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Genetic Architecture of Congenital Hypogonadotropic Hypogonadism: Insights from Analysis of a Portuguese Cohort.
No full textStudy question: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)?
Summary answer: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included.
What is known already: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility.
Study design size duration: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls.
Participants/materials setting methods: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS).
Main results and the role of chance: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls.
Large scale data: N/A.
Limitations reasons for caution: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken.
Wider implications of the findings: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH.
Study funding/competing interests: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests
Detection of Elusive DNA Copy-Number Variations in Hereditary Disease and Cancer Through the Use of Noncoding and Off-Target Sequencing Reads.
No full textCopy-number variants (CNVs) play a substantial role in the molecular pathogenesis of hereditary disease and cancer, as well as in normal human interindividual variation. However, they are still rather difficult to identify in mainstream sequencing projects, especially involving exome sequencing, because they often occur in DNA regions that are not targeted for analysis. To overcome this problem, we developed OFF-PEAK, a user-friendly CNV detection tool that builds on a denoising approach and the use of "off-target" DNA reads, which are usually discarded by sequencing pipelines. We benchmarked OFF-PEAK on data from targeted sequencing of 96 cancer samples, as well as 130 exomes of individuals with inherited retinal disease from three different populations. For both sets of data, OFF-PEAK demonstrated excellent performance (>95% sensitivity and >80% specificity vs. experimental validation) in detecting CNVs from in silico data alone, indicating its immediate applicability to molecular diagnosis and genetic research
Reprodutibilidade e Validade da Versão Portuguesa da Escala de Fragilidade de Edmonton em Doentes de Cirurgia Cardíaca
No full textIntroduction: Frailty is a multidimensional syndrome characterized by the loss of functional reserve, associated with higher mortality and less functional survival in cardiac surgery patients. The Edmonton Frail Scale (EFS) is a comprehensive tool devised for brief frailty detection. To the best of our knowledge, there are no culturally adapted and validated frailty screening tools that enable the identification of vulnerability domains suited for use in the preoperative setting in Portugal. This was the motivation for this study.
Objectives: To assess the validity and reproducibility of the Portuguese version of the EFS.
Methods: Prospective observational study, in a sample of elective cardiac surgery patients. The Edmonton Frail Scale (EFS) translation and backtranslation were performed. Demographic and clinical data were collected, and the translated EFS translated, Geriatric Depression Scale, and Mini Mental State Examination Portuguese versions, Katz and Clinical Frailty Scales were administered. To assess validity Mann-Whitney test, Spearman's correlation coefficient, marginal homogeneity test and Kappa coefficient were employed. Reproducibility was assessed estimating kappa coefficient for the frailty diagnosis and the 11 EFS items. Intra-class correlation coefficients and the corresponding 95% confidence interval were estimated using linear mixed effects model.
Results: The EFS Portuguese version revealed construct validity for frailty identification, as well as criterion validity for cognition and mood domains. Reproducibility was demonstrated, with k=0.62 (95% confidence interval (CI) 0.42-0.82) and intraclass correlation (ICC)=0.94 (95% CI 0.89-0.97) in inter-observer test and k=0.48 (95% CI 0.26-0.70) and ICC=0.85 (95% CI 0.72-0.92) in intra-observer test.
Conclusions: The EFS Portuguese version is valid and reproducible for use, suiting pre-operative frailty screening in a cardiac surgery setting.Introdução: A fragilidade é uma síndrome multidimensional caracterizada pela perda de reserva funcional, associada a maior mortalidade e menor sobrevivência funcional após cirurgia cardíaca. A Escala de Fragilidade de Edmonton (EFS) é uma ferramenta abrangente de deteção de fragilidade. Não existe ainda em Portugal uma ferramenta de rastreio culturalmente adaptada e validada que permita a identificação de domínios específicos de vulnerabilidade para utilização no pré-operatório.
Objetivos: Avaliar a validade e reprodutibilidade da versão portuguesa da EFS.
Métodos: Estudo prospetivo observacional, realizado numa amostra de doentes propostos para cirurgia cardíaca. A EFS foi traduzida e retrotraduzida. Colheram-se dados demográficos e clínicos, aplicaram-se as versões traduzidas da EFS, Escala de Depressão Geriátrica e MMSE, as escalas de Katz e Clinical Frailty Scale. Validade avaliada utilizando o teste de Mann-Whitney, o coeficiente de correlação de Spearman, o teste de homogeneidade marginal e o coeficiente Kappa. Reprodutibilidade avaliada pelo cálculo do coeficiente kappa para o diagnóstico de fragilidade e para os 11 itens da escala. Coeficientes de correlação intraclasse e correspondentes intervalos de confiança a 95% estimados usando um modelo linear de efeitos mistos.
Resultados: A versão portuguesa da EFS demonstrou validade de constructo, assim como validade de critério nos domínios de cognição e humor. É reprodutível, com k=0,62 (95% IC 0,42-0,82) e CCI=0,94 (95% IC 0,89-0,97) no teste interobservador e k=0,48 (95% IC 0,26-0,70) e CCI=0,85 (95% IC 0,72-0,92) no teste intraobservador.
Conclusões: A versão portuguesa da EFS é adequada para rastreio pré-operatório de fragilidade em cirurgia cardíaca.info:eu-repo/semantics/publishedVersio
Administração Intermitente de Levosimendan em Hospital de Dia de Insuficiência Cardíaca: Experiência Unicêntrica de 200 Tratamentos
No full textIntroduction: Patients with advanced heart failure (HF) have high morbidity and mortality, with only a small proportion being eligible for advanced therapies. Intermittent outpatient levosimendan infusion has been shown to provide symptomatic relief and reduce the rate of HF events. Our aim was to assess the safety and efficacy of outpatient levosimendan administration in an advanced HF population.
Methods: This is a report of a single-center experience of consecutive advanced HF patients referred for intermittent intravenous outpatient administration of levosimendan, between January 2018 and March 2021. Baseline and follow-up evaluation included clinical assessment, laboratory tests, transthoracic echocardiography and cardiopulmonary exercise testing. Baseline and clinical follow-up data were compared using the Wilcoxon signed-rank test.
Results: A total of 24 patients (60.8 years, 83% male, mean left ventricular ejection fraction [LVEF] 24%), with a median of 1.5 HF hospitalizations in the previous six months, were referred for outpatient levosimendan pulses, the majority as a bridge to transplantation or due to clinical deterioration. At six-month follow-up there was a significant reduction in HF hospitalizations to 0.4±0.7 (p<0.001). NYHA class IV (52.2% to 12.5%, p=0.025) and NT-proBNP (8812.5 to 3807.4 pg/ml, p=0.038) were also significantly reduced. Exercise capacity was significantly improved, including peak oxygen uptake (p=0.043) and VE/VCO2 slope (p=0.040). LVEF improved from 24.0% to 29.7% (p=0.008). No serious adverse events were reported.
Conclusion: Repeated levosimendan administration in advanced HF patients is a safe procedure and was associated with a reduction in HF hospitalizations, functional and LVEF improvement, and reduction in NT-proBNP levels during follow-up.info:eu-repo/semantics/publishedVersio
Spontaneous Preterm Birth and Congenital Heart Defects: What Is Known?
No full textinfo:eu-repo/semantics/publishedVersio
Hypnobirthing: Confiança e Empoderamento no Trabalho de Parto
No full textEste artigo tem como objetivo dar a conhecer o Hypnobirthing (HB) não só como método de preparação para o parto que harmoniza mente, corpo e feto, promovendo a confiança da mulher e o empoderamento das suas capacidades instintivas para o nascimento, mas também enquanto filosofia de cuidados do enfermeiro especialista em saúde materna e obstetrícia (ESMO), ao entender o nascimento como um evento fisiológico e natural. Propõe-se, portanto, compreender o impacto do ciclo medo-tensão-dor na evolução do trabalho de parto e na experiência de parto de cada mulher, as ferramentas utilizadas por este método e a forma como poderão ser implementadas na prática de cuidados do enfermeiro ESMO.info:eu-repo/semantics/publishedVersio
Results of Surgery Versus Stereotactic Body Radiotherapy for Lung Cancer
No full textinfo:eu-repo/semantics/publishedVersio
Oropharyngeal and Laryngeal Manifestations of human Monkeypox
No full textinfo:eu-repo/semantics/publishedVersio
Post Liver Transplantation Delirium Assessment Using the CAM-ICU-7 Scale: a Cohort Analysis
No full textBackground: We applied the Confusion Assessment Method (CAM)-Intensive Care Unit (ICU)-7 delirium scale to patients who underwent liver transplant (LT).
Methods: Retrospective cohort including patients who underwent LT for cirrhosis admitted to the ICU from June 2013 to June 2016 at the University of Alberta Hospital, Canada. Delirium was assessed using the CAM-ICU-7 scale (0-7 points) twice daily on days one and 3 post LT, with the highest score being considered. Primary endpoint was hospital mortality.
Results: Among all patients, 101/150 (67.3%) were men and mean age was 52.4 (SD 11.8) years. On days 1 and 3 post LT, mean CAM-ICU-7 scores were 1.8 (SD 1.3) and 1.6 (SD 1.8), respectively. Therefore, on days 1 and 3 post LT, 38/150 (25.3%) and 26/95 (27.4%) patients had delirium. While delirium on day 3 post LT was associated with higher hospital mortality (11.5% versus 0%; p = 0.019), it was not associated with length-of-hospital stay (29.2 versus 34.4 days; p = 0.36). Following adjustment for APACHEII score, delirium on day 3 post LT was associated with higher odds of hospital mortality (adjusted odds ratio [aOR] 1.89 [95% CI 1.02-3.50]). Following adjustment for Glasgow Coma Scale and mechanical ventilation, serum creatinine was associated with higher odds of delirium on day 3 post LT (aOR 2.02 [95% CI 1.08-3.77]).
Conclusions: Using the CAM-ICU-7 scale, delirium was diagnosed in a fourth of patients who underwent LT. Delirium on day 3 post LT was associated with higher odds of hospital mortality.info:eu-repo/semantics/publishedVersio