A functional survey of the regulatory landscape of estrogen-receptor-positive breast cancer evolution.

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer (HDBC), potentially explaining ~40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of non-coding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies triggers the emergence of transient features which could ultimately be exploited to hinder the adaptive process.

Anger and disgust shape judgments of social sanctions across cultures, especially in high individual autonomy societies.

When someone violates a social norm, others may think that some sanction would be appropriate. We examine how the experience of emotions like anger and disgust relate to the judged appropriateness of sanctions, in a pre-registered analysis of data from a large-scale study in 56 societies. Across the world, we find that individuals who experience anger and disgust over a norm violation are more likely to endorse confrontation, ostracism and, to a smaller extent, gossip. Moreover, we find that the experience of anger is consistently the strongest predictor of judgments of confrontation, compared to other emotions. Although the link between state-based emotions and judgments may seem universal, its strength varies across countries. Aligned with theoretical predictions, this link is stronger in societies, and among individuals, that place higher value on individual autonomy. Thus, autonomy values may increase the role that emotions play in guiding judgments of social sanctions.

Prostate cancer treatment in Portugal: a nationwide analysis.

Different treatment options exist for localized prostate cancer. Treatments performed in high-volume hospitals are associated with better results. Our objective was to describe time trends in prostate cancer treatments in Portugal and case volume per hospital. We used the national database of diagnosis-related group of the Portuguese Central Administration of the Health System to describe the number of radical prostatectomy (RP), brachytherapy (BT) and external radiotherapy (eRT) treatments performed in all National Health System hospitals. There was a rapid increase in the annual number of RP until 2006 and then a deceleration; BT treatments augmented significantly until 2011. The utilization of eRT also increased, surpassing RP after 2010. From the 46 hospitals performing RP, only eight had a case-volume > 50 treatments/year, and from the nine hospitals performing BT, only four accomplished > 15 treatments/year. In the 11 hospitals with eRT, nine performed > 50/year. Regarding RP, there was negative correlation between the hospital volume and length of stay (r = - 0.303; p = 0.041). In the Portuguese National Health Service there was a steep increase in the number of prostate cancer treatments, and there is an ample margin for concentration of RP and BT treatments, for improvement of the hospitals case volume.

Assessment of energy sharing coefficients under the new Portuguese renewable energy communities regulation.

The recent published European legal framework (Directives (EU) 2018/2001 and 2019/944) on renewable energy consumption, and its Portuguese transposition (the Decree-Law 15/2022), opens the possibility for buildings to operate as energy communities. One of the objectives is to increase the use of locally generated energy from renewable sources, by sharing available surplus among participants, using sharing coefficients defined by the entire community. Taking the actual legal framework into consideration, this paper presents an analysis of the energy sharing coefficients proposed by the newly published Portuguese legislation via the assessment of a renewable energy community, formed by public buildings, whose operation varies according to different sharing coefficient applied. Results show that time-variable energy sharing coefficients are the best option to the considered renewable energy community. Collected results also show that larger consumers can extract higher benefits from being integrated on a renewable energy community. These benefits decrease when buildings are allowed to self-consume local generated energy prior to the sharing process as demand inequalities become less important for the computation of the considered sharing coefficients. The entire community also presents better performance in this case.

Psychometric Assessment of the Physicians' Job Demands and Resources Scale.

Job demands and resources have been consistently associated with the burnout syndrome in physicians, however the literature points to a lack of robust measures to assess these job characteristics across various medical specialties. This study aimed to develop a theoretically and empirically grounded physician-specific job demands and resources self-report measure - the Physicians' Job Demands and Resources Scale. Relevant dimensions of physicians' job demands and resources were identified, corresponding measurement items were generated and pre-tested, and the factor structure of the resulting 44 items was tested with a sample of 9,176 Portuguese physicians. The results of EFAs and CFAs with two random split samples provided consistent evidence of a nine-factor structure with 38 of the 44 items. Importantly, the nine-factor structure is consistent with the dimensions identified in the literature. The paper discusses the theoretical and practical impacts of the scale.

Selection of Rattus norvegicus cumulus-oocyte complex for vitrification by brilliant cresyl blue.

The influence of the method of evaluating developmentally competent oocytes on their viability after cryopreservation still needs to be better understood. The objective of this study was to determine the cleavage and embryo developmental rates after parthenogenetic activation of cumulus-oocyte complexes (COCs) selected by different concentrations of brilliant cresyl blue (BCB) and cryopreservation. In the first experiment, COCs were separated into groups and incubated for 1 h in medium containing BCB (13 µM, 16 µM, or 20 µM). The control group was not exposed to BCB staining. In the second experiment, COCs were divided into four groups: 13 µM BCB(+), 13 µM BCB(-), fresh control (selected by morphologic observation and immediately in vitro matured) and vitrified control (selected by morphologic evaluation, vitrified, and in vitro matured). In the first experiment, the 13 µM BCB group displayed greater development rates at the morula stage (65.45%, 36/55) when compared with the other groups. In the second experiment, cleavage (47.05%, 72/153) and morula development (33.55%, 51/153) of the control group of fresh COCs were increased compared with the other groups. However, when comparing morula rates between vitrified COC control and BCB(+) groups, the BCB(+) group had better results (19.23%, 5/26 and 64.7%, 11/17, respectively). Our best result in rat COC selection by BCB staining was obtained using a concentration of 13 µM. This selection could be a valuable tool to improve vitrification outcomes, as observed by the BCB(+) group that demonstrated better results compared with the vitrified COC control.

Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens.

YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.

Querying semantic catalogues of biomedical databases.

BACKGROUND: Secondary use of health data is a valuable source of knowledge that boosts observational studies, leading to important discoveries in the medical and biomedical sciences. The fundamental guiding principle for performing a successful observational study is the research question and the approach in advance of executing a study. However, in multi-centre studies, finding suitable datasets to support the study is challenging, time-consuming, and sometimes impossible without a deep understanding of each dataset. METHODS: We propose a strategy for retrieving biomedical datasets of interest that were semantically annotated, using an interface built by applying a methodology for transforming natural language questions into formal language queries. The advantages of creating biomedical semantic data are enhanced by using natural language interfaces to issue complex queries without manipulating a logical query language. RESULTS: Our methodology was validated using Alzheimer's disease datasets published in a European platform for sharing and reusing biomedical data. We converted data to semantic information format using biomedical ontologies in everyday use in the biomedical community and published it as a FAIR endpoint. We have considered natural language questions of three types: single-concept questions, questions with exclusion criteria, and multi-concept questions. Finally, we analysed the performance of the question-answering module we used and its limitations. The source code is publicly available at https://bioinformatics-ua.github.io/BioKBQA/. CONCLUSION: We propose a strategy for using information extracted from biomedical data and transformed into a semantic format using open biomedical ontologies. Our method uses natural language to formulate questions to be answered by this semantic data without the direct use of formal query languages.

Beyond the promise: evaluating and mitigating off-target effects in CRISPR gene editing for safer therapeutics.

Over the last decade, CRISPR has revolutionized drug development due to its potential to cure genetic diseases that currently do not have any treatment. CRISPR was adapted from bacteria for gene editing in human cells in 2012 and, remarkably, only 11 years later has seen it's very first approval as a medicine for the treatment of sickle cell disease and transfusion-dependent beta-thalassemia. However, the application of CRISPR systems is associated with unintended off-target and on-target alterations (including small indels, and structural variations such as translocations, inversions and large deletions), which are a source of risk for patients and a vital concern for the development of safe therapies. In recent years, a wide range of methods has been developed to detect unwanted effects of CRISPR-Cas nuclease activity. In this review, we summarize the different methods for off-target assessment, discuss their strengths and limitations, and highlight strategies to improve the safety of CRISPR systems. Finally, we discuss their relevance and application for the pre-clinical risk assessment of CRISPR therapeutics within the current regulatory context.

Crime Stereotypicality and Severity Database (CriSSD): Subjective norms for 63 crimes.

The existence of crime-related racial stereotypes has been well documented. People tend to associate certain groups with specific crimes, which, in turn, impacts criminal-sentencing decisions through the perceptions of crime severity. This evidence calls for regular updating of rating norms combining these variables. With this objective, and given that most of the normative studies provide norms for a small number of crimes and/or with an insufficient number of participants, a new norming study was conducted. Furthermore, norms from European countries are absent, and the existing ones (mostly with USA-based populations) do not simultaneously examine crime stereotypicality and crime severity. The Crime Stereotypicality and Severity Database (CriSSD) presents normative ratings for a set of 63 crimes on three dimensions: White stereotypicality, Black stereotypicality, and crime severity. The crimes were selected according to a comprehensive procedure. A total of 340 Portuguese participants (72.6% female; Mage = 26.86, SD = 7.65) answered an online survey. Each crime was evaluated by a range of 46-60 participants. Data allowed us to identify a crime typology with three clusters. We present descriptive data (means, standard deviations, and 95% confidence intervals) for each crime. Crime evaluations were associated with sociodemographic characteristics. Additionally, this study gives input regarding the understudied link between crime stereotypes and crime severity, showing that crime severity is predicted by ratings of both Black and White stereotypicality. The CriSSD (available at osf.io/gkbrm ) provides a valuable resource for researchers in the field of social psychology to conduct studies with controlled materials on potential disparities in criminal-sentencing decisions.

Semantic Data Visualisation for Biomedical Database Catalogues.

Biomedical databases often have restricted access policies and governance rules. Thus, an adequate description of their content is essential for researchers who wish to use them for medical research. A strategy for publishing information without disclosing patient-level data is through database fingerprinting and aggregate characterisations. However, this information is still presented in a format that makes it challenging to search, analyse, and decide on the best databases for a domain of study. Several strategies allow one to visualise and compare the characteristics of multiple biomedical databases. Our study focused on a European platform for sharing and disseminating biomedical data. We use semantic data visualisation techniques to assist in comparing descriptive metadata from several databases. The great advantage lies in streamlining the database selection process, ensuring that sensitive details are not shared. To address this goal, we have considered two levels of data visualisation, one characterising a single database and the other involving multiple databases in network-level visualisations. This study revealed the impact of the proposed visualisations and some open challenges in representing semantically annotated biomedical datasets. Identifying future directions in this scope was one of the outcomes of this work.

The role of stereotypical information on medical judgements for black and white patients.

THIS ARTICLE USES WORDS OR LANGUAGE THAT IS CONSIDERED PROFANE, VULGAR, OR OFFENSIVE BY SOME READERS. The new generation of direct-acting antivirals has improved dramatically the rates of cure for chronic hepatitis C. Yet, evidence shows that racial groups are deemed more often ineligible for hepatitis C treatment, despite no clinical evidence supporting differential treatment for Black and White patients. One possible explanation has to do with providers' racial biases. This investigation sought to explore medical students' racial stereotypes (Study 1, N = 171) and the role of stereotypical cues on perceptions of medical adherence of Black and White patients (Study 2, N = 208). In Study 1, we first sought to identify health-related aspects that are consistently associated with Blacks as part of a stereotype. In Study 2, we experimentally manipulated racial stereotypes identified in Study 1 by asking participants to read a clinical vignette depicting a patient (Black vs. White) and their medical history (cause of exposure to hepatitis C: unprotected sex vs. non-injectable drugs use). The results show that the impact of stereotypicality on patient perceived compliance varies as a function of medical students' racial prejudice. Implications for further applied health inequalities research and for medical training are discussed.

Discovery of Biomedical Databases Through Semantic Questioning.

Many clinical studies are greatly dependent on an efficient identification of relevant datasets. This selection can be performed in existing health data catalogues, by searching for available metadata. The search process can be optimised through questioning-answering interfaces, to help researchers explore the available data present. However, when searching the distinct catalogues the lack of metadata harmonisation imposes a few bottlenecks. This paper presents a methodology to allow semantic search over several biomedical database catalogues, by extracting the information using a shared domain knowledge. The resulting pipeline allows the converted data to be published as FAIR endpoints, and it provides an end-user interface that accepts natural language questions.

Staged upper and lower lip reanimation following facial palsy: Peer-reviewed, patient-rated and objective outcomes.

BACKGROUND: One approach to reanimating both upper and lower lips following facial palsy is through staged surgery: cross-face nerve grafting at stage I, free gracilis muscle transfer to levators at stage II and pedicled anterior belly of digastric muscle transfer (ABDMT) to depressors at stage III. The results of this approach were hitherto unquantified. METHODS: This study retrospectively assessed peer-reviewed, patient-rated and objective outcomes following staged reanimation in adults between 2010 and 2020. Demographics, palsy characteristics and surgery details were recorded. Pre- and postoperative videos were rated by independent assessors using Terzis' aesthetic and symmetry scale. Photographs were analysed using Emotrics and patients completed the Glasgow Benefit Inventory (GBI) patient-rated outcome measure. RESULTS: Ten patients [mean age = 34 (SD = 12.48)] were eligible. All regained lip elevation and depression. All markers of symmetry improved after gracilis transfer. All markers were also improved after ABDMT except for lower lip height when smiling with teeth showing (p > 0.05). Five patients (50%) responded to the GBI (mean score = +39.44). No patients reported detriment from the reanimations. Mean Terzis' scores preoperatively and after stages II and III were 1.5, 2.26 and 2.39, respectively (p < 0.05). Nine patients underwent aesthetic refinements [lipofilling to lower lip notches (n = 5), debulking of gracilis bulk (n = 6), repositioning of muscle insertion (n = 5) and facelifts (n = 2)]. CONCLUSION: The outcomes were positive objectively and as judged by peers and patients themselves. Aesthetic refinements may also be required to enhance these results.

Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure.

Levodopa (L-DOPA) is an oral Parkinson's Disease drug that generates the active metabolite - dopamine (DA) in vivo. However, oral L-DOPA exhibits low oral bioavailability, limited brain uptake, peripheral DA-mediated side effects and its poor brain bioavailability can lead to long-term complications. Here we show that L-DOPA forms stable (for at least 5 months) 300 nm nanoparticles when encapsulated within N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ). A nano-in-microparticle GCPQ-L-DOPA formulation (D50 = 7.2 µm), prepared by spray-drying, was stable for one month when stored at room and refrigeration temperatures and was capable of producing the original GCPQ-L-DOPA nanoparticles upon aqueous reconstitution. Nasal administration of reconstituted GCPQ-L-DOPA nanoparticles to rats resulted in significantly higher DA levels in the brain (Cmax of 94 ng g-1 above baseline levels 2 h post-dosing) when compared to nasal administration of L-DOPA alone, with DA being undetectable in the brain with the latter. Furthermore, nasal GCPQ-L-DOPA resulted in higher levels of L-DOPA in the plasma (a 17-fold increase in the Cmax, when compared to L-DOPA alone) with DA undetectable in the plasma from both formulations. These data provide evidence of effective delivery of DA to the brain with the GCPQ-L-DOPA formulation.

Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin.

Strategies targeting nucleolin have enabled a significant improvement in intracellular bioavailability of their encapsulated payloads. In this respect, assessment of the impact of target cell heterogeneity and nucleolin homology across species (structurally and functionally) is of major importance. This work also aimed at mathematically modelling the nucleolin expression levels at the cell membrane, binding and internalization of pH-sensitive pegylated liposomes encapsulating doxorubicin and functionalized with the nucleolin-binding F3 peptide (PEGASEMP), and resulting cytotoxicity against cancer cells from mouse, rat, canine, and human origin. Herein, it was shown that nucleolin expression levels were not a limitation on the continuous internalization of F3 peptide-targeted liposomes, despite the saturable nature of the binding mechanism. Modeling enabled the prediction of nucleolin-mediated total doxorubicin exposure provided by the experimental settings of the assessment of PEGASEMP's impact on cell death. The former increased proportionally with nucleolin-binding sites, a measure relevant for patient stratification. This pattern of variation was observed for the resulting cell death in nonsaturating conditions, depending on the cancer cell sensitivity to doxorubicin. This approach differs from standard determination of cytotoxic concentrations, which normally report values of incubation doses rather than the actual intracellular bioactive drug exposure. Importantly, in the context of development of nucleolin-based targeted drug delivery, the structural nucleolin homology (higher than 84%) and functional similarity across species presented herein, emphasized the potential to use toxicological data and other metrics from lower species to infer the dose for a first-in-human trial.

Lower lip depressor reanimation using anterior belly of digastric muscle transfer improves psychological wellbeing in facial palsy patients.

The authors previously published positive peer-reviewed (21 raters using the Terzis scale) and photogrammetric (Emotrics) outcomes in patients who had undergone two-stage lower lip reanimations up to 2018. Other series have published surgeon and peer-rated results, but we know of only two (n=12) that have assessed patients' views using patient satisfaction surveys. This paper presents patient-rated outcomes (PROMS) in an 11-year series of both single and two-stage anterior belly of digastric muscle (ABDM) lower lip reanimations. Demographics, paralysis characteristics, operative details, and complications were recorded. Patients were telephoned and requested to complete the Glasgow Benefit Inventory (GBI) to assess patient-rated outcomes. Thirty-two patients were eligible (mean age 36.4 years). Twenty-one (63.6%) completed the GBI (mean score +33.3). More patients reported benefit than detriment (95.2% vs 4.8%). Complications were infrequent and included three cases of superficial infections and one of dermatitis. Four patients (12.5%) underwent minor revisions, mostly lipofilling of lip notches. The median (range) duration of follow up was 2.8 (0.3 - 8.5) years. ABDM transfer for lower lip reanimation is a safe, low morbidity procedure that enhances the psychological wellbeing of patients with facial palsy.

From Optical Tracking to Tactical Performance via Voronoi Diagrams: Team Formation and Players' Roles Constrain Interpersonal Linkages in High-Level Football.

Football performance behaviour relies on the individual and collective perceptual attunement to the opportunities for action (affordances) available in a given competitive environment. Such perception-action coupling is constrained by players' spatial dominance. Aiming to understand the influence of team formation and players' roles in their dynamic interaction (interpersonal linkages), Voronoi diagrams were used to assess the differences in players' spatial dominance resulting from their interactions according to ball-possession status in high-performance football. Notational (i.e., team formation, players' role, and ball-possession status) and positional data (from optical sensors) from ten matches of the men's French main football league were analysed. Voronoi diagrams were computed from players' positional data for both teams. Probability density functions of the players' Voronoi cell areas were then computed and compared, using the Kolmogorov-Smirnov test, for the different variables (i.e., team formation, player role, and ball-possession status) and their classes. For these variables, the players' Voronoi cell areas presented statistical differences, which were sensitive to team formation classes (i.e., defenders, midfielders, and forwards) and relative pitch location (interior or exterior in the effective play space). Differences were also found between players with similar roles when in different team formations. Our results showed that team formation and players' roles constrain their interpersonal linkages, resulting in different spatial dominance patterns. Using positional data captured by optical sensors, Voronoi diagrams can be computed into compound variables, which are meaningful for understanding the match and thus offer information to the design representative training tasks.

Virtual Reality Rehabilitation's Impact on Negative Symptoms and Psychosocial Rehabilitation in Schizophrenia Spectrum Disorder: A Systematic Review.

BACKGROUND: Schizophrenia is a chronic psychiatric disorder with symptoms that can severely affect patients' quality of life. While drug administration inhibits most of the positive symptoms, it fails to effectively treat the negative symptoms and in turn relies on rehabilitation therapies. With technological progress, virtual reality (VR) has been the target of recent studies in terms of mental health rehabilitation and has been shown to be a tool with ecological validity in order to introduce the individual to situations similar to their daily life. METHODS: From July to August 2021, we conducted a systematic review with the purpose of understanding the impact of virtual reality rehabilitation on negative symptoms and psychosocial rehabilitation in the schizophrenia spectrum. The searches were performed in the databases Web of Science, Scopus, and PubMed. RESULTS: In our search, we identified 201 results, where 108 duplicates were excluded, resulting in a final balance of 93. After reading and assessing the titles and abstracts, 66 studies were excluded. Of the remaining 27 reports, 23 were excluded for not meeting the previously defined eligibility criteria, resulting in the inclusion of four studies in this systematic review. CONCLUSIONS: The available data on the specific topic was limited and could have been more complete. However, in our review, we were able to identify statistically relevant results demonstrating the effectiveness of intervention. We could find medium to large effects, allowing VR to be an ally for rehabilitation of symptoms related to schizophrenia.

SARS-CoV-2 inhibition using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray.

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of - 3 to - 4 at a concentration of 10-100 µg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 µg/ mL (p < 0.05 compared to untreated controls). In vivo studies using transgenic mice expressing the ACE-2 receptor, dosed nasally with SARS-COV-2 (426,000 TCID50/mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ's electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.