Enhancing drug and cell line representations via contrastive learning for improved anti-cancer drug prioritization.

Due to cancer's complex nature and variable response to therapy, precision oncology informed by omics sequence analysis has become the current standard of care. However, the amount of data produced for each patient makes it difficult to quickly identify the best treatment regimen. Moreover, limited data availability has hindered computational methods' abilities to learn patterns associated with effective drug-cell line pairs. In this work, we propose the use of contrastive learning to improve learned drug and cell line representations by preserving relationship structures associated with drug mechanisms of action and cell line cancer types. In addition to achieving enhanced performance relative to a state-of-the-art method, we find that classifiers using our learned representations exhibit a more balanced reliance on drug- and cell line-derived features when making predictions. This facilitates more personalized drug prioritizations that are informed by signals related to drug resistance.

Diaphragm thickness and mobility elicited by two different modalities of inspiratory muscle loading in heart failure participants: A randomized crossover study.

OBJECTIVES: To analyze diaphragmatic thickness, at end-inspiration and end-expiration, diaphragmatic thickening index and mobility via US under two different modalities of inspiratory muscle loading, in two different modalities of inspiratory muscle loading and different load intensities at full-vital capacity maneuvers and the relationship between diaphragmatic thickness with pulmonary function tests in participants with HF. METHODS: This randomized crossover trial, enrolled with 17 HF subjects, evaluated diaphragm thickness (Tdi, mm), fractional thickness (TFdi, %), and mobility (mm) US during low and high intensities (30% and 60% of maximal inspiratory pressure-MIP) with two modalities of inspiratory muscle loading mechanical threshold loading (MTL) and tapered flow-resistive loading (TFRL). RESULTS: Both MTL and TFRL produced a increase in Tdi, but only with high intensity loading compared to baseline-2.21 (0.26) vs. 2.68 (0.33) and 2.73 (0.44) mm; p = .01. TFdi was greater than baseline under all conditions, except during low intensity of TFRL. Diaphragm mobility was greater than baseline under all conditions, and high intensity of TFRL elicited greater mobility compared to all other conditions. Additionally, baseline Tdi was moderately correlated with pulmonary function tests. CONCLUSIONS: MTL and TFRL modalities elicit similar increases in diaphragm thickness at loads, but only during high intensity loading it was greater than baseline. Diaphragm mobility was significantly greater than baseline under both loads and devices, and at high intensity compared to low intensity, although TFRL produced greater mobility compared to modalities of inspiratory muscle loading. There is an association between diaphragm thickness and pulmonary function tests.

Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.

BACKGROUND: Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood. METHODS: Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay. RESULTS: A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity. CONCLUSIONS: We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities. IMPACT: Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

Modeling Path Importance for Effective Alzheimer's Disease Drug Repurposing.

Recently, drug repurposing has emerged as an effective and resource-efficient paradigm for AD drug discovery. Among various methods for drug repurposing, network-based methods have shown promising results as they are capable of leveraging complex networks that integrate multiple interaction types, such as protein-protein interactions, to more effectively identify candidate drugs. However, existing approaches typically assume paths of the same length in the network have equal importance in identifying the therapeutic effect of drugs. Other domains have found that same length paths do not necessarily have the same importance. Thus, relying on this assumption may be deleterious to drug repurposing attempts. In this work, we propose MPI (Modeling Path Importance), a novel network-based method for AD drug repurposing. MPI is unique in that it prioritizes important paths via learned node embeddings, which can effectively capture a network's rich structural information. Thus, leveraging learned embeddings allows MPI to effectively differentiate the importance among paths. We evaluate MPI against a commonly used baseline method that identifies anti-AD drug candidates primarily based on the shortest paths between drugs and AD in the network. We observe that among the top-50 ranked drugs, MPI prioritizes 20.0% more drugs with anti-AD evidence compared to the baseline. Finally, Cox proportional-hazard models produced from insurance claims data aid us in identifying the use of etodolac, nicotine, and BBB-crossing ACE-INHs as having a reduced risk of AD, suggesting such drugs may be viable candidates for repurposing and should be explored further in future studies.

Modeling Path Importance for Effective Alzheimer's Disease Drug Repurposing.

Recently, drug repurposing has emerged as an effective and resource-efficient paradigm for AD drug discovery. Among various methods for drug repurposing, network-based methods have shown promising results as they are capable of leveraging complex networks that integrate multiple interaction types, such as protein-protein interactions, to more effectively identify candidate drugs. However, existing approaches typically assume paths of the same length in the network have equal importance in identifying the therapeutic effect of drugs. Other domains have found that same length paths do not necessarily have the same importance. Thus, relying on this assumption may be deleterious to drug repurposing attempts. In this work, we propose MPI (Modeling Path Importance), a novel network-based method for AD drug repurposing. MPI is unique in that it prioritizes important paths via learned node embeddings, which can effectively capture a network's rich structural information. Thus, leveraging learned embeddings allows MPI to effectively differentiate the importance among paths. We evaluate MPI against a commonly used baseline method that identifies anti-AD drug candidates primarily based on the shortest paths between drugs and AD in the network. We observe that among the top-50 ranked drugs, MPI prioritizes 20.0% more drugs with anti-AD evidence compared to the baseline. Finally, Cox proportional-hazard models produced from insurance claims data aid us in identifying the use of etodolac, nicotine, and BBB-crossing ACE-INHs as having a reduced risk of AD, suggesting such drugs may be viable candidates for repurposing and should be explored further in future studies.

Health outcomes and service use patterns associated with co-located outpatient mental health care and alcohol and other drug specialist treatment: A systematic review.

ISSUES: Despite long-standing recommendations to integrate mental health care and alcohol and other drug (AOD) treatment, no prior study has synthesised evidence on the impact of physically co-locating these specialist services on health outcomes. APPROACH: We searched Medline, PsycINFO, Embase, Web of Science and CINAHL for studies examining health outcomes associated with co-located outpatient mental health care and AOD specialist treatment for adults with a dual diagnosis of substance use disorder and mental illness. Due to diversity in study designs, patient populations and outcome measures among the included studies, we conducted a narrative synthesis. Risk of bias was assessed using the MASTER scale. KEY FINDINGS: Twenty-eight studies met our inclusion criteria. We found provisional evidence that integrated care that includes co-located mental health care and AOD specialist treatment is associated with reductions in substance use and related harms and mental health symptom severity, improved quality of life, decreased emergency department presentations/hospital admissions and reduced health system expenditure. Many studies had a relatively high risk of bias and it was not possible to disaggregate the independent effect of physical co-location from other common aspects of integrated care models such as care coordination and the integration of service processes. IMPLICATIONS: There are few high-quality, peer-reviewed studies establishing the impact of co-located mental health care and AOD specialist treatment on health outcomes. Further research is required to inform policy, guide implementation and optimise practice. CONCLUSION: Integrated care that includes the co-location of mental health care and AOD specialist treatment may yield health and economic benefits.

Cardiopulmonary Exercise Testing in Post-COVID-19 Patients: Where Does Exercise Intolerance Come From? / Teste Cardiopulmonar em Pacientes Pós-COVID-19: De Onde vem a Intolerância ao Exercício?

BACKGROUND: Post-COVID-19 exercise intolerance is poorly understood. Cardiopulmonary exercise testing (CPET) can identify the underlying exercise limitations. OBJECTIVES: To evaluate the source and magnitude of exercise intolerance in post-COVID-19 subjects. METHODS: Cohort study assessing subjects with different COVID-19 illness severities and a control group selected by propensity score matching. In a selected sample with CPET prior to viral infection, before and after comparisons were performed. Level of significance was 5% in the entire analysis. RESULTS: One hundred forty-four subjects with COVID-19 were assessed (median age: 43.0 years, 57% male), with different illness severities (60% mild, 21% moderate, 19% severe). CPET was performed 11.5 (7.0, 21.2) weeks after disease onset, with exercise limitations being attributed to the peripheral muscle (92%), and the pulmonary (6%), and cardiovascular (2%) systems. Lower median percent-predicted peak oxygen uptake was observed in the severe subgroup (72.2%) as compared to the controls (91.6%). Oxygen uptake differed among illness severities and controls at peak and ventilatory thresholds. Conversely, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse were similar. Subgroup analysis of 42 subjects with prior CPET revealed significant reduction in only peak treadmill speed in the mild subgroup and in oxygen uptake at peak and ventilatory thresholds in the moderate/severe subgroup. By contrast, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse did not change significantly. CONCLUSIONS: Peripheral muscle fatigue was the most common exercise limitation etiology in post-COVID-19 patients regardless of the illness severity. Data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components.

FUNDAMENTO: A intolerância ao exercício pós-COVID-19 não é bem entendida. O teste de esforço cardiopulmonar (TECP) pode identificar as limitações ao exercício subjacentes. OBJETIVOS: Avaliar a etiologia e a magnitude da intolerância ao exercício em sujeitos pós-COVID-19. MÉTODOS: Estudo de coorte que avaliou sujeitos com níveis de gravidades diferentes da doença COVID-19 e um grupo de controle selecionado por pareamento por escores de propensão. Em uma amostra seleta com TECP anterior à infecção viral disponível, foram realizadas comparações antes e depois. O nível de significância foi de 5% em toda a análise. RESULTADOS: Foram avaliados cento e quarenta e dois sujeitos com COVID-19 (idade mediana: 43 anos, 57% do sexo masculino), com níveis de gravidade de doença diferentes (60% leve, 21% moderada, 19% grave). O TECP foi realizado 11,5 (7,0, 21,2) semanas após o aparecimento da doença, com as limitações ao exercício sendo atribuídas aos sistemas muscular periférico (92%), pulmonar (6%), e cardiovascular (2%). Menor valor mediano do consumo de oxigênio pico percentual foi observado no subgrupo com níveis graves de doença (72,2%) em comparação com os controles (91,6%). O consumo de oxigênio foi diferente entre os grupos com diferentes níveis de gravidade de doença e o controle no pico e nos limiares ventilatórios. Inversamente, os equivalentes ventilatórios, a inclinação da eficiência do consumo de oxigênio, e o pico do pulso de oxigênio foram semelhantes. A análise do subgrupo de 42 sujeitos com TECP prévio revelou uma redução significativa no pico de velocidade da esteira no subgrupo com nível leve de doença, e no consumo de oxigênio no pico e nos limiares ventilatórios nos subgrupos com níveis moderado/grave. Por outro lado, os equivalentes ventilatórios, a inclinação da eficiência do consumo de oxigênio e o pico do pulso de oxigênio não apresentaram alterações significativas. CONCLUSÕES: A fadiga do músculo periférico foi a etiologia de limitação de exercício mais comum em pacientes pós-COVID-19 independentemente da gravidade da doença. Os dados sugerem que o tratamento deve enfatizar programas de reabilitação abrangentes, incluindo componentes aeróbicos e de fortalecimento muscular.

Impact of COVID-19's on Cardiovascular Rehabilitation Programs in Brazil: An Online Survey-Based Cross-Sectional Study. / Impacto da COVID-19 nos Programas de Reabilitação Cardiovascular no Brasil: Um Estudo Transversal Baseado em uma Pesquisa Online.

BACKGROUND: The COVID-19 pandemic had an impact on cardiovascular rehabilitation (CR) programs in Brazil. OBJECTIVES: To describe the characteristics of CR programs in Brazil, the impacts of the first epidemiological wave of COVID-19 (first 60 days) on the programs and present the initiatives used to overcome the impacts. METHOD: This cross-sectional and retrospective study utilized a specific online survey. Participants were coordinators of CR programs. Variables were presented by Brazilian geographic region and as the following categories: demographic, clinical and operational characteristics. The significance level for statistical analysis was set at 5%. RESULTS: Fifty-nine CR programs were responsible for 5,349 patients, of which only 1,817 were post-acute cardiovascular events, which corresponded to 1.99% of hospitalized patients in the month prior to the survey (n=91,231). The greatest impact was the suspension of on-site activities, which occurred similarly in areas with the highest and the lowest rates of COVID-19 in the period. Forty-five programs (75%) were shortly interrupted, while three (5%) were ended. All 42 programs that already used remote rehabilitation strategies noticed a substantial increase in activities, based primarily on the use of media and video calling. Only three (5%) considered safe to see patients during the first 60 days. CONCLUSIONS: There was a reduction in the number of CR programs with the COVID-19 pandemic. Telerehabilitation activities increased during the first two months of the COVID-19 pandemic, but this was not enough to overcome the reduction in CR program activities across Brazil.

FUNDAMENTO: A pandemia da COVID-19 teve um impacto sobre os programas de reabilitação cardiovasculares (RC) no Brasil. OBJETIVOS: Descrever características dos programas de RC no Brasil, os impactos da primeira onda epidemiológica da COVID-19 (primeiros 60 dias) sobre os programas, e apresentar as iniciativas usadas para superar esses impactos. MÉTODOS: Este estudo transversal e retrospectivo usou um questionário online específico. Os participantes eram coordenadores de programas de RC. As variáveis foram apresentadas por região geográfica do Brasil, como as seguintes categorias: característica demográficas, clínicas e operacionais. O nível de significância estatística foi definido em 5%. RESULTADOS: Cinquenta e nove programas de RC atendiam 5349 pacientes, dos quais somente 1817 eram pacientes após eventos cardiovasculares agudos, o que correspondia a 1,99% dos pacientes internados no mês anterior à pesquisa (n=91.231). O maior impacto foi a suspensão das atividades presenciais, o que ocorreu de maneira similar em áreas com as taxas mais altas e áreas com as taxas mais baixas de COVID-19 no período. Quarenta e quatro (75%) programas foram interrompidos de forma breve, e três (5%) foram encerrados. Todos os 42 programas que já utilizavam estratégias de reabilitação remota notaram aumento substancial nas atividades, baseadas principalmente no uso da mídia e chamadas por vídeo. Somente três (5%) consideraram seguro atender pacientes durante os primeiros 60 dias. CONCLUSÕES: Houve redução no número de programas de RC devido a pandemia da COVID-19. Atividades de telerreabilitação aumentaram durante os primeiros dois meses da pandemia da COVID-19, mas que não foi suficiente para superar a redução nas atividades dos programas de RC no Brasil.

Teste Cardiopulmonar em Pacientes Pós-COVID-19: De Onde vem a Intolerância ao Exercício? / Cardiopulmonary Exercise Testing in Post-COVID-19 Patients: Where Does Exercise Intolerance Come From?

Resumo Fundamento A intolerância ao exercício pós-COVID-19 não é bem entendida. O teste de esforço cardiopulmonar (TECP) pode identificar as limitações ao exercício subjacentes. Objetivos Avaliar a etiologia e a magnitude da intolerância ao exercício em sujeitos pós-COVID-19. Métodos Estudo de coorte que avaliou sujeitos com níveis de gravidades diferentes da doença COVID-19 e um grupo de controle selecionado por pareamento por escores de propensão. Em uma amostra seleta com TECP anterior à infecção viral disponível, foram realizadas comparações antes e depois. O nível de significância foi de 5% em toda a análise. Resultados Foram avaliados cento e quarenta e dois sujeitos com COVID-19 (idade mediana: 43 anos, 57% do sexo masculino), com níveis de gravidade de doença diferentes (60% leve, 21% moderada, 19% grave). O TECP foi realizado 11,5 (7,0, 21,2) semanas após o aparecimento da doença, com as limitações ao exercício sendo atribuídas aos sistemas muscular periférico (92%), pulmonar (6%), e cardiovascular (2%). Menor valor mediano do consumo de oxigênio pico percentual foi observado no subgrupo com níveis graves de doença (72,2%) em comparação com os controles (91,6%). O consumo de oxigênio foi diferente entre os grupos com diferentes níveis de gravidade de doença e o controle no pico e nos limiares ventilatórios. Inversamente, os equivalentes ventilatórios, a inclinação da eficiência do consumo de oxigênio, e o pico do pulso de oxigênio foram semelhantes. A análise do subgrupo de 42 sujeitos com TECP prévio revelou uma redução significativa no pico de velocidade da esteira no subgrupo com nível leve de doença, e no consumo de oxigênio no pico e nos limiares ventilatórios nos subgrupos com níveis moderado/grave. Por outro lado, os equivalentes ventilatórios, a inclinação da eficiência do consumo de oxigênio e o pico do pulso de oxigênio não apresentaram alterações significativas. Conclusões A fadiga do músculo periférico foi a etiologia de limitação de exercício mais comum em pacientes pós-COVID-19 independentemente da gravidade da doença. Os dados sugerem que o tratamento deve enfatizar programas de reabilitação abrangentes, incluindo componentes aeróbicos e de fortalecimento muscular.

Abstract Background Post-COVID-19 exercise intolerance is poorly understood. Cardiopulmonary exercise testing (CPET) can identify the underlying exercise limitations. Objectives To evaluate the source and magnitude of exercise intolerance in post-COVID-19 subjects. Methods Cohort study assessing subjects with different COVID-19 illness severities and a control group selected by propensity score matching. In a selected sample with CPET prior to viral infection, before and after comparisons were performed. Level of significance was 5% in the entire analysis. Results One hundred forty-four subjects with COVID-19 were assessed (median age: 43.0 years, 57% male), with different illness severities (60% mild, 21% moderate, 19% severe). CPET was performed 11.5 (7.0, 21.2) weeks after disease onset, with exercise limitations being attributed to the peripheral muscle (92%), and the pulmonary (6%), and cardiovascular (2%) systems. Lower median percent-predicted peak oxygen uptake was observed in the severe subgroup (72.2%) as compared to the controls (91.6%). Oxygen uptake differed among illness severities and controls at peak and ventilatory thresholds. Conversely, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse were similar. Subgroup analysis of 42 subjects with prior CPET revealed significant reduction in only peak treadmill speed in the mild subgroup and in oxygen uptake at peak and ventilatory thresholds in the moderate/severe subgroup. By contrast, ventilatory equivalents, oxygen uptake efficiency slope, and peak oxygen pulse did not change significantly. Conclusions Peripheral muscle fatigue was the most common exercise limitation etiology in post-COVID-19 patients regardless of the illness severity. Data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components.

Impacto da COVID-19 nos Programas de Reabilitação Cardiovascular no Brasil: Um Estudo Transversal Baseado em uma Pesquisa Online / Impact of COVID-19's on Cardiovascular Rehabilitation Programs in Brazil: An Online Survey-Based Cross-Sectional Study

Resumo Fundamento A pandemia da COVID-19 teve um impacto sobre os programas de reabilitação cardiovasculares (RC) no Brasil. Objetivos Descrever características dos programas de RC no Brasil, os impactos da primeira onda epidemiológica da COVID-19 (primeiros 60 dias) sobre os programas, e apresentar as iniciativas usadas para superar esses impactos. Métodos Este estudo transversal e retrospectivo usou um questionário online específico. Os participantes eram coordenadores de programas de RC. As variáveis foram apresentadas por região geográfica do Brasil, como as seguintes categorias: característica demográficas, clínicas e operacionais. O nível de significância estatística foi definido em 5%. Resultados Cinquenta e nove programas de RC atendiam 5349 pacientes, dos quais somente 1817 eram pacientes após eventos cardiovasculares agudos, o que correspondia a 1,99% dos pacientes internados no mês anterior à pesquisa (n=91.231). O maior impacto foi a suspensão das atividades presenciais, o que ocorreu de maneira similar em áreas com as taxas mais altas e áreas com as taxas mais baixas de COVID-19 no período. Quarenta e quatro (75%) programas foram interrompidos de forma breve, e três (5%) foram encerrados. Todos os 42 programas que já utilizavam estratégias de reabilitação remota notaram aumento substancial nas atividades, baseadas principalmente no uso da mídia e chamadas por vídeo. Somente três (5%) consideraram seguro atender pacientes durante os primeiros 60 dias. Conclusões Houve redução no número de programas de RC devido a pandemia da COVID-19. Atividades de telerreabilitação aumentaram durante os primeiros dois meses da pandemia da COVID-19, mas que não foi suficiente para superar a redução nas atividades dos programas de RC no Brasil.

Abstract Background The COVID-19 pandemic had an impact on cardiovascular rehabilitation (CR) programs in Brazil. Objectives To describe the characteristics of CR programs in Brazil, the impacts of the first epidemiological wave of COVID-19 (first 60 days) on the programs and present the initiatives used to overcome the impacts. Method This cross-sectional and retrospective study utilized a specific online survey. Participants were coordinators of CR programs. Variables were presented by Brazilian geographic region and as the following categories: demographic, clinical and operational characteristics. The significance level for statistical analysis was set at 5%. Results Fifty-nine CR programs were responsible for 5,349 patients, of which only 1,817 were post-acute cardiovascular events, which corresponded to 1.99% of hospitalized patients in the month prior to the survey (n=91,231). The greatest impact was the suspension of on-site activities, which occurred similarly in areas with the highest and the lowest rates of COVID-19 in the period. Forty-five programs (75%) were shortly interrupted, while three (5%) were ended. All 42 programs that already used remote rehabilitation strategies noticed a substantial increase in activities, based primarily on the use of media and video calling. Only three (5%) considered safe to see patients during the first 60 days. Conclusions There was a reduction in the number of CR programs with the COVID-19 pandemic. Telerehabilitation activities increased during the first two months of the COVID-19 pandemic, but this was not enough to overcome the reduction in CR program activities across Brazil.

A Case Report on Longitudinal Collection of Tumour Biopsies for Gene Expression-Based Tumour Microenvironment Analysis from Pancreatic Cancer Patients Treated with Endoscopic Ultrasound Guided Radiofrequency Ablation.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) are metastatic at presentation with dismal prognosis warranting improved systemic therapy options. Longitudinal sampling for the assessment of treatment response poses a challenge for validating novel therapies. In this case study, we evaluate the feasibility of collecting endoscopic ultrasound (EUS)-guided longitudinal fine-needle aspiration biopsies (FNABs) from two PDAC patients and conduct gene expression studies associated with tumour microenvironment changes associated with radiofrequency ablation (RFA). METHODS: EUS-guided serial/longitudinal FNABs of tumour were collected before and after treatment from two stage III inoperable gemcitabine-treated PDAC patients treated with targeted RFA three times. Biopsies were analysed using a custom NanoString panel (144 genes) consisting of cancer and cancer-associated fibroblast (CAFs) subtypes and immune changes. CAF culture was established from one FNAB and characterised by immunofluorescence and immunoblotting. RESULTS: Two-course RFA led to the upregulation of the CD1E gene (involved in antigen presentation) in both patients 1 and 2 (4.5 and 3.9-fold changes) compared to baseline. Patient 1 showed increased T cell genes (CD4-8.7-fold change, CD8-35.7-fold change), cytolytic function (6.4-fold change) and inflammatory response (8-fold change). A greater than 2-fold upregulation of immune checkpoint genes was observed post-second RFA in both patients. Further, two-course RFA led to increased PDGFRα (4.5-fold change) and CAF subtypes B and C genes in patient 1 and subtypes A, B and D genes in patient 2. Patient 2-derived CAFs post-first RFA showed expression of PDGFRα, POSTN and MYH11 proteins. Finally, RFA led to the downregulation of classical PDAC subtype-specific genes in both patients. CONCLUSIONS: This case study suggests longitudinal EUS-FNAB as a potential resource to study tumour and microenvironmental changes associated with RFA treatment. A large sample size is required in the future to assess the efficacy and safety of the treatment and perform comprehensive statistical analysis of EUS-RFA-based molecular changes in PDAC.

Improving MHC class I antigen-processing predictions using representation learning and cleavage site-specific kernels.

In this work, we propose a new deep-learning model, MHCrank, to predict the probability that a peptide will be processed for presentation by MHC class I molecules. We find that the performance of our model is significantly higher than that of two previously published baseline methods: MHCflurry and netMHCpan. This improvement arises from utilizing both cleavage site-specific kernels and learned embeddings for amino acids. By visualizing site-specific amino acid enrichment patterns, we observe that MHCrank's top-ranked peptides exhibit enrichments at biologically relevant positions and are consistent with previous work. Furthermore, the cosine similarity matrix derived from MHCrank's learned embeddings for amino acids correlates highly with physiochemical properties that have been experimentally demonstrated to be instrumental in determining a peptide's favorability for processing. Altogether, the results reported in this work indicate that MHCrank demonstrates strong performance compared with existing methods and could have vast applicability in aiding drug and vaccine development.

Exome sequencing in multiplex families with left-sided cardiac defects has high yield for disease gene discovery.

Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant's effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes.

Relação da Função Pulmonar e da Força Inspiratória com Capacidade Aeróbica e com Prognóstico na Insuficiência Cardíaca / Relationship of Lung Function and Inspiratory Strength with Exercise Capacity and Prognosis in Heart Failure

Resumo Fundamento A espirometria é subutilizada na insuficiência cardíaca (IC) e não está claro o grau de associação de cada defeito com a capacidade de exercício e com o prognóstico desses pacientes. Objetivo Determinar a relação da %CVF prevista (ppCVF) e do VEF1/CVF contínuos com: 1) pressão inspiratória máxima (PImáx), fração de ejeção do ventrículo esquerdo (FEVE) e desempenho ao exercício; e 2) prognóstico, para o desfecho composto de morte cardiovascular, transplante cardíaco ou implante de dispositivo de assistência ventricular. Métodos Coorte de 111 participantes com IC (estágios AHA C/D) sem pneumopatia; foram submetidos a espirometria, manovacuometria e teste cardiopulmonar máximo. As magnitudes de associação foram verificadas por regressões lineares e de Cox (HR; IC 95%), ajustadas para idade/sexo, e p <0,05 foi considerado significativo. Resultados Com idade média 57±12 anos, 60% eram homens, 64% em NYHAIII. A cada aumento de 10% no VEF1/CVF [β 7% (IC 95%: 3-10)] e no ppCVF [4% (2-6)], foi associado à reserva ventilatória (VRes); no entanto, apenas o ppCVF associado à PImáx [3,8cmH2O (0,3-7,3)], à fração de ejeção do ventrículo esquerdo (FEVE) [2,1% (0,5-3,8)] e ao VO2 pico [0,5mL/kg/min (0,1-1,0)], considerando idade/sexo. Em 2,2 anos (média), ocorreram 22 eventos; tanto FEV1/FVC (HR 1,44; IC 95%: 0,97-2,13) quanto ppCVF (HR 1,13; 0,89-1,43) não foram associados ao desfecho. Apenas no subgrupo FEVE ≤50% (n=87, 20 eventos), VEF1/CVF (HR 1,50; 1,01-2,23), mas não ppCVF, foi associado a risco. Conclusão Na IC crônica, ppCVF reduzido associou-se a menor PImáx, FEVE, VRes e VO2 pico, mas não distinguiu pior prognóstico em 2,2 anos de acompanhamento. Entretanto, VEF1/CVF associou-se apenas com VRes, e, em participantes com FEVE ≤50%, o VEF1/CVF reduzido mostrou pior prognóstico proporcional. Portanto, VEF1/CVF e ppFVC contribuem para melhor fenotipagem de pacientes com IC.

Abstract Background Spirometry is underused in heart failure (HF) and the extent to which each defect associates with exercise capacity and prognosis is unclear. Objective To determine the distinct relationship of continuous %predicted FVC (ppFVC) and FEV1/FVC with: 1) maximal inspiratory pressure (MIP), left ventricular ejection fraction (LVEF), exercise performance; and 2) prognosis for the composite of cardiovascular death, heart transplantation or left ventricular assist device implant. Methods A cohort of 111 HF participants (AHA stages C/D) without diagnosed pneumopathy, spirometry, manovacuometry and maximum cardiopulmonary test. The association magnitudes were verified by linear and Cox (HR; 95% CI) regressions, age/sex adjusted. A p<0.05 was considered significant. Results Age was 57±12 years, 60% men, 64% in NYHA III. Every 10%-point increase in FEV1/FVC [β 7% (95% CI: 3-10)] and ppFVC [4% (2-6)] associated with ventilatory reserve (VRes), however only ppFVC associated with MIP [3.8 cmH2O (0.3-7.3)], LVEF [2.1% (0.5-3.8)] and VO2peak [0.5 mL/kg/min (0.1-1.0)], accounting for age/sex. In 2.2 years (mean), 22 events occurred, and neither FEV1/FVC (HR 1.44; 95% CI: 0.97-2.13) nor ppFVC (HR 1.13; 0.89-1.43) was significantly associated with the outcome. Only in the LVEF ≤50% subgroup (n=87, 20 events), FEV1/FVC (HR 1.50; 1.01-2.23), but not ppFVC, was associated with greater risk. Conclusions In chronic HF, reduced ppFVC associated with lower MIP, LVEF, VRes and VO2peak, but no distinct poorer prognosis over 2.2 years of follow-up. Distinctively, FEV1/FVC was associated only with VRes, and, in participants with LVEF ≤50%, FEV1/FVC reduction proportionally worsened prognosis. Therefore, FEV1/FVC and ppFVC add supplementary information regarding HF phenotyping.

Relationship of Lung Function and Inspiratory Strength with Exercise Capacity and Prognosis in Heart Failure. / Relação da Função Pulmonar e da Força Inspiratória com Capacidade Aeróbica e com Prognóstico na Insuficiência Cardíaca.

BACKGROUND: Spirometry is underused in heart failure (HF) and the extent to which each defect associates with exercise capacity and prognosis is unclear. OBJECTIVE: To determine the distinct relationship of continuous %predicted FVC (ppFVC) and FEV1/FVC with: 1) maximal inspiratory pressure (MIP), left ventricular ejection fraction (LVEF), exercise performance; and 2) prognosis for the composite of cardiovascular death, heart transplantation or left ventricular assist device implant. METHODS: A cohort of 111 HF participants (AHA stages C/D) without diagnosed pneumopathy, spirometry, manovacuometry and maximum cardiopulmonary test. The association magnitudes were verified by linear and Cox (HR; 95% CI) regressions, age/sex adjusted. A p<0.05 was considered significant. RESULTS: Age was 57±12 years, 60% men, 64% in NYHA III. Every 10%-point increase in FEV1/FVC [ß 7% (95% CI: 3-10)] and ppFVC [4% (2-6)] associated with ventilatory reserve (VRes), however only ppFVC associated with MIP [3.8 cmH2O (0.3-7.3)], LVEF [2.1% (0.5-3.8)] and VO2peak [0.5 mL/kg/min (0.1-1.0)], accounting for age/sex. In 2.2 years (mean), 22 events occurred, and neither FEV1/FVC (HR 1.44; 95% CI: 0.97-2.13) nor ppFVC (HR 1.13; 0.89-1.43) was significantly associated with the outcome. Only in the LVEF ≤50% subgroup (n=87, 20 events), FEV1/FVC (HR 1.50; 1.01-2.23), but not ppFVC, was associated with greater risk. CONCLUSIONS: In chronic HF, reduced ppFVC associated with lower MIP, LVEF, VRes and VO2peak, but no distinct poorer prognosis over 2.2 years of follow-up. Distinctively, FEV1/FVC was associated only with VRes, and, in participants with LVEF ≤50%, FEV1/FVC reduction proportionally worsened prognosis. Therefore, FEV1/FVC and ppFVC add supplementary information regarding HF phenotyping.

FUNDAMENTO: A espirometria é subutilizada na insuficiência cardíaca (IC) e não está claro o grau de associação de cada defeito com a capacidade de exercício e com o prognóstico desses pacientes. OBJETIVO: Determinar a relação da %CVF prevista (ppCVF) e do VEF1/CVF contínuos com: 1) pressão inspiratória máxima (PImáx), fração de ejeção do ventrículo esquerdo (FEVE) e desempenho ao exercício; e 2) prognóstico, para o desfecho composto de morte cardiovascular, transplante cardíaco ou implante de dispositivo de assistência ventricular. MÉTODOS: Coorte de 111 participantes com IC (estágios AHA C/D) sem pneumopatia; foram submetidos a espirometria, manovacuometria e teste cardiopulmonar máximo. As magnitudes de associação foram verificadas por regressões lineares e de Cox (HR; IC 95%), ajustadas para idade/sexo, e p <0,05 foi considerado significativo. RESULTADOS: Com idade média 57±12 anos, 60% eram homens, 64% em NYHAIII. A cada aumento de 10% no VEF1/CVF [ß 7% (IC 95%: 3-10)] e no ppCVF [4% (2-6)], foi associado à reserva ventilatória (VRes); no entanto, apenas o ppCVF associado à PImáx [3,8cmH2O (0,3-7,3)], à fração de ejeção do ventrículo esquerdo (FEVE) [2,1% (0,5-3,8)] e ao VO2 pico [0,5mL/kg/min (0,1-1,0)], considerando idade/sexo. Em 2,2 anos (média), ocorreram 22 eventos; tanto FEV1/FVC (HR 1,44; IC 95%: 0,97-2,13) quanto ppCVF (HR 1,13; 0,89-1,43) não foram associados ao desfecho. Apenas no subgrupo FEVE ≤50% (n=87, 20 eventos), VEF1/CVF (HR 1,50; 1,01-2,23), mas não ppCVF, foi associado a risco. CONCLUSÃO: Na IC crônica, ppCVF reduzido associou-se a menor PImáx, FEVE, VRes e VO2 pico, mas não distinguiu pior prognóstico em 2,2 anos de acompanhamento. Entretanto, VEF1/CVF associou-se apenas com VRes, e, em participantes com FEVE ≤50%, o VEF1/CVF reduzido mostrou pior prognóstico proporcional. Portanto, VEF1/CVF e ppFVC contribuem para melhor fenotipagem de pacientes com IC.

Test of incremental respiratory endurance as home-based, stand-alone therapy in chronic obstructive pulmonary disease: A case report.

BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is increasing worldwide, and at the same time it is associated with increased mortality and reduced quality of life. Efforts to build sustainable rehabilitation approaches to COPD treatment and prevention are crucial. The system of long-term pulmonary rehabilitation care is insufficient. The main reasons for the absence of these outpatient programs are the lack of experience, the lack of interest of insurance companies in secondary prevention programs, and the lack of healthcare facilities in large geographical areas. The possibility of at-home pulmonary rehabilitation models (telemonitoring and telecoaching) could solve this problem. CASE SUMMARY: A 71-year-old man with severe COPD, Global Initiative for Obstructive Lung Diseases stage 3 underwent an 8-wk remotely monitored inspiratory muscle training with a device based on the test of incremental respiratory endurance method. Spirometry, body plethysmography, test of incremental respiratory endurance examination, 6-min walking test, body mass index, airflow obstruction, dyspnea, exercise capacity index, and subjective perception of dyspnea were performed as part of the initial and final examination. The patient performed training at home, and the physiotherapist monitored the patient remotely through a web application that allowed the physiotherapist to evaluate all training parameters in real-time and respond to any problems. After 8 wk of home training, there was a significant increase in all monitored values: maximal inspiratory pressure, a novel parameter sustained maximal inspiratory pressure, forced expiratory volume in 1 s, total lung capacity, forced vital capacity, peak expiratory flow, and inspiratory capacity. There was also an improvement in the perception of dyspnea according to the COPD Assessment Test and a modified Medical Research Council Breathlessness Scale, an increase in exercise tolerance according to the 6-min walking test, and a decrease in the exercise capacity index as a predictor of prognosis. CONCLUSION: Respiratory telerehabilitation was greatly beneficial in a cooperative patient with COPD and may represent an alternative therapeutic approach to the increasing incidence of all lung diseases.

Use of machine learning to classify high-risk variants of uncertain significance in lamin A/C cardiac disease.

BACKGROUND: Variation in lamin A/C results in a spectrum of clinical disease, including arrhythmias and cardiomyopathy. Benign variation is rare, and classification of LMNA missense variants via in silico prediction tools results in a high rate of variants of uncertain significance (VUSs). OBJECTIVE: The goal of this study was to use a machine learning (ML) approach for in silico prediction of LMNA pathogenic variation. METHODS: Genetic sequencing was performed on family members with conduction system disease, and patient cell lines were examined for LMNA expression. In silico predictions of conservation and pathogenicity of published LMNA variants were visualized with uniform manifold approximation and projection. K-means clustering was used to identify variant groups with similarly projected scores, allowing the generation of statistically supported risk categories. RESULTS: We discovered a novel LMNA variant (c.408C>A:p.Asp136Glu) segregating with conduction system disease in a multigeneration pedigree, which was reported as a VUS by a commercial testing company. Additional familial analysis and in vitro testing found it to be pathogenic, which prompted the development of an ML algorithm that used in silico predictions of pathogenicity for known LMNA missense variants. This identified 3 clusters of variation, each with a significantly different incidence of known pathogenic variants (38.8%, 15.0%, and 6.1%). Three hundred thirty-nine of 415 head/rod domain variants (81.7%), including p.Asp136Glu, were in clusters with highest proportions of pathogenic variants. CONCLUSION: An unsupervised ML method successfully identified clusters enriched for pathogenic LMNA variants including a novel variant associated with conduction system disease. Our ML method may assist in identifying high-risk VUS when familial testing is unavailable.

Reduced exercise capacity and self-perceived health status in high-risk patients undergoing lung resection.

BACKGROUND: Lung resection represents the main curative treatment modality of non-small cell lung cancer. Patients with high-risk to develop postoperative pulmonary complications have been classified as "high-risk patients." Characterizing this population could be important to improve their approach and rehabilitation. AIM: To identify the differences between high and low-risk patients in exercise capacity and self-perceived health status after hospitalization. METHODS: A longitudinal observational prospective cohort study was carried out. Patients undergoing lung resection were recruited from the "Hospital Virgen de las Nieves" (Granada) and divided into two groups according to the risk profile criteria (age ≥ 70 years, forced expiratory volume in 1 s ≤ 70% predicted, carbon monoxide diffusion capacity ≤ 70% predicted or scheduled pneumonectomy). Outcomes included were exercise capacity (Fatigue Severity Scale, Unsupported Upper-Limb Exercise, handgrip dynamometry, Five Sit-to-stand test, and quadriceps hand-held dynamometry) and patient-reported outcome (Euroqol-5 dimensions 5 Levels Visual Analogue Scale). RESULTS: In total, 115 participants were included in the study and divided into three groups: high-risk, low-risk and control group. At discharge high-risk patients presented a poorer exercise capacity and a worse self-perceived health status (P < 0.05). One month after discharge patients in the high-risk group maintained these differences compared to the other groups. CONCLUSION: Our results show a poorer recovery in high-risk patients at discharge and 1 mo after surgery, with lower self-perceived health status and a poorer upper and lower limb exercise capacity. These results are important in the rehabilitation field.

Acute and Time-Course Effects of Osteopathic Manipulative Treatment on Vascular and Autonomic Function in Patients With Heart Failure: A Randomized Trial.

OBJECTIVE: The purposed of this study was to valuate the effect of osteopathic manipulative treatment (OMT) on flow-mediated dilation and heart rate variability of patients with heart failure. BACKGROUND: Osteopathic manipulative treatment modulates both the vascular and autonomic nervous system (ANS) in healthy volunteers. However, the acute and time-course effects of the OMT on patients with an overactive ANS remain unclear. METHODS: This randomized controlled trial study included 20 patients with heart failure aged 50 to 60 years, allocated to a single session of OMT (base of the skull, retromaxillary region, heart, and thoracic duct) or sham. Flow-mediated dilation (FMD) at the brachial artery, hemodynamic measures, and heart rate variability were assessed in 3 periods (baseline, immediately after the intervention, and after 15 minutes). Multivariate analysis of variance procedure was used to compare intervention and periods. RESULTS: The OMT group had a greater FMD modulation compared with the sham (FMD,% =  9.5 vs. -5.6, 95% confidence interval (CI): [6.6, -12.35] vs. [-14.25, 2.8]; p = 0.001) and grater peak diameter (PD, mm =  0.77 vs -0.16 mm, 95% CI: [0.31,-1.24] vs [-0.63, 0.29]; P =  0.001), suggesting an important acute and time-course vascular effect from OMT. We also found some relevant heart rate variability modulation after 15 minutes from OMT: high frequency (HF, ms2 = 295 vs -354, 95% CI: [144.2, -769]; P = .001) and low frequency (LF, ms2) = 670 vs 775, 95% CI: [-98, 3591]; P = .001), suggesting a time-course ANS modulation after OMT. CONCLUSIONS: Osteopathic manipulative treatment was effective at increasing brachial blood flow and stimulating the vagal system in patients with heart failure. Moreover, vascular changes seem to precede the autonomic modulation.

Moderate-intensity exercise with blood flow restriction on cardiopulmonary kinetics and efficiency during a subsequent high-intensity exercise in young women: A cross-sectional study.

ABSTRACT: Blood flow restriction (BFR) training applied prior to a subsequent exercise has been used as a method to induce changes in oxygen uptake pulmonary kinetics (O2P) and exercise performance. However, the effects of a moderate-intensity training associated with BFR on a subsequent high-intensity exercise on O2P and cardiac output (QT) kinetics, exercise tolerance, and efficiency remain unknown.This prospective physiologic study was performed at the Exercise Physiology Lab, University of Brasilia. Ten healthy females (mean ±â€ŠSD values: age = 21.3 ±â€Š2.2 years; height = 1.6 ±â€Š0.07 m, and weight = 55.6 ±â€Š8.8 kg) underwent moderate-intensity training associated with or without BFR for 6 minutes prior to a maximal high-intensity exercise bout. O2P, heart rate, and QT kinetics and gross efficiency were obtained during the high-intensity constant workload exercise test.No differences were observed in O2P, heart rate, and QT kinetics in the subsequent high-intensity exercise following BFR training. However, exercise tolerance and gross efficiency were significantly greater after BFR (220 ±â€Š45 vs 136 ±â€Š30 seconds; P < .05, and 32.8 ±â€Š6.3 vs 27.1 ±â€Š5.4%; P < .05, respectively), which also resulted in lower oxygen cost (1382 ±â€Š227 vs 1695 ±â€Š305 mL min-1).We concluded that moderate-intensity BFR training implemented prior to a high-intensity protocol did not accelerate subsequent O2P and QT kinetics, but it has the potential to improve both exercise tolerance and work efficiency at high workloads.