Blinded patient preference for morphine compared to placebo in the setting of chronic refractory breathlessness – an exploratory study

Context Patients’ preference for morphine therapy has received little attention in the setting of chronic refractory breathlessness. However, this is one important factor in considering longer term therapy. Objectives The aim of this secondary analysis is to explore blinded patient preference of morphine compared to placebo for this indication and to define any predictors of preference. Methods Data were pooled from three randomized, double-blind, crossover, placebo-controlled studies of morphine (four days each) in chronic refractory breathlessness. Blinded patient preferences were chosen at the end of each study. A multivariable regression model was used to establish patient predictors of preference. Results Sixty-five participants provided sufficient data (60 males; median age 74 years; heart failure 55%, chronic obstructive pulmonary disease 45%; median Eastern Cooperative Oncology Group performance status 2). Forty-three percent of participants preferred morphine (32% placebo and 25% no preference). Morphine preference and younger age were strongly associated: odds ratio = 0.85, 95% confidence interval 0.78, 0.93;

Investigation of early night sleep effects on subsequent fear extinction learning and recall

Extinction learning is considered an important underlying process of successful treatment of posttraumatic stress disorder (PTSD). However, sleep disturbances may impede this learning process: Current accounts postulate that sleep facilitates encoding by promoting neural plasticity during slow wave sleep (SWS). Based on this hypothesis, we tested whether early night sleep, with high amounts of SWS, facilitates subsequent extinction learning and recall. Sixty-three participants took part in a trauma-adapted fear conditioning experiment. One group received a three-hour sleep opportunity in the early night half, whereas the other group stayed awake. Thereafter, both groups underwent extinction training and a return-of-fear test. Retention was assessed after another sleep opportunity in both groups. Linear mixed-effects models and Bayesian inference did not support the hypothesis of strengthened fear extinction by prior early night sleep. Subsequent exploratory analyses, in contrast, point to a role of rapid eye movement sleep in promoting successful fear extinction learning. Further confirmatory research should re-investigate these effects and their implications for the treatment of PTSD

Opioids for breathlessness: a narrative review

ABSTRACT Chronic breathlessness is a disabling and distressing condition for which there is a growing evidence base for a range of interventions. Non-pharmacological interventions are the mainstay of management and should be optimised prior to use of opioid medication. Opioids are being implemented variably in practice for chronic breathlessness. This narrative review summarises the evidence defining current opioids for breathlessness best practice and identifies remaining research gaps.There is level 1a evidence to support the use of opioids for breathlessness. The best evidence is for 10mg to 30mg daily de novo low dose oral sustained-release morphine in opioid-naïve patients. This should be considered the current standard of care following independent, regulatory scrutiny by one of the world’s therapeutics regulatory bodies.Optimal benefits are seen in steady state, however, there are few published data about longer term benefits or harms. Morphine-related adverse events are common but mostly mild and self-limiting on withdrawal of drug. Early and meticulous management of constipation, nausea and vomiting is needed particularly in the first week of administration. Serious adverse events are no more common than placebo in clinical studies. Observational studies in severe chronic lung disease do not show excess mortality or hospital admission in those taking opioids. We have no long term data on immune or endocrine function.There are promising data regarding prophylaxis for exertion-related breathlessness, but given the risks associated with transmucosal fentanyl, caution is needed with regard to clinical use pending longer-term, robust safety data

Retinal neurodegeneration in different risk phenotypes of diabetic retinal disease

Diabetic retinopathy (DR) has been considered a microvascular disease, but it has become evident that neurodegeneration also plays a key role in this complex pathology. Indeed, this complexity is reflected in its progression which occurs at different rates in different type 2 diabetic (T2D) individuals. Based on this concept, our group has identified three DR progression phenotypes that might reflect the interindividual differences: phenotype A, characterized by low microaneurysm turnover (MAT <6), phenotype B, low MAT (<6) and increased central retinal thickness (CRT); and phenotype C, with high MAT (≥6). In this study, we evaluated the progression of DR neurodegeneration, considering ganglion cell+inner plexiform layers (GCL+IPL) thinning, in 170 T2D individuals followed for a period of 5 years, to explore associations with disease progression or risk phenotypes. Ophthalmological examinations were performed at baseline, first 6 months, and annually. GCL+IPL average thickness was evaluated by optical coherence tomography (OCT). Microaneurysm turnover (MAT) was evaluated using the RetMarkerDR. ETDRS level and severity progression were assessed in seven-field color fundus photography. In the overall population there was a significant loss in GCL+IPL (−0.147 μm/year), independently of glycated hemoglobin, age, sex, and duration of diabetes. Interestingly, this progressive thinning in GCL + IPL reached higher values in phenotypes B and C (−0.249 and −0.238 μm/year, respectively), whereas phenotype A remained relatively stable. The presence of neurodegeneration in all phenotypes suggests that it is the retinal vascular response to the early neurodegenerative changes that determines the course of the retinopathy in each individual. Therefore, classification of different DR phenotypes appears to offer relevant clarification of DR disease progression and an opportunity for improved management of each T2D individual with DR, thus playing a valuable role for the implementation of personalized medicine in DR.info:eu-repo/semantics/publishedVersio

Selection of aptamers against triple negative breast cancer cells using high throughput sequencing

Triple-negative breast cancer is the most aggressive subtype of invasive breast cancer with a poor prognosis and no approved targeted therapy. Hence, the identification of new and specific ligands is essential to develop novel targeted therapies. In this study, we aimed to identify new aptamers that bind to highly metastatic breast cancer MDA-MB-231 cells using the cell-SELEX technology aided by high throughput sequencing. After 8 cycles of selection, the aptamer pool was sequenced and the 25 most frequent sequences were aligned for homology within their variable core region, plotted according to their free energy and the key nucleotides possibly involved in the target binding site were analyzed. Two aptamer candidates, Apt1 and Apt2, binding specifically to the target cells with Kd values of 44.3 ± 13.3 nM and 17.7 ± 2.7 nM, respectively, were further validated. The binding analysis clearly showed their specificity to MDA-MB-231 cells and suggested the targeting of cell surface receptors. Additionally, Apt2 revealed no toxicity in vitro and showed potential translational application due to its affinity to breast cancer tissue sections. Overall, the results suggest that Apt2 is a promising candidate to be used in triple-negative breast cancer treatment and/or diagnosis. © 2021, The Author(s).Tis study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020—Programa Operacional Regional do Norte. Débora Ferreira (DF) is the recipient of a fellowship supported by a doctoral advanced training (call NORTE-69-2015-15) funded by the European Social Fund under the scope of Norte2020—Programa Operacional Regional do Norte. Joaquim Barbosa (JB) and Diana A. Sousa (DAS) acknowledge FCT for the Grants SFRH/BD/51109/2010 and PD/BD/139083/2018, respectively.info:eu-repo/semantics/publishedVersio

Regulation of biological paternity investigation: comparative perspective

O objetivo deste artigo analisar comparativamente a legisla o relativa investiga o de paternidade biológica de crianças nascidas fora do casamento no brasil e em países europeus, com base em pesquisa de documentos legislativos pela internet e na consulta de bibliografia jurídica no mbito do direito da família. Foi elaborada uma tipologia legislativa verdade biológica absoluta e verdade biológica relativa atendendo s seguintes variáveis: formas de atribui o da paternidade (voluntária/ordem do tribunal); tipo de consentimento exigido para realiza o do teste genético (voluntário/forçado); autor da investiga o (estado/outros); e limite temporal da investiga o (existência de prazos processuais/ausência de prazo processual). A verdade biológica absoluta ocorre quando a investigação de paternidade decorre obrigatoriamente, podendo ser ordenado e forçado pelo tribunal o recurso ao teste genético. observou-se a prevalência da verdade biológica relativa. Em todos os países analisados verificou-se que o recurso ao teste genético preponderante no estabelecimento das relações de filiação. Mesmo em países em que necessário o consentimento para a realização de teste de DNA existem modalidades de submiss o mais subtis, que incluem a aplicação de multas ou a gera o da presunção da paternidade com base na recusa em realizar exame genético.The aim of this article is to do a comparative analysis relative to the investigation of biological paternity of children born out of wedlock in Brazil and european countries, based on the research of legislative documents through the internet and the consultation of legal bibliography in the area of family law. The legislative typology was made - absolute biological truth and relative biological truth according to the following variables: forms of paternal attribution (voluntary/court ordered), type of demanded consent for the performance of the genetic test (voluntary/forced), author of the investigation (state/other) and the time limit of the investigation (existence of process deadlines/no process deadlines). The absolute biological truth occurs when the investigation of paternity is compulsory and the court might order and force the submission to a genetic test. The dominating trend is relative biological truth. In all analysed countries it has been verified that the resource to genetic testing is preponderant when establishing affiliation relations. Even in countries where it's not possible to force an individual to the submission of a genetic exam, there are more subtle ways of submission, that include the application of fines or the assumption of paternity based on a refusal to perform the genetic exam.info:eu-repo/semantics/publishedVersio

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

The Time to Offer Treatments for COVID-19

Introduction: COVID-19 has several overlapping phases. Treatment has focused on the late stage of the disease in hospital. Yet, the continuation of the pandemic is by propagation of the disease in outpatients. The current public health strategy relies solely on vaccines to prevent disease. Areas Covered: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results with subject numbers of 100 or more on, and used a targeted search to find announcements of unpublished trial results. As of 2/15/2021, we found 111 publications reporting findings in human studies on 14 classes of agents, and on 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care, the rest all in hospitalized patients. Remdesivir and convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but the supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries Expert Opinion: Worldwide vaccination is now underway. Vaccines and antibodies are highly antigen specific and new variants are appearing. There is a need for treatment of outpatients who contract the disease, in addition to mass immunization. We call on public health authorities to authorize treatments with known low risk and potential benefit for use in parallel with mass immunization

Poly (A)+ Transcriptome Assessment of ERBB2-Induced Alterations in Breast Cell Lines

We report the first quantitative and qualitative analysis of the poly (A)+ transcriptome of two human mammary cell lines, differentially expressing (human epidermal growth factor receptor) an oncogene over-expressed in approximately 25% of human breast tumors. Full-length cDNA populations from the two cell lines were digested enzymatically, individually tagged according to a customized method for library construction, and simultaneously sequenced by the use of the Titanium 454-Roche-platform. Comprehensive bioinformatics analysis followed by experimental validation confirmed novel genes, splicing variants, single nucleotide polymorphisms, and gene fusions indicated by RNA-seq data from both samples. Moreover, comparative analysis showed enrichment in alternative events, especially in the exon usage category, in ERBB2 over-expressing cells, data indicating regulation of alternative splicing mediated by the oncogene. Alterations in expression levels of genes, such as LOX, ATP5L, GALNT3, and MME revealed by large-scale sequencing were confirmed between cell lines as well as in tumor specimens with different ERBB2 backgrounds. This approach was shown to be suitable for structural, quantitative, and qualitative assessment of complex transcriptomes and revealed new events mediated by ERBB2 overexpression, in addition to potential molecular targets for breast cancer that are driven by this oncogene