the WHO/IUIS allergen nomenclature as Lin u 1, and 11S globulin. Inhibition assays revealed in vitro IgE-mediated cross-reactivity between Lin u 1 and peanut and cashew nut proteins, while IgE-mediated recognition of 11S globulin by patients’ sera was partially inhibited by several plant-derived sources. Conclusions: Seed storage proteins from flaxseed were involved in the development of severe symptoms in the 5 patients studied and exhibited cross-reactivity with other allergenic sources. Besides the severity of flaxseed allergy in patients sensitized to 2S albumin, this is the first time that 11S globulin has been identified as a potential allergen. Taking these data into account should ensure a more accurate diagnosis. (AU)

Antecedentes: Dada la creciente popularidad de la linaza en las comidas, se han notificado varios casos de alergia a estas semillas. La información acerca de los alérgenos implicados en las reacciones de hipersensibilidad a estas semillas es escasa. El presente trabajo pretende identificar los alérgenos implicados en las reacciones mediadas por IgE en cinco pacientes con una historia clínica de síntomas sistémicos graves tras el consumo de linaza. Métodos: Las proteínas susceptibles de ser alérgenos con capacidad de unir IgE se purificaron a partir del extracto de linaza mediante técnicas cromatográficas. Su identificación se realizó mediante espectrometría de masas MALDI-TOF. Se realizaron inmunoensayos con los sueros de los cinco pacientes alérgicos, utilizados de forma individual o como mezclas. Resultados: Cuatro de los cinco pacientes reconocieron una proteína de baja masa molecular (alrededor de 13 kDa) en inmunoensayos con extracto de linaza, mientras que dos pacientes reconocieron una proteína de aproximadamente 55 kDa. Se identificaron por espectrometría de masas como albúmina 2S de linaza, incluida en la nomenclatura de alérgenos de la OMS/IUIS como Lin u 1, y globulina 11S, respectivamente. Los ensayos de inhibición in vitro revelaron la existencia de reactividad cruzada de la Lin u 1 con las proteínas del cacahuete y del anacardo, mientras que el reconocimiento por parte de la IgE de la globulina 11S por parte de los sueros de los pacientes fue parcialmente inhibido por varias fuentes vegetales. Conclusiones: Las proteínas de almacenamiento de las semillas de lino estaban implicadas en el desarrollo de síntomas graves en cinco individuos y mostraron una reactividad cruzada con otras fuentes alergénicas. Además de la gravedad de la alergia a la linaza en los pacientes sensibilizados a la albúmina 2S, es la primera vez que se identifica la globulina 11S como un alérgeno potencial.

Lactic acid bacteria biofilms and their ability to mitigate Escherichia coli O157:H7 surface colonization.

Lactic acid bacteria (LAB) exert antagonistic activities against diverse microorganisms, including pathogens. In this work, we aimed to investigate the ability of LAB strains isolated from food to produce biofilms and to inhibit growth and surface colonization of Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 at 10°C. The ability of 100 isolated LAB to inhibit EHEC O157:H7 NCTC12900 growth was evaluated in agar diffusion assays. Thirty-seven LAB strains showed strong growth inhibitory effect on EHEC. The highest inhibitory activities corresponded to LAB strains belonging to Lactiplantibacillus plantarum, Pediococcus acidilactici and Pediococcus pentosaceus species. Eighteen out of the 37 strains that showed growth inhibitory effects on EHEC also had the ability to form biofilms on polystyrene surfaces at 10°C and 30°C. Pre-established biofilms on polystyrene of four of these LAB strains were able to reduce significantly surface colonization by EHEC at low temperature (10°C). Among these four strains, Lact. plantarum CRL 1075 not only inhibited EHEC but also was able to grow in the presence of the enteric pathogen. Therefore, this strain proved to be a good candidate for further technological studies oriented to its application in food-processing environments to mitigate undesirable surface contaminations of E. coli.

[Evolution of antimicrobial resistance and mortality in Staphylococcus aureus endocarditis during 15 years in a university hospital]. / Evolución de la resistencia antimicrobiana y mortalidad en la endocarditis por Staphylococcus aureus durante 15 años en un hospital universitario.

OBJECTIVE: One of the most aggressive microorganisms in infective endocarditis (IE) is Staphylococcus aureus. We analyse the resistance of S. aureus to antibiotics and its impact on the clinical course of IE in a recent 15-year period. METHODS: Retrospective study of patients with IE in a university hospital from 2005 to 2019. Bivariate and multivariate analysis of severity at admission, comorbidities, minimum inhibitory concentrations (MIC) and mortality. RESULTS: Of the 293 IE cases, 66 (22.5%) were due to S. aureus, and 21 (7.2%) were methicillin-resistant S. aureus (MRSA). The prevalence of strains with a MIC to vancomycin ≥ 1mg/L increased from 4.8% to 63.6% (p <0.001) and the cases of MRSA from 38 to 27.3% (p = 0.045). Older age (p= 0.02), comorbidity (p <0.01) and nosohusial origin (p = 0.01), were factors associated with MRSA. But the antimicrobial resistance and severity on admission were not associated with exitus; predictive factors were the right-sided IE (OR = 0.08; 95% CI: 0.01-0.51), comorbidities (OR per Charlson index point = 1.30; 95% CI: 1.01-1.69) and creatinine on admission (OR per mg / dL = 1.56; 95% CI = 1.01- 2.35; p = 0.04). CONCLUSIONS: We have experienced an increase in IE cases with MIC to vancomycin ≥ 1mg/L, without significant variation in infections due to MRSA. Antimicrobial resistance was not associated with mortality, but comorbidity and left involvement were predictive factors.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases.

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy. (AU)

Las Redes Temáticas de Investigación Cooperativa en Salud (RETICS) son unas estructuras organizativas promovidas por el Instituto de Salud Carlos III del Ministerio de e Sanidad, Consumo y Bienestar Social con el objetivo de llevar a cabo proyectos de investigación colaborativos que aborden desafíos de interés general para la sociedad en el campo de la salud. La RETICS de Asma, Reacciones Adversas a Fármacos y Alérgicas (ARADyAL) comenzó en 2016 y fue financiada por un periodo de 5 años (2017-2021). ARADyAL integra la investigación básica y clínica en diferentes áreas de conocimiento, alergia, inmunología, genética, nanomedicina, farmacología y química, con especial interés en la investigación de nuevos biomarcadores, y el diseño y evaluación de nuevas estrategias de intervención para pacientes alérgicos con fenotipos graves. El consorcio está compuesto por 28 grupos de toda España, que incluyen 171 investigadores clínicos y básicos: 17 grupos clínicos que cubren a más de 10.000.000 de pacientes de todas las edades y de áreas tanto urbanas como rurales; 11 grupos básicos que desarrollan sus actividades principalmente en universidades e institutos de investigación. ARADyAL propone un programa de investigación organizado en tres áreas diferentes centradas en la medicina de precisión: Programa 1. Mecanismos y predicción de reacciones adversas a medicamentos y enfermedades alérgicas; Programa 2. Hacia un diagnóstico preciso de enfermedades alérgicas; y Programa 3. Predicción de intervenciones en enfermedades alérgicas. Además, hay un programa transversal dedicado a la formación. La red cuenta con un Comité de Dirección y un Comité Científico Asesor Externo, que asesoran a la coordinadora de la red la cual tiene experiencia reconocida en el campo. ARADyAL es un punto de encuentro único para médicos y científicos básicos que ya están trabajando en alergias.

First electrochemical immunosensor for the rapid detection of mustard seeds in plant food extracts.

This paper describes the first biosensor reported to date for the determination of mustard seed traces. The biosensor consists of an amperometric immunosensing platform able to sensitively and selectively determine Sin a 1 content, the major allergen of yellow mustard and the most abundant protein of these seeds. The immunosensing platform exploits the coupling of magnetic microbeads (MBs) modified with sandwich-type immune complexes, comprising polyclonal and monoclonal antibodies, selective to the target protein for its capturing and detection, respectively. In addition, a HRP-conjugated secondary antibody was used for enzymatic labelling of the monoclonal antibody, and amperometric transduction was made at screen-printed carbon electrodes (SPCEs) using the hydroquinone (HQ)/H2O2 system. The electrochemical immunosensor allows the simple and fast detection (a single 1-h incubation step) of Sin a 1 with a limit of detection of 0.82 ng mL-1 (20.5 pg of protein in 25 µL of sample) with high selectivity against structurally similar non-target allergenic proteins (such as Pin p 1 from pine nut). The developed immunoplatform was successfully used for the analysis of peanut, rapeseed, cashew, pine nut and yellow mustard extracts, giving only positive response for the yellow mustard extract with a Sin a 1 content, in full agreement with that provided by conventional ELISA methodology.

Mucocele apendicular como hallazgo casual en prueba de imagen / Appendicular mucocele as an incidental finding on imaging test

El mucocele apendicular (MA) es una entidad poco frecuente. Su incidencia sitúa entre el 0,2 y 0,4% de todas las apendicectomías y del 8 al 10% de todos los tumores apendiculares. El término mucocele consiste en la dilatación del apéndice causada por la producción moco, secundario a un proceso benigno o maligno (cistoadenoma o cistoadenocarcinoma). Presentamos el caso de una paciente de 63 años de edad asintomática y que en el estudio por sospecha de hidronefrosis izquierda se encontró como hallazgo en la ecografía de abdomen, una imagen sugerente de mucocele apendicular que se constató en la tomo-grafía computarizada (TC). Se realizó una apendicectomía laparoscópica. El estudio histológico mostró un mucocele apendicular con bordes libres y sin signos de malignidad. Un año después de la intervención la paciente está libre de enfermedad y de otro proceso asociado. El propósito del presente estudio es el de realizar una revisión relacionada con la incidencia, manifestaciones clínicas, métodos diagnósticos, tratamiento, evolución, diagnóstico diferencial y anatomopatológico

Appendicular mucocele (AM) is a rare entity. Its frequency is estimated between 0.2 and 0.4% of all appendectomies and 8 to 10% of all appendicular tumors. The term mucocele refers to the dilation of the appendix by mucus, caused by a benign or malignant process (cystadenoma or cystadenocarcinoma).We present the case of an asymptomatic 63-year-old patient who, in the study of suspected left hydronephrosis, found an image suggestive of appendicular mucocele as a finding on abdominal ultrasound, which was confirmed by computed tomography (CT). A laparoscopic appendectomy was performed. The histological study showed an appendicular mucocele without malignancy and free edges. One year after the intervention, the patient is free of disease and of another synchronous or metachronous process. The purpose of the present study is to carry out a review regarding the incidence, clinical manifestations, diagnostic methods, treatment, evolution and pathological diagnosis

Incorporation of fragmented visuo-olfactory episodic memory into dreams and its association with memory performance.

The question of a possible link between dream content and memory consolidation remains open. After a comprehensive review of the literature, we present novel findings from an experiment testing whether the incorporation of recently learned stimuli into dream reports is associated with improved post-sleep memory performance. Thirty-two high dream recallers freely explored new visuo-olfactory episodes for 3 consecutive days. During the nights following each non-explicit encoding, participants wore a wrist actimeter, and woke up at 5am and their usual waking time to record their dreams (intensity of all oneiric sensory perception was assessed using scales). A total of 120 dreams were reported and elements related to the encoding phase were identified in 37 of them, either learning-related (mainly visual- and rarely olfactory-related elements), or experiment-related (lab- or experimenters-related elements). On the 4th day, we found that participants with learning-related (n = 16) and participants with learning-related and/or experiment-related dreams (n = 21) had similar odor recognition and odor-evoked episodic memory with the other participants. However, they had significantly better visuo-spatial memory of the episodes in comparison to the other participants. Our results support the hypothesis that the learning phase is loosely incorporated into dreams and that this incorporation is associated with sleep related memory consolidation.

Analysis of lambing distribution in the Ripollesa sheep breed. II. Environmental and genetic sources of variation.

Seasonal reproduction patterns are typically observed in small ruminants and are a major limitation for production efficiency in most meat- and dairy-type production systems. Indeed, selection for reduced seasonality could be an appealing strategy for the small ruminant industry worldwide, although its genetic background has been poorly analyzed. One of the main limitations relied on the availability of appropriate analytical tools to cope with the circular (i.e. year-round) pattern of lambing and kidding data. The recent development of a heteroskedastic circular mixed model provided the statistical tool to go deeply into the knowledge of seasonality in small ruminants. In this study, 26 005 lambing distribution records from 4764 Ripollesa ewes collected in 20 purebred flocks were analyzed. The model accounted for systematic (lambing interval and ewe age), permanent environmental (flock-year-season and ewe) and additive genetic sources of variation influencing both mean and dispersion pattern (i.e. heteroskedasticity). Systematic effects suggested that first-lambing ewes and short lambing intervals delayed lambing date (~30 days) and increased dispersion of the lambing period. Nevertheless, this was partially compensated by ewe age, given that youngest females tended to concentrate the lambing peak. Flock-year-season, permanent ewe and additive genetic sources of variation reached moderate variance components for direct (and residual) effects on lambing distribution, they being 0.119 (0.156), 0.092 (0.132) and 0.195 (0.170) radians2, respectively. Moreover, all 95% credibility intervals were placed far from the null estimate. Covariances between direct and residual effects where high and positive for additive genetic (posterior mean, 0.814) and permanent ewe effects (posterior mean, 0.917), whereas it was not relevant for flock-year-season. Selection for direct additive genetic effects should be able to advance or delay the lambing peak, whereas selection applied on residual additive genetic effects should increase or reduce seasonality (i.e. concentrate or flatten the lambing peak). Moreover, the positive and relevant genetic covariance between direct and residual effects also suggested correlated genetic responses. As example, genetic selection for earlier lambing peaks must also reduce seasonality, whereas selection for narrower lambing seasons may originate a delay in the lambing peak. These results must be viewed as the first attempt to analyze systematic, environmental and genetic sources of variation of lambing distribution within the circular paradigm, they providing a reliable characterization of these effects within the context of an heteroskedastic model.

Analysis of lambing distribution in the Ripollesa sheep breed. I. Development and comparison of circular von Mises models.

Circular data originates in a wide range of scientific fields and can be analyzed on the basis of directional statistics and special distributions wrapped around the circumference. However, both propensity to transform non-linear to linear data and complexity of directional statistics limited the generalization of the circular paradigm in the animal breeding framework, among others. Here, we generalized a circular mixed (CM) model within the context of Bayesian inference. Three different parametrizations with different hierarchical structures were developed on basis of the von Mises distribution; moreover, both goodness of fit and predictive ability from each parametrization were compared through the analyses of 110 116 lambing distribution records collected from Ripollesa sheep herds between 1976 and 2017. The naive circular (NC) model only accounted for population mean and homogeneous circular variance, and reached the lowest goodness-of-fit and predictive ability. The CM model assumed a hierarchical structure for the population mean by accounting for systematic (ewe age and lambing interval) and permanent environmental sources of variation (flock-year-season and ewe). This improved goodness of fit by reducing both the deviance information criterion (DIC; -2520 units) and the mean square error (MSE; -12.4%) between simulated and predicted lambing data when compared against the NC model. Finally, the last parametrization expanded CM model by also assuming a hierarchical structure with systematic and permanent environmental factors for the variance parameter of the von Mises distribution (i.e. circular canalization (CC) model). This last model reached the best goodness of fit to lambing distribution data with a DIC estimate 5425 units lower than the one for NC model (MSE reduced 13.2%). The same pattern revealed when models were compared in terms of predictive ability. The superiority revealed by CC model emphasized the relevance of heteroskedasticity for the analysis of lambing distribution in the Ripollesa breed, and suggested potential applications for the sheep industry, even genetic selection for canalization. The development of CM models on the basis of the von Mises distribution has allowed to integrate flexible hierarchical structures accounting for different sources of variation and affecting both mean and dispersion terms. This must be viewed as a useful statistical tool with multiple applications in a wide range of research fields, as well as the livestock industry. The next mandatory step should be the inclusion of genetic terms in the hierarchical structure of the models in order to evaluate their potential contribution to current selection programs.