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Abstract Gene expression is an intricate biological process that bridges gap between the genotype and the phenotype. Canonical and hereditable epigenetic mechanisms, such as histone and DNA modifications, regulate the release of genetic information encoded in DNA without altering the underlying sequence. Many other non-canonical players, such as chromatin regulators and noncoding RNAs, are also involved in regulating gene expression. Recently, RNA modifications (epitranscriptomics) have been shown to hold enormous potential in shaping cellular transcriptomes. However, their co-transcriptional nature and uncertain heritability mean that they fall outside the current definition of epigenetics, sparking an ongoing debate in the field. Here we will discuss the relationship between canonical and non-canonical epigenetic mechanisms that govern gene expression and offer our perspective on whether (or not) epitranscriptomic modifications can be classified as epigenetic mechanisms.

Abstract Background Risk stratification and treatment benefit prediction models are urgent to improve negative sentinel lymph node (SLN-) melanoma patient selection, thus avoiding costly and toxic treatments in patients at low risk of recurrence. To this end, the application of artificial intelligence (AI) could help clinicians to better calculate the recurrence risk and choose whether to perform adjuvant therapy. Methods We made use of AI to predict recurrence-free status (RFS) within 2-years from diagnosis in 94 SLN- melanoma patients. In detail, we detected quantitative imaging information from H&E slides of a cohort of 71 SLN- melanoma patients, who registered at Istituto Tumori “Giovanni Paolo II” in Bari, Italy (investigational cohort, IC). For each slide, two expert pathologists firstly annotated two Regions of Interest (ROIs) containing tumor cells alone (TUMOR ROI) or with infiltrating cells (TUMOR + INF ROI). In correspondence of the two kinds of ROIs, two AI-based models were developed to extract information directly from the tiles in which each ROI was automatically divided. This information was then used to predict RFS. Performances of the models were computed according to a 5-fold cross validation scheme. We further validated the prediction power of the two models on an independent external validation cohort of 23 SLN- melanoma patients (validation cohort, VC). Results The TUMOR ROIs have revealed more informative than the TUMOR + INF ROIs. An Area Under the Curve (AUC) value of 79.1% and 62.3%, a sensitivity value of 81.2% and 76.9%, a specificity value of 70.0% and 43.3%, an accuracy value of 73.2% and 53.4%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the IC cohort, respectively. An AUC value of 76.5% and 65.2%, a sensitivity value of 66.7% and 41.6%, a specificity value of 70.0% and 55.9%, an accuracy value of 70.0% and 56.5%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the VC cohort, respectively. Conclusions Our approach represents a first effort to develop a non-invasive prognostic method to better define the recurrence risk and improve the management of SLN- melanoma patients.

Abstract Several studies have emphasised how positive and negative human papillomavirus (HPV+ and HPV−, respectively) oropharyngeal squamous cell carcinoma (OPSCC) has distinct molecular profiles, tumor characteristics, and disease outcomes. Different radiomics-based prediction models have been proposed, by also using innovative techniques such as Convolutional Neural Networks (CNNs). Although some of these models reached encouraging predictive performances, there evidence explaining the role of radiomic features in achieving a specific outcome is scarce. In this paper, we propose some preliminary results related to an explainable CNN-based model to predict HPV status in OPSCC patients. We extracted the Gross Tumor Volume (GTV) of pre-treatment CT images related to 499 patients (356 HPV+ and 143 HPV−) included into the OPC-Radiomics public dataset to train an end-to-end Inception-V3 CNN architecture. We also collected a multicentric dataset consisting of 92 patients (43 HPV+ , 49 HPV−), which was employed as an independent test set. Finally, we applied Gradient-weighted Class Activation Mapping (Grad-CAM) technique to highlight the most informative areas with respect to the predicted outcome. The proposed model reached an AUC value of 73.50% on the independent test. As a result of the Grad-CAM algorithm, the most informative areas related to the correctly classified HPV+ patients were located into the intratumoral area. Conversely, the most important areas referred to the tumor edges. Finally, since the proposed model provided additional information with respect to the accuracy of the classification given by the visualization of the areas of greatest interest for predictive purposes for each case examined, it could contribute to increase confidence in using computer-based predictive models in the actual clinical practice.

Abstract Local adaptation can increase fitness under stable environmental conditions. However, in rapidly changing environments, compensatory mechanisms enabled through plasticity may better promote fitness. Climate change is causing devastating impacts on coral reefs globally and understanding the potential for adaptive and plastic responses is critical for reef management. We conducted a four-year, three-way reciprocal transplant of the Caribbean coral Siderastrea siderea across forereef, backreef, and nearshore populations in Belize to investigate the potential for environmental specialization versus plasticity in this species. Corals maintained high survival within forereef and backreef environments, but transplantation to nearshore environments resulted in high mortality, suggesting that nearshore environments present strong environmental selection. Only forereef-sourced corals demonstrated evidence of environmental specialization, exhibiting the highest growth in the forereef. Gene expression profiling 3.5 years post-transplantation revealed that transplanted coral hosts exhibited profiles more similar to other corals in the same reef environment, regardless of their source location, suggesting that transcriptome plasticity facilitates acclimatization to environmental change in S. siderea. In contrast, algal symbiont (Cladocopium goreaui) gene expression showcased functional variation between source locations that was maintained post-transplantation. Our findings suggest limited acclimatory capacity of some S. siderea populations under strong environmental selection and highlight the potential limits of coral physiological plasticity in reef restoration.

Introduction: Autologous stem cell transplantation (ASCT) is the standard consolidation option for transplant-eligible patients with multiple myeloma (MM). The aim of this study is to report the overall survival (OS) and progression-free survival (PFS) outcomes after frontline ASCT in newly-diagnosed MM (NDMM) patients in a real-world setting. Methods: We conducted a retrospective, survival analysis of all NDMM patients included in the MM Uruguayan Registry. Results: We included 151 NDMM patients treated with induction therapy followed by high-dose melphalan and ASCT as consolidation. The median age at diagnosis was 59 years, and the international staging system (ISS) risk groups were ISS-III 32.9%, ISS-II 37.8%, and ISS-I 29.4%. Frontline induction regimens included bortezomib in 61.6% of cases, and maintenance therapy was used in 63.9% of reported cases. With a median follow-up of 42 months, the 36-month OS and PFS for the whole group were 82.4% (95% CI 75.9% to 89.4%) and 63.8% (95% CI 55.6% to 73.3%), respectively, median OS of 98 months and median PFS of 47 months. The 100-month OS and PFS for the entire group were 48.0% (95% CI 34.9% to 66.0%) and 17.3% (95% CI 8.4% to 35.8%), respectively. Conclusion: ASCT is a feasible, safe, and potent strategy that provides a prolonged median OS and PFS in NDMM patients. This approach can be implemented in low-income countries.

Abstract Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a ‘bring-your-own-device’ solution that remotely measures a user’s mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input (‘active tests’). Levels of mobility of study participants (‘life-space measurement’) were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

Background: Oncology nurses support cancer patients in meeting their self-care needs, often neglecting their own emotions and self-care needs. This study aims to investigate the variations in the five facets of holistic mindfulness among Italian oncology nurses based on gender, work experience in oncology, and shift work. Method: A cross-sectional study was carried out in 2023 amongst all registered nurses who were employed in an oncology setting and working in Italy. Results: There were no significant differences in all five facets of holistic mindfulness (p ≥ 0.05) according to gender, work experience in the oncology field, and shift work. Conclusion: Could holistic mindfulness be defined as an intrinsic individual characteristic? Surely, more insights will be necessary to better define the holistic trend in oncology nursing.

Our study investigates the post-mortem findings of the diaphragm's muscular structural changes in mechanically ventilated COVID-19 patients. Diaphragm samples of the right side from 42 COVID-19 critically ill patients were analyzed and correlated with the type and length of mechanical ventilation (MV), ventilatory parameters, prone positioning, and use of sedative drugs. The mean number of fibers was 550±626. The cross-sectional area was 4120±3280 μm2, while the muscular fraction was 0.607±0.126. The overall population was clustered into two distinct populations (clusters 1 and 2). Cluster 1 showed a lower percentage of slow myosin fiber and higher fast fiber content than cluster 2, 68% versus 82%, p

BackgroundPeople living with multiple sclerosis (MS) face a higher likelihood of being diagnosed with a depressive disorder than the general population. Although many low-cost screening tools and evidence-based interventions exist, depression in people living with MS is underreported, underascertained by clinicians, and undertreated. ObjectiveThis study aims to design a closed-loop tool to improve depression care for these patients. It would support regular depression screening, tie into the point of care, and support shared decision-making and comprehensive follow-up. After an initial development phase, this study involved a proof-of-concept pilot randomized controlled trial (RCT) validation phase and a detailed human-centered design (HCD) phase. MethodsDuring the initial development phase, the technological infrastructure of a clinician-facing point-of-care clinical dashboard for MS management (BRIDGE) was leveraged to incorporate features that would support depression screening and comprehensive care (Care Technology to Ascertain, Treat, and Engage the Community to Heal Depression in people living with MS [MS CATCH]). This linked a patient survey, in-basket messages, and a clinician dashboard. During the pilot RCT phase, a convenience sample of 50 adults with MS was recruited from a single MS center with 9-item Patient Health Questionnaire scores of 5-19 (mild to moderately severe depression). During the routine MS visit, their clinicians were either asked or not to use MS CATCH to review their scores and care outcomes were collected. During the HCD phase, the MS CATCH components were iteratively modified based on feedback from stakeholders: people living with MS, MS clinicians, and interprofessional experts. ResultsMS CATCH links 3 features designed to support mood reporting and ascertainment, comprehensive evidence-based management, and clinician and patient self-management behaviors likely to lead to sustained depression relief. In the pilot RCT (n=50 visits), visits in which the clinician was randomized to use MS CATCH had more notes documenting a discussion of depressive symptoms than those in which MS CATCH was not used (75% vs 34.6%; χ21=8.2; P=.004). During the HCD phase, 45 people living with MS, clinicians, and other experts participated in the design and refinement. The final testing round included 20 people living with MS and 10 clinicians including 5 not affiliated with our health system. Most scoring targets for likeability and usability, including perceived ease of use and perceived effectiveness, were met. Net Promoter Scale was 50 for patients and 40 for clinicians. ConclusionsCreated with extensive stakeholder feedback, MS CATCH is a closed-loop system aimed to increase communication about depression between people living with MS and their clinicians, and ultimately improve depression care. The pilot findings showed evidence of enhanced communication. Stakeholders also advised on trial design features of a full year long Department of Defense–funded feasibility and efficacy trial, which is now underway. Trial RegistrationClinicalTrials.gov NCT05865405; http://tinyurl.com/4zkvru9x

Introduction Depression occurs in over 50% of individuals living with multiple sclerosis (MS) and can be treated using many modalities. Yet, it remains: under-reported by patients, under-ascertained by clinicians and under-treated. To enhance these three behaviours likely to promote evidence-based depression care, we engaged multiple stakeholders to iteratively design a first-in-kind digital health tool. The tool, MS CATCH (Care technology to Ascertain, Treat, and engage the Community to Heal depression in patients with MS), closes the communication loop between patients and clinicians. Between clinical visits, the tool queries patients monthly about mood symptoms, supports patient self-management and alerts clinicians to worsening mood via their electronic health record in-basket. Clinicians can also access an MS CATCH dashboard displaying patients’ mood scores over the course of their disease, and providing comprehensive management tools (contributing factors, antidepressant pathway, resources in patient’s neighbourhood). The goal of the current trial is to evaluate the clinical effect and usability of MS CATCH in a real-world clinical setting.Methods and analysis MS CATCH is a single-site, phase II randomised, delayed start, trial enrolling 125 adults with MS and mild to moderately severe depression. Arm 1 will receive MS CATCH for 12 months, and arm 2 will receive usual care for 6 months, then MS CATCH for 6 months. Clinicians will be randomised to avoid practice effects. The effectiveness analysis is superiority intent-to-treat comparing MS CATCH to usual care over 6 months (primary outcome: evidence of screening and treatment; secondary outcome: Hospital Anxiety Depression Scale-Depression scores). The usability of the intervention will also be evaluated (primary outcome: adoption; secondary outcomes: adherence, engagement, satisfaction).Ethics and dissemination University of California, San Francisco Institutional Review Board (22-36620). The findings of the study are planned to be shared through conferences and publishments in a peer-reviewed journal. The deidentified dataset will be shared with qualified collaborators on request, provision of CITI and other certifications, and data sharing agreement. We will share the results, once the data are complete and analysed, with the scientific community and patient/clinician participants through abstracts, presentations and manuscripts.Trial registration number NCT05865405.

Renal and genitourinary ultrasound are fundamental resources employed by emergency and critical care healthcare providers to make prompt diagnoses and perform ultrasound-guided procedures. At the bedside, ultrasound can aid in the diagnosis of relevant pathologies, such as post-renal obstruction or kidney stones, and life-threatening conditions such as aortic dissection or hemoperitoneum. A narrative overview was performed, providing an updated review of renal and genitourinary ultrasound for emergency and critical care healthcare providers, emphasizing its advantages and the latest advances in the field. A thorough summary that can be utilized as a guide for emergency and critical care healthcare providers is presented. The daily hemodynamic management of critically ill patients involves the implementation of new protocols, such as VexUS or the evaluation of the renal resistance index. The role of ultrasound in managing acute nephropathy and genitourinary issues is increasingly crucial given its bedside availability, thus this imaging modality not only facilitates the initiation of therapeutic interventions but also provides swift prognostic insights that are vital to provide tailored patient care. As further advances in ultrasound will arise, it is important for healthcare providers to foster the use of these technologies capable of improving patient outcomes.

Abstract Time-of-day influences both physical and mental performances. Its impact on motor learning is, however, not well established yet. Here, using a finger tapping-task, we investigated the time-of-day effect on skill acquisition (i.e., immediately after a physical or mental practice session) and consolidation (i.e., 24 h later). Two groups (one physical and one mental) were trained in the morning (10 a.m.) and two others (one physical and one mental) in the afternoon (3 p.m.). We found an enhancement of motor skill following both types of practice, whatever the time of the day, with a better acquisition for the physical than the mental group. Interestingly, there was a better consolidation for both groups when the training session was scheduled in the afternoon. Overall, our results indicate that the time-of-day positively influences motor skill consolidation and thus must be considered to optimize training protocols in sport and clinical domains to potentiate motor learning.

Introduction There is growing attention towards the possible long-term effect of COVID-19 on neuropsychiatric disorders. Material and methods We tested the effect of a combined nutraceutical (Synaid) with known nootropic effects in 40 elderly patients with self-perceived cognitive decline after SARS-CoV-2 infection, treated at home or in hospital. Results After 3 months of treatment, Synaid significantly improved functional status, MMSE and the main psychological disorders associated with mild cognitive impairment, both in patients previously cared for at home and in hospital because of SARS-CoV-2 infection. Conclusions Synaid was well tolerated and effective in improving cognitive function and psychosocial parameters after SARS-CoV-2 infection.

Designing targeted treatments for breast cancer patients after primary tumor removal is necessary to prevent the occurrence of invasive disease events (IDEs), such as recurrence, metastasis, contralateral and second tumors, over time. However, due to the molecular heterogeneity of this disease, predicting the outcome and efficacy of the adjuvant therapy is challenging. A novel ensemble machine learning classification approach was developed to address the task of producing prognostic predictions of the occurrence of breast cancer IDEs at both 5- and 10-years. The method is based on the concept of voting among multiple models to give a final prediction for each individual patient. Promising results were achieved on a cohort of 529 patients, whose data, related to primary breast cancer, were provided by Istituto Tumori "Giovanni Paolo II" in Bari, Italy. Our proposal greatly improves the performances returned by the baseline original model, i.e., without voting, finally reaching a median AUC value of 77.1% and 76.3% for the IDE prediction at 5-and 10-years, respectively. Finally, the proposed approach allows to promote more intelligible decisions and then a greater acceptability in clinical practice since it returns an explanation of the IDE prediction for each individual patient through the voting procedure.

Global change driven by anthropogenic carbon emissions is altering ecosystems at unprecedented rates, especially coral reefs, whose symbiosis with algal symbionts is particularly vulnerable to increasing ocean temperatures and altered carbonate chemistry. Here, we assess the physiological responses of three Caribbean coral (animal host + algal symbiont) species from an inshore and offshore reef environment after exposure to simulated ocean warming (28, 31°C), acidification (300-3290 μatm), and the combination of stressors for 93 days. We used multidimensional analyses to assess how a variety of coral physiological parameters respond to ocean acidification and warming. Our results demonstrate reductions in coral health in Siderastrea siderea and Porites astreoides in response to projected ocean acidification, while future warming elicited severe declines in Pseudodiploria strigosa. Offshore S. siderea fragments exhibited higher physiological plasticity than inshore counterparts, suggesting that this offshore population was more susceptible to changing conditions. There were no plasticity differences in P. strigosa and P. astreoides between natal reef environments, however, temperature evoked stronger responses in both species. Interestingly, while each species exhibited unique physiological responses to ocean acidification and warming, when data from all three species are modelled together, convergent stress responses to these conditions are observed, highlighting the overall sensitivities of tropical corals to these stressors. Our results demonstrate that while ocean warming is a severe acute stressor that will have dire consequences for coral reefs globally, chronic exposure to acidification may also impact coral physiology to a greater extent in some species than previously assumed. Further, our study identifies S. siderea and P. astreoides as potential 'winners' on future Caribbean coral reefs due to their resilience under projected global change stressors, while P. strigosa will likely be a 'loser' due to their sensitivity to thermal stress events. Together, these species-specific responses to global change we observe will likely manifest in altered Caribbean reef assemblages in the future.

How cells with different genetic makeups compete in tissues is an outstanding question in developmental biology and cancer research. Studies in recent years have revealed that cell competition can either be driven by short-range biochemical signalling or by long-range mechanical stresses in the tissue. To date, cell competition has generally been characterised at the population scale, leaving the single-cell-level mechanisms of competition elusive. Here, we use high time-resolution experimental data to construct a multi-scale agent-based model for epithelial cell competition and use it to gain a conceptual understanding of the cellular factors that governs competition in cell populations within tissues. We find that a key determinant of mechanical competition is the difference in homeostatic density between winners and losers, while differences in growth rates and tissue organisation do not affect competition end result. In contrast, the outcome and kinetics of biochemical competition is strongly influenced by local tissue organisation. Indeed, when loser cells are homogenously mixed with winners at the onset of competition, they are eradicated; however, when they are spatially separated, winner and loser cells coexist for long times. These findings suggest distinct biophysical origins for mechanical and biochemical modes of cell competition.

El mieloma múltiple representa la segunda neoplasia hematológica en frecuencia. Es una enfermedad incurable, cuya sobrevida se ha duplicado en los últimos años, vinculado esto a la aparición de nuevos fármacos. Los planes con bortezomib mejoran la respuesta, sobrevida libre de progresión y sobrevida global. En Uruguay, desde 2009, este fármaco tiene cobertura por parte del Fondo Nacional de Recursos. Este estudio tiene como objetivo analizar la efectividad y toxicidad de bortezomib en pacientes con diagnóstico de mieloma múltiple asistidos en el Hospital de Clínicas. Método: estudio observacional, retrospectivo y descriptivo en el que se incluyeron todos los pacientes con diagnóstico de mieloma múltiple que recibieron tratamiento con bortezomib en primera, segunda o tercera línea en el Hospital de Clínicas de Montevideo, Uruguay, desde 2009 a 2016. Resultados: 36 pacientes recibieron bortezomib. El plan más utilizado fue ciclofosfamida-bortezomib-dexametasona. La vía de administración fue subcutánea en 53,8%. La tasa de respuesta global fue de 79,5% (87% en primera línea y 68,8% en segunda o tercera línea). El 47,2% desarrolló polineuropatía y 30,6% citopenias. Con una mediana de seguimiento de 26 meses la sobrevida global fue de 61% y la sobrevida libre de progresión de 35 meses (IC 95%, 22,6-47,4). Conclusión: el tratamiento con bortezomib logró buena tasa de respuesta. La neuropatía fue la toxicidad más frecuente. Bortezomib es un fármaco efectivo y con adecuado perfil de seguridad para el tratamiento del mieloma múltiple en primera, segunda y tercera línea.

The 2018 West Nile Virus (WNV) season in Europe was characterized by an extremely high infection rate and an exceptionally higher burden when compared to previous seasons. Overall, there was a 10.9-fold increase in incidence in Italy, with 577 human cases, 230 WNV neuroinvasive diseases (WNNV) and 42 WNV-attributed deaths. Methods: in this paper we retrospectively reported the neurological presentation of 7 patients admitted to University Hospital of Udine with a diagnosis of WNNV, especially focusing on two patients who presented with atypical severe brain stem involvement. Conclusions: the atypical features of some of these forms highlight the necessity to stay vigilant and suspect the diagnosis when confronted with neurological symptoms. We strongly encourage clinicians to consider WNNV in patients presenting with unexplained neurological symptoms in mild climate-areas at risk.

Background: The objective of this study was to evaluate those factors, both intrinsic and extrinsic to the emergency department (ED) that influence two specific components of throughput: “door-to-doctor” time and dwell time.Methods: We used a prospective observational study design to determine the variables that played a significant role in determining ED flow. All adult patients seen or waiting to be seen in the ED were observed at 8pm (Monday-Friday) during a three-month period. Variables measured included daily ED volume, patient acuity, staffing, ED occupancy, daily admissions, ED boarder volume, hospital volume, and intensive care unit volume. Both log-rank tests and time-to-wait (survival) proportional-hazard regression models were fitted to determine which variables were most significant in predicting “door-to-doctor” and dwell times, with full account of the censoring for some patients.Results: We captured 1,543 patients during our study period, representing 27% of total daily volume. The ED operated at an average of 85% capacity (61-102%) with an average of 27% boarding. Median “door-to-doctor” time was 1.8 hours, with the biggest influence being triage category, day of the week, and ED occupancy. Median dwell time was 5.5 hours with similar variable influences.Conclusion: The largest contributors to decreased patient flow through the ED at our institution were triage category, ED occupancy, and day of the week. Although the statistically significant factors influencing patient throughput at our institution involve problems with inflow, an increase in ED occupancy could be due to substantial outflow obstruction and may indicate the necessity for increased capacity both within the ED and hospital. [West J Emerg Med. 2010; 11(1):10-15]

In order to obtain further information on the pathophysiology of functional tremor, we assessed tactile discrimination threshold and proprioceptive temporal discrimination motor threshold values in 11 patients with functional tremor, 11 age- and sex-matched patients with essential tremor and 13 healthy controls.Tactile discrimination threshold in both the right and left side was significantly higher in patients with functional tremor than in the other groups. Proprioceptive temporal discrimination threshold for both right and left side was significantly higher in patients with functional and essential tremor than in healthy controls. No significant correlation between discrimination thresholds and duration or severity of tremor was found.Temporal processing of tactile and proprioceptive stimuli is impaired in patients with functional tremor. The mechanisms underlying this impaired somatosensory processing and possible ways to apply these findings clinically merit further research.