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Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Kawasaki Disease (KD) is a systemic vasculitis of small and medium arteries, preferably affecting coronary arteries. It is one of the most frequent causes of acquired heart disease in children. Despite being comprehensively studied, its etiopathogenesis is not totally explained. The surgical procedures usually become necessary during the late follow-up and may be coronary artery bypass grafting, cardiac defibrillator implantation with or without cardiac resynchronization therapy, or cardiac transplantation.

Apesar da alta frequência de intoxicações na clínica médica de pe­quenos animais, acidentes com anfíbios são considerados emergên­cias médicas devido ao elevado potencial tóxico de seu veneno, o qual tende a direcionar o curso clínico do paciente intoxicado para eventos fisiopatológicos, principalmente cardiovasculares e neuro­lógicos. Este estudo tem por finalidade descrever as principais alte­rações clínicas e laboratoriais observadas em um cão intoxicado por veneno de sapo identificado como sendo Rhinella icterica (Anura: Bufonidae), mediante identificação do anfíbio por imagens obtidas pelos tutores. A instituição precoce das estratégias terapêuticas ime­diatas (estabilização clínica) e tardias (terapia intensiva), assim como o estadiamento de lesões em outros órgãos e sistemas pelos exames complementares realizados de maneira simultânea, caracterizaram-se como essenciais para a melhora no prognóstico do animal.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of personal epigenomes, for ∼25 tissues and >10 assays in four donors (>1500 open-access functional genomic and proteomic datasets, in total). Each dataset is mapped to a matched, diploid personal genome, which has long-read phasing and structural variants. The mappings enable us to identify >1 million loci with allele-specific behavior. These loci exhibit coordinated epigenetic activity along haplotypes and less conservation than matched, non-allele-specific loci, in a fashion broadly paralleling tissue-specificity. Surprisingly, they can be accurately modelled just based on local nucleotide-sequence context. Combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci and enables models for transferring known eQTLs to difficult-to-profile tissues. Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Tumors harbor a complex ecosystem of malignant, immune, and stromal cells. While malignant cells dictate much of the tumor biology, there is evidence that the tumor microenvironment (TME) also plays a major role in disease etiology. Given the complexity and abundance of the TME cellular composition, investigating the role of immune cell types will yield novel biomarkers for tumor progression and response to therapies. The role of B cells as a prognostic biomarker remains elusive. For instance, infiltrating B cells in CRC have both positive and negative prognostic value. Thus, a scalable approach to quantify B cells and the B-cell receptor (BCR) repertoire could yield novel insights into the role of B cells in tumor biology. To address this, we have developed immune cell quantification (InfiltrateID࣪) and immune receptor repertoire profiling (RepertoireID࣪) methods as part of the ImmunoID NeXT Platform®, an augmented, immuno-oncology-optimized exome/transcriptome platform. We estimate B cell abundance and BCR repertoire by profiling FFPE and PBMC samples using ImmunoID NeXT࣪. In expanding upon InfiltrateID to further estimate B cell abundance, here we regress the bulk RNA-seq readout from a reference signature from purified immune cell types. We also generate orthogonal quantifications of B cell abundance by profiling samples with cytometry by time of flight, single-cell RNA-seq, flow cytometry, and immunohistochemistry (IHC). We compare BCR results from ImmunoID NeXT to a standalone sequencing approach to evaluate the concordance of top clones. We then utilize BCR profiling from ImmunoID NeXT to analyze clonality and isotype composition in tumor samples. We first use InfiltrateID to estimate absolute B cell fractions in over 50 samples. Overall, we observe a high correlation between InfiltrateID results and orthogonal data sets in both PBMC and tumor FFPE samples (R2=0.90). When comparing BCR results from RepertoireID to a standalone BCR sequencing method that profiles IgM and IgG, we identify 475 and 387 of the top 500 clones in IgG and IgM, respectively, with highly concordant abundances across all clones (R2>0.72 and R2>0.82 in IgM and IgG, respectively). Next, we use InfiltrateID to estimate absolute B cell fractions in over 650 samples from 14 tumor types. On average, samples display B cell fractions in agreement with the literature and IHC quantifications, with higher B cell fractions in lung, breast, and cervical tumors. We also observe a range of BCR clonality values across tumor types. Finally, we observe differences in B cell composition and repertoire diversity in tumor samples from patients who underwent checkpoint blockade therapy. We show that InfiltrateID and RepertoireID accurately capture the composition and clone diversity of infiltrating B cells in tumor samples. Citation Format: Fabio Navarro, Eric Levy, Pamela Milani, Qiang Li, Shruti Bhide, Upasana Dutta, Charles W. Abbott, Jose Jacob, Rena McClory, John West, John Lyle, Sean Boyle, Richard O. Chen. Accurate quantification of infiltrating B cell composition and clone diversity in tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5021.

e21554 Background: Single modality biomarkers such as tumor mutational burden (TMB) fail to reliably predict response to immune checkpoint blockade (ICB) in part due to their incomplete characterization of complex tumor-immune interactions impacting response. We previously developed the composite biomarker, neoantigen presentation score (NEOPSTM), which integrates neoantigen processing and presentation information and showed it outperformed TMB and other single analyte biomarkers in predicting response in melanoma. Here we combined NEOPS with tumor immune infiltration analysis, and demonstrated further improved patient stratification for ICB response. Methods: We assessed the effect of 17 different immune and stromal cells on NEOPS using logistic regression with interactions in a retrospective cohort of 45 stage III/IV melanoma patients who underwent anti-PD-1 therapy. NEOPS and immune cell infiltration status were both generated using Personalis’ ImmunoID NeXT Platform®. The identified immune-selected phenotype that had a significant effect on NEOPS performance was validated in a cohort of 109 anti-PD1 treated late-stage melanoma patients. Results: The predictive strength of NEOPS was enhanced by considering the infiltration status of 4 distinct immune cell types derived from expression signatures: naïve CD4/CD8 T, exhausted CD8 T, and CD8 T cells. Highly correlated cells were aggregated into naïve (naïve CD4/8 T) and CD8 (exhausted and CD8 T) features. Both features independently boosted the accuracy of NEOPS in the validation cohort (naïve: Pint. = 0.048; CD8: Pint. = 0.11). In immune-selected patients in the validation cohort displaying both high naïve and CD8 features, NEOPS achieved an improved accuracy of 77.2% (vs 69.7% baseline performance, P = 0.013) and an AUC of 0.74 (vs 0.66, P = 0.055). In anti-CTLA4 treatment naïve patients, the immune-selected group attained even better NEOPS performance, with an accuracy of 81.8% (vs 70.6%, P = 0.015) and an AUC of 0.89 (vs 0.68, P = 0.005) in the validation cohort. A separate approach integrating NEOPS with naïve and CD8 features into a single composite biomarker resulted in an AUC of 0.82 (cross validation: 0.78 vs 0.71 baseline). Conclusions: Stratifying immune-selected patients based on cellular composition of the tumor microenvironment significantly increased the accuracy of our neoantigen-based biomarker of ICB response, NEOPS. These data highlight the potential for combining tumor microenvironment information with neoantigen analysis into a composite biomarker to provide more sensitive prediction of immunotherapy response.[Table: see text]

O conhecimento dos padrões de suscetibilidade e resistência dos isolados bacterianos das piometras caninas tem extrema importância do ponto de vista terapêutico, especialmente pela grande incidência desta afecção na espécie e potencial para o desenvolvimento de sepse. O presente trabalho avaliou a frequência dos isolados bacterianos em cadelas durante cinco anos por meio de diagnósticos ultrassonográficos e, subsequentemente, por meio de cultura e antibiograma da secreção uterina. Descreve-se a sensibilidade das bactérias isoladas aos fármacos antimicrobianos empregados com maior frequência na clínica médica e cirúrgica de pequenos animais. Foram analisados 132 prontuários de cadelas pertencentes a 29 raças, ou sem raça definida, que foram os mais prevalentes (14,39%), seguidos de lhasa apso (12,12%) e yorkshire terrier (9,84%). A idade média dos cães foi de 9 anos, e o agente etiológico mais frequente foi Escherichia coli (73,48%), seguido de Staphylococcus spp., Streptococcus spp., Proteus spp., Pseudomonas aeruginosa, Serratia spp., Citrobacter spp., bacilo Gram-negativo não fermentador e Enterococcus spp. A sensibilidade das estirpes isoladas aos antimicrobianos testados corroborou parcialmente a literatura, ressaltando a relevância microbiológica para que o sucesso terapêutico seja atingido.

DESENHO DO ESTUDO: Ensaio Clínico randomizado com avaliador cegado as intervenções. OBJETIVO: foi avaliar os efeitos da realidade virtual como recurso adicional na função dos pacientes com Osteoartrite (OA) de joelho. INTRODUÇÃO: A OA de joelho é uma das doenças ortopédicas mais prevalentes na população idosa, de caráter degenerativo e progressivo que acomete a cartilagem articular, limitando a amplitude de movimento (ADM) articular com rigidez e causando restrições funcionais importantes. A Realidade Virtual (RV) é um dos instrumentos que podem ajudar no processo de reabilitação dos pacientes, motivando e permitindo movimentações e exercícios mais assertivos. MÉTODOS: Noventa pacientes (65 mulheres e 25 homens), entre 50 e 70 anos, com diagnóstico médico de OA em pelo menos um dos joelhos participaram do estudo. Após responderem os questionários Womac e Lequesne, foram avaliados em relação a dor e força muscular. Responderam o Termo de Consentimento e foram divididos aleatoriamente, com envelopes opacos e lacrados, em 3 grupos: Controle que realizou um programa de fisioterapia convencional com exercícios aeróbicos e de fortalecimento muscular; Experimental 1 (Wii) que além do programa convencional fez uso dos jogos do Wii Fit da Nintendo; Experimental 2 (Kinect) que complementou o tratamento convencional com o sistema de vídeo game da Kinect Xbox. RESULTADOS: O estudo revelou redução da dor, melhora da força muscular e função no Questionário Lequesne para todos os grupos após a intervenção (p < .001), entretanto a melhora foi mais acentuada nos grupos Wii e Kinect do que no grupo controle. Quando comparada a dimensão de dor e rigidez, todos os grupos apresentaram reduções significativas no questionário WOMAC A, (p < .001) e somente o Kinect apresentou diferença estatisticamente significante pós intervenção na dimensão CONCLUSÃO: A associação do Vídeo Game no programa de reabilitação de pacientes com OA de joelhos apresenta resultados superiores do que a Fisioterapia convencional. E o recurso Kinect apresentou resultados superiores na função dos pacientes quando comparado ao sistema Wii. Novos estudos, com tecnologias diferentes são essenciais para identificar se os recursos de Realidade Virtual imersiva podem ajudar os pacientes com OA de joelho STUDY DESIGN: Randomized clinical trial. OBJECTIVE: Evaluate the effects of video games associated with conventional physiotherapy in relation to pain relief, muscular strength, and function. INTRODUCTION: Knee OA is one of the most prevalent orthopedic diseases in the adult and elderly populations, with a degenerative and progressive character that affects the articular cartilage, limiting the articular range of motion (ROM) due to rigidity and causing important functional restrictions. Virtual Reality (VR) is one of the instruments that can help in the rehabilitation process of patients, motivating them and enabling more assertive movements. METHOD: Ninety patients (65 women and 25 men) between 50 and 70 years old, with a medical diagnosis of OA in at least one knee participated in the study. After completing the WOMAC (Western Ontario and McMaster Universities Arthritis Index) and Lequesne questionnaires, they were evaluated for pain (Visual Analogical Scale - VAS) and muscle strength (hand-held dynamometer).The volunteers signed the Consent Term and were then randomly divided, using opaque, sealed envelopes, into 3 groups: Control group - performed a conventional physiotherapy program with aerobic and muscle strengthening exercises; Experimental group 1 (Wii) - in addition to the conventional program used Nintendo\'s Wii Fit games; Experimental group 2 (Kinect) - complemented the conventional treatment with the Xbox Kinect video game system. RESULTS: The findings of the study demonstrated reduced pain and improved muscular strength and function in the Lequesne Questionnaire for all groups after the intervention (p < .001), however the improvement was more pronounced in the Wii and Kinect groups than in the control group. When comparing the pain and stiffness dimensions, all groups presented significant reductions in the WOMAC questionnaire, dimension A (p < .001), and only the Kinect presented a statistically significant difference post-intervention in dimension C. CONCLUSION: The association of Video Games in the rehabilitation program of patients with knee OA presents superior results to conventional physiotherapy. In addition, the Kinect feature demonstrated superior results regarding patient performance when compared to the Wii system. New studies using different technology are essential to identify whether immersive Virtual Reality features can help patients with knee OA

Urinary tract infections, which are usually of bacterial origin, are some of the most common disorders in small animal clinics. Female canines are most frequently affected. This study aimed to characterize epidemiological and microbiological aspects of patients and their isolated urinary pathogens through analysis of 836 urine cultures of 462 dogs collected over a nine-year period (2006-2014). Cultures were segregated according to patient history (single or recurrent urinary tract infections). Results suggest that etiological distribution patterns of canine urinary tract infections change according to development time, and that mongrel dogs between 11 and 15 years old are the most affected.

A trombocitopenia imunomediada, destruição plaquetária mediada pelas respostas humoral e celular, é observada com frequência na espécie canina, especialmente nas fêmeas de meia-idade das raças spaniel e Doberman. A primeira linha terapêutica envolve a administração de corticoides em doses imunossupressoras e, nos casos refratários, a associação farmacológica a outros agentes imunomoduladores faz-se necessária. A presente descrição de caso objetiva relatar o sucesso na associação do sulfato de vincristina à corticoideterapia (Dexametasona), durante o período de hospitalização de cão com trombocitopenia imunomediada primária e sangramentos espontâneos relacionados, bem como discutir as modalidades terapêuticas presentes na literatura.

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, and strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three human parent–child trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (

The objective of this study was to determine the efficacy of a modified Shannon trap to capture adult insects that are involved in cadaveric decomposition processes. The Shannon trap proposed here is composed of a thin fabric tent with a top formed by a transparent bottle containing a compartment filled with alcohol gel on which the captured insects are affixed. The trap was effective both for weather resistance and the quantity, quality and diversity of insects caught.

Introduction: The evaluation of changes in joint position sense (JPS) of the knee may be crucial for the identification of disorders that could start during the development of patellofemoral pain syndrome (PFPS). Objective: To evaluate JPS of the knee in PFPS. Methods: Twenty nine women (15 healthy and 14 with PFPS) reproduced knee flexion angles of 45° and 60° during open kinetic chain exercises and of 45° during closed kinetic chain exercises. Results: The absolute error in the active reproduction of 45° in open kinetic chain exercises was significantly higher in the experimental group. There were significant differences in absolute and relative errors between the groups for active reproduction at 45° in open and closed kinetic chain exercises. Conclusions: This study suggests that PFPS alters JPS during active reproduction of the 45° angle in both open and closed kinetic chain exercises.

Relatamos o caso de paciente do sexo feminino, com 32 anos de idade, com sintomas álgicos na região occipital, compressivos de forte intensidade e com irradiação frontal, supraorbitária e orbitária esquerda, relacionada a movimentos de flexão e extensão do pescoço, com característica lancinante e duração de até 9 segundos. A investigação radiológica, clínica, neurocirúrgica e neuropatológica evidenciou um meduloblastoma que aderia à membrana tentorial promovendo espessamento e compressão das estruturas venosas desta região. Atribuímos ao estímulo mecânico sobre estas estruturas vasculares tentoriais as manifestações álgicas envolvendo as conexões entre o trigêmeo e os primeiros segmentos medulares cervicais.

Introduction: Performing dual task for neurological patients is complex and it can be influenced by the localization of the neurological lesion. Objective: Comparing the impact of dual task on gait in patients with Parkinson's disease, stroke and ataxia. Method: Subjects with Parkinson's disease (PD) in initial phase, stroke and ataxia, with independent gait, were evaluated while doing simple gait, with cognitive, motor and cognitive-motor gait demand, assessing average speed and number of steps. Results: Ataxia and stroke patients, compared with PD, showed an increase in the number of steps and decrease the average speed on the march with cognitive demand. Subjects with PD performed better on tasks when compared to others. Conclusion: In this study the impact of dual task was lower in Parkinson's disease patients. Introdução: A realização de dupla tarefa para pacientes neurológicos é considerada complexa e pode ser determinada pela topografia da lesão neurológica. Objetivo: Comparar o impacto da dupla tarefa na marcha de pacientes com Doença de Parkinson em fase inicial (DP), Acidente Vascular Cerebral(AVC) e Ataxia. Método: Sujeitos com DP em fase inicial, AVC e Ataxia cerebelar, com marcha independente, foram avaliados realizando marcha simples, com demanda cognitiva, com demanda motora e com demanda cognitivo-motora, mensurando-se velocidade média e número de passos. Resultados: Os atáxicos e AVE comparados com os DP, apresentaram aumento do número de passos e diminuição da velocidade média na marcha com demanda cognitiva. Os sujeitos com DP apresentaram melhor desempenho nas tarefas comparados aos demais. Conclusão: O impacto da dupla tarefa apresentou-se menor nos pacientes com DP.

RESUMO Introdução: As disfunções temporomandibulares têm sido objeto de estudo crescente, no entanto, estão somente relacionadas com a má oclusão bucal, lesões por contato nos esportes, entre outros. Neste estudo, uma nova visão das disfunções foi observada, uma vez que a analise eletromiográfica dos músculos masseteres foi coletada durante o gesto esportivo da rebatida do baseball, o que pode possibilitar a verificação de possíveis alterações funcionais das disfunções. Objetivo: Analisar a atividade elétrica do músculo masseter em atletas de beisebol durante realização do gesto esportivo de rebatida. Materiais e Métodos: Foram avaliadas 5 atletas de beisebol, sexo feminino, idade média de 21 anos, selecionadas para a seleção brasileira a disputar o pan-americano 2007, sem lesões previas ou disfunções diagnosticadas. Cada atleta realizou 5 repetições do gesto esportivo enquanto a atividade eletromiográfica dos masseteres eram coletadas com eletromiógrafo. Resultados: Após análise estatística dos dados, foi observado que as atletas realizam uma contração dos músculos masseteres durante o gesto esportivo de rebatida estatisticamente significativa com p > 0,5 utilizando Teste-t. Sendo que duas das cinco atletas avaliadas, apresentaram uma atividade elétrica do músculo muito diferente da média, sendo uma bem acima e outra bem abaixo da média do grupo. Discussão: VIERA 1997 afirma que o desequilíbrio muscular é um fator gerador e agravante de disfunção temporomandibular. Em nosso estudo foi notado esse desequilíbrio entres os masseteres direito e esquerdo de forma que em uma das atletas a atividade elétrica média do lado direito é quase o dobro do valor captado no lado esquerdo. Conclusão: As atletas realizaram contração muscular do músculo masseter durante o gesto esportivo e o desequilíbrio muscular entre os dois músculos masseteres teve uma diferença significativa, o que em longo prazo pode causar uma disfunção temporomandibular.

Introdução. A Esclerose Múltipla (ME) é uma desordem neurológica progressiva degenerativa da bainha de mielina, que compromete a substância branca do Sistema Nervoso Central, afetando o controle motor, principalmente a marcha. O objetivo deste trabalho foi avaliar pacientes portadores de EM a fim de estabelecer a correlação entre o recrutamento muscular, força e a velocidade de marcha, compa­rado a um grupo controle. Método. Para o grupo experimental fo­ram selecionados 7 indivíduos portadores de EM, e o grupo controle formado de 7 indivíduos saudáveis. Foi utilizada uma plataforma de 10m, mensurada a velocidade de marcha, além do recrutamento do músculo tibial anterior durante a mesma. Resultados. Observou-se redução importante na velocidade de marcha auto-selecionada e acelerada (p=0,017 e 0,009) e aumento significativo no recrutamento muscular durante a marcha auto-selecionada e acelerada (p

International audience; Bovine leptospirosis causes substantial reproductive failure in cattle, mainly due to infections with serovar (sv) Hardjo infection. Notwithstanding, other serovars from the serogroup (sg) Sejroe could also have important roles in bovine leptospirosis. The objective was to investigate genetic diversity of serogroup Sejroe isolates obtained from asymptomatic cattle in the state of Rio de Janeiro, Brazil. Urine and vaginal fluid (VF) were collected from clinically healthy cattle immediately after slaughter. Five isolates were recovered and characterized (serogrouping) as belonging to sg Sejroe. Sequencing of rrs and secY genes further identified them as Leptospira santarosai. Analysis of secY sequences indicated a high level of sequence homology to sv Guaricura strains. Based on culture and sequence data, we inferred that other members of sg Sejroe may be important in bovine leptospiral infection, particularly genotypes of L. santarosai serovar Guaricura.