Miracle-dz/UniFAR-FTUs huggingface dataset:
Treating brain metastases in melanoma: What is the optimal CNS-directed and systemic management?

Treatments for melanoma have significantly advanced with the approval of targeted treatments against the BRAF/MEK pathway and immunotherapy in the form of checkpoint inhibitors. Studies have shown the effectiveness of these treatments against brain metastases. However, the optimum treatment strategy utilising CNS-directed treatments such as stereotactic radiosurgery (SRS) and neurosurgical resection is less clear. Over six years, 70 patients with metastatic melanoma were treated for brain metastases at a tertiary treatment centre. The median overall survival (OS) for all patients was 10.2 months. 51 patients received localised treatment; 7 resection (median OS 10 months), 11 resection and SRS (median OS 17.3 months) and 33 SRS alone (median OS 17.4 months). For patients treated with SRS those who had <2 cm3 treated had a better median OS (20.5 months) compared to those who had >2 cm3 treated (12 months). 69 Patients received systemic treatment. The median OS of patients who did not have CNS-directed treatment was poor (median OS 1.2 months). Patients treated with first line dual immunotherapy had the best median OS (26.7 months), compared to anti-PD-1 (14.1 months), ipilimumab (14.3 months) and kinase inhibitors (10.9 months). Despite advancements in treatment, the development of brain metastases in melanoma is associated with worse outcomes. A combination of CNS-directed and systemic treatment is important to improve survival. Dual immunotherapy appears to be the most effective systemic treatment and the use of SRS improved outcomes. As metastatic melanoma treatments evolve there need to be an ongoing focus to ensure these strategies adequately treat intracranial disease.
Safety evaluation of current therapies for high-risk severely ill patients with carbapenem-resistant infections

ABSTRACT Introduction Infections due to carbapenem-resistant Gram-negative bacteria (CR-GNB) are increasingly frequent events, which are associated with a high mortality rate. Traditionally, combination regimens including high doses of “old antibiotics” such as polymyxins, tigecycline, and aminoglycosides have been used to treat these infections, but they were often associated with low efficacy and high excess of side effects and toxicity, especially nephrotoxicity. Along with the development of new compounds, the last decade has seen substantial improvements in the management of CR infections. Areas covered In this review, we aimed to discuss the safety characteristics and tolerability of different new options for treatment of CR infections. Expert opinion The availability of new drugs showing a potent in vitro activity against CR-GNB represents a unique opportunity to face the threat of resistance, while potentially reducing toxicity. A thorough understanding of the safety profile from clinical trials may guide the use of these new drugs in critically ill patients at high risk for the development of adverse events. Future data coming from real-life studies for drugs targeting CR infections are crucial to confirm the safety profile observed in pivotal trials.
Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc

Supplemental Digital Content is available in the text Background: Temsavir (TMR), the active agent of the gp120-directed attachment inhibitor fostemsavir (FTR), the CD4-directed attachment inhibitor ibalizumab (IBA), and the CCR5 antagonist maraviroc (MVC) are antiretroviral agents that target steps in HIV-1 viral entry. Although mechanisms of inhibition of the three agents are different, it is important to understand whether there is potential for cross-resistance between these agents, as all involve interactions with gp120. Methods: Envelopes derived from plasma samples from participants in the BRIGHTE study who experienced protocol-derived virologic failure (PDVF) and were co-dosed with FTR and either IBA or MVC were analyzed for susceptibility to the agents. Also, CCR5-tropic MVC-resistant envelopes from the MOTIVATE trials were regenerated and studies were performed to understand whether susceptibility to multiple agents were linked. Results: The cloned envelopes exhibited reduced susceptibility to TMR and resistance to the co-dosed agent. At PDVF, emergent or preexisting amino acid substitutions were present at TMR positions of interest. When amino acid substitutions at these positions were reverted to the consensus sequence, full susceptibility to TMR was restored without effecting resistance to the co-dosed agent. In addition, five envelopes from MOTIVATE were regenerated and exhibited R5-tropic-MVC-resistance. Only one exhibited reduced susceptibility to TMR and it contained an M426L polymorphism. When reverted to 426M, full sensitivity for TMR was restored, but it remained MVC resistant. Conclusion: The data confirm that decreased susceptibility to TMR and resistance to IBA or MVC are not linked and that there is no cross-resistance between either of these two agents and FTR.
Soil extension needs to be a continuum of learning; soil workshop reflections 10 years on

Effective extension of soil research builds landholder capacity to manage soils productively and sustainably. Government‐funded extension programmes also aim to improve the state of the environment through efficient use of resources and mitigating or preventing further land degradation. To these ends, a soil extension programme aimed at farmers in south‐eastern Australia was conducted during 2005–2008. The programme was designed to equip landholders with the knowledge, skills and confidence to diagnose and address soil constraints, as well as compile spatial information on soil properties. The programme involved four workshops that covered agricultural productivity, soil management and potential off‐site impacts. Workshops were held on‐farm and involved discussion, theory supported with practical exercises, and field visits. More than 1,400 participants were provided with subsidized soil tests to encourage soil monitoring and underpin the workshop theory on land capability and soil constraints (e.g., soil acidity, sodicity, salinity, nutrient decline and toxicities). Prior to the course, most participants did not regularly soil test so training on monitoring protocols was provided. The soil data indicated considerable phosphorus deficiencies, low organic carbon levels, and acidity across both cropping and pasture systems. Participant knowledge and land management intentions were tracked throughout the workshop series using surveys. The surveys identified a positive shift in the knowledge, understanding and confidence of most participants. However, a follow‐up survey 10 years later indicated that these changes may not have been broadly sustained. Based on our study, we recommend continued engagement of landholders along a learning pathway to maximize investment in soil extension.
Single-Task or Dual-Task? Gait Assessment as a Potential Diagnostic Tool for Alzheimer’s Dementia

Background: A person’s gait performance requires the integration of sensorimotor and cognitive systems. Therefore, a person’s gait may be influenced by concurrent cognitive load such as simultaneous talking. Although it has been known that gait performance of people with Alzheimer’s dementia (AD) is compromised when they attempt a dual-task walking task, it is unclear if using a dual-task gait performance during an AD assessment yields higher diagnostic accuracy. Objective: This study was designed to compare the predictive power for AD of dual-task gait performance in an AD assessment to that of single-task gait performance. Methods: Participants (14 with AD and 15 healthy controls) walked across the GAITRite© Portable Walkway mat under three different cognitive load conditions: no simultaneous cognitive load, walking while counting numbers by ones, and walking while completing category naming. Results: Multiple logistic regression revealed that the gait performance under a dual-task condition (i.e., concurrent counting or category naming) increased the proportion of variance explained by the FAP, SL, and DST, of the incidence of AD. Conclusion: Dual-task walking and talking may be a more effective diagnostic feature than single-task walking in a comprehensive AD diagnostic assessment.
The Online Representation of Palliative Care by Practice, Policy, and Advocacy Organizations: Definitional Variations and Discursive Tensions

Negative beliefs and a lack of clarity surrounding the meaning of palliative care have been widely reported as obstacles to its uptake. Information available to the public possibly contributes to this. A descriptive and discourse-theoretical analysis was conducted of information spread online by palliative care policy, advocacy, and practice organizations. Discrepancies were found in the way palliative care was defined in relation to curative, end-of-life, terminal, and supportive care. Beyond these definitional variations, meaning was generated through the representation of palliative care as a culture, connected to total care, compassion, and openness. Tensions arose around the concepts of autonomy, a natural death, and an emphasis on the quality of life away from death and dying. Overall, this study showed that the online information of palliative care is a potential source of confusion and might even contribute to its stigmatization. Insights are provided that may help improve clarity toward the public.
MiR-1-3p and MiR-124-3p Synergistically Damage the Intestinal Barrier in the Ageing Colon

Abstract Background and Aims Disruption of the intestinal barrier of the digestive tract is a common pathophysiological change in the elderly, which may partly contribute to gut dysfunction and inflammatory bowel disease [IBD]. This study aimed to discover new interactive epigenetic regulation patterns involved in intestinal barrier dysfunction and colitis in elderly populations. Methods Intestinal barrier function and structure were evaluated in naturally ageing mice and elderly people. High-throughput analysis was performed on colonic tissues from humans and mice. The synergistic roles of miR-1-3p and miR-124-3p were identified using microRNA mimic/agomirs. Related genes were examined in biopsies of old IBD patients. Results A defective mucus barrier was observed before mucosal microstructural damage during ageing. Elevated miR-1-3p expression in the colons of older individuals impaired the mucus barrier by directly targeting T-synthase, similarly to the mechanism of miR-124-3p, which we reported previously. Importantly, the synergistic effect of a half dose of each microRNA supplement on T-synthase and CDK4/6 was stronger than that of a full dose of miR-1-3p or miR-124-3p alone, and mice co-treated with two microRNAs showed greater susceptibility to chemical-induced colitis than mice treated with either microRNA alone. These two microRNAs were up-expressed in old IBD patients. Conclusions The slight increases in miR-1-3p and miR-124-3p expression with ageing may be important contributors to the breakdown of intestinal homeostasis by targeting divergent genes in different cells. These data reveal the potential ability of multiple microRNAs to exert synergistic effects to damage the intestinal barrier and promote inflammatory bowel disease development in elderly populations.
Fatty Pancreas Represents a Risk Factor for Acute Pancreatitis

Objectives Fatty pancreas (FP), previously believed to be without clinical significance, recently has been shown to be associated with comorbid diseases. We aimed to explore whether FP predispose to acute pancreatitis. Methods Patients who underwent endoscopic ultrasound for hepatobiliary indications were included. Patients with pathological pancreato-biliary findings other than FP were excluded. The cohort was divided into patients with a history of pancreatitis (within 6 months of endoscopic ultrasound, group A) and patients without (group B). Results Overall, 189 patients were included. Sixty-one (32.3%) patients were in group A, and 128 (67.7%) patients were in group B. The average age in group A was 55.5 (standard deviation, 17.7) versus 58.5 (standard deviation, 13.5) in group B. The prevalence of FP in group A (37.7%) was higher compared with group B (4.7%) (P = 0.001). On univariate analysis, FP showed significant correlation with a history of acute pancreatitis [odds ratio (OR), 5.14, P = 0.006] and hyperlipidemia (OR, 4.19; P = 0.002). On multivariate analysis, FP remained significantly associated with a history of acute pancreatitis after stratification for obesity and hyperlipidemia (OR, 10.78; 95% confidence interval, 3.75–30.89; P < 0.0001). Conclusions Fatty pancreas was associated with acute pancreatitis. Clinicians should be aware of this association.
Radioembolization of Intrahepatic Cholangiocarcinoma: Patient Selection, Outcomes, and Competing Therapies

Abstract Intrahepatic cholangiocarcinoma is the second most common primary hepatic malignancy and poses a therapeutic challenge owing to its late-stage presentation and treatment-resistant outcomes. Most patients are diagnosed with locally advanced, unresectable disease and are treated with a combination of systemic and local regional therapies. Transarterial radioembolization offers a survival benefit and a favorable side effect profile, with a growing body of evidence to support its use. Herein, we review patient selection and detail outcomes of radioembolization for intrahepatic cholangiocarcinoma, together with mention of competing treatments.
Recovery of Screening Mammogram Cancellations During COVID-19

Background In response to the COVID-19 pandemic, the American Society of Breast Surgeons and American College of Radiology released a joint statement recommending that all breast screening studies be postponed effective March 26, 2020. Study Design A retrospective review of all canceled mammograms at a single tertiary care institution from January 1-August 31, 2020 was performed to evaluate the effect of this recommendation by quantifying both the number and reason for mammogram cancellations before and after March 26, 2020. Utilization of the electronic patient portal for appointment cancellation as a surrogate for telehealth uptake was noted. Results During the study period, 5340 mammogram appointments were kept and 2784 mammogram appointments were canceled. From a baseline of 30 (10.8%) canceled mammograms in January, cancellations peaked in March (576, 20.6%) and gradually decreased to a low in August (197, 7%). Reasons for cancellations varied significantly by month (P < .0001) and included COVID-19 related (236, 8.5%), unspecified patient reasons (1,210, 43.5%), administrative issues (147, 5.3%), provider requests (46, 1.7%), sooner appointments available (31, 1.1%), and reasons not given (486, 17.5%). In addition, compared to a baseline in January (51, 16.5%), electronic patient portal access peaked in August (67, 34.0%). Conclusion Screening mammogram cancellations have gradually recovered after early COVID-19 restrictions were lifted and increasing use of electronic patient access appears to be sustained. Consequences for future staging at the time of diagnosis remain unknown. Understanding to what extent the pandemic affected screening may help surgeons plan for post-pandemic breast cancer care.
Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Nav1.5-subunit mutations

Brugada syndrome (BrS) is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death. Considering that its heterogeneity in clinical manifestations may result from genetic background, the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) may help to reveal cell phenotype characteristics underlying different genetic variations. Here, to verify and compare the pathogenicity of mutations (SCN5A c.4213G>A andSCN1B c.590C>T) identified from two BrS patients, we generated two novel BrS iPS cell lines that carried missense mutations inSCN5A or SCN1B, compared their structures and electrophysiology, and evaluated the safety of quinidine in patient-specific iPSC-derived CMs. Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration, and varying degrees of decreased Vmax, but no structural difference. After applying different concentrations of quinidine, drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration (ETPC). The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A orSCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.
Neurovascular dysfunction and neuroinflammation in a Cockayne syndrome mouse model

Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER (Csa−/−/Xpa−/−), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age. Although this CS model exhibits a severe progeroid phenotype, we found no evidence of in vitro endothelial cell dysfunction, as assessed by measuring population doubling time, migration capacity, and ICAM-1 expression. Furthermore, aortas from CX mice did not exhibit early senescence nor reduced angiogenesis capacity. Despite these observations, CX mice presented blood brain barrier disruption and increased senescence of brain endothelial cells. This was accompanied by an upregulation of inflammatory markers in the brains of CX mice, such as ICAM-1, TNFα, p-p65, and glial cell activation. Inhibition of neovascularization did not exacerbate neither astro- nor microgliosis, suggesting that the pro-inflammatory phenotype is independent of the neurovascular dysfunction present in CX mice. These findings have implications for the etiology of this disease and could contribute to the study of novel therapeutic targets for treating Cockayne syndrome patients.
Mid-air haptics for shape recognition of virtual objects

Abstract This paper presents an experiment in which participants had to discriminate three mid-air haptic shapes (circle, square, point) by reporting whether the haptic stimulus (e.g. circle on the palm of the hand) was compatible with an image (e.g. a circle) or a word (e.g. ‘circle’) displayed on a screen. Results indicate that only the ‘point’ stimulus was appreciably recognised and discriminated in terms of accuracy and time needed for the identification. Accuracy increased with repetition, and response time decreased, suggesting a learning effect. The comparison between visual and textual labels shows that for the haptic point stimulus there is no significant difference but a tendency to have greater accuracy with images than with texts, while the opposite result is found for the circle stimulus. This outcome suggests the need for new experiments focussed of the effect of visual/textual labels to make the recognition/discrimination tasks of haptic stimuli easier. Practitioner Summary: Three haptic shapes were presented with images or texts, matching or not the stimuli. The point was easy to recognise, while the circle and the square were difficult to discriminate against each other. Visual/textual labels bring contradictory results for different shapes. Abbreviations: 1D: one-dimensional; 2D: two-dimensional; 3D: three-dimensional; API: application programming interface; cm: centimeter; GLMM: generalised linear mixed-effect model; HCI: human-computer interaction; Hz: hertz; LMM: linear mixed-effect model; MCC: Matthews' correlation coefficient; mm: millimeter; ms: millisecond; QQ-plot: Quantile-Quantile plot; SD: standard deviation
Efflorescence of acquired epidermodysplasia verruciformis due to immune reconstitution inflammatory syndrome-like mechanisms following anti-HPV vaccination in a HIV-positive patient

Epidermodysplasia verruciformis (EV) is a rare cutaneous pre-cancerous condition characterized by presence of flat, scaly macules, verruca-like papillomatous papules, seborrheic keratosis-like lesions, and pink-red pityriasis versicolor-like macules. The disease is caused by abnormal susceptibility to certain specific beta-HPV subtypes, most commonly 5 and 8. Classic EV is genetically determined, but in immunocompromised individuals, an acquired form can occur. Only 48 cases of acquired EV (AEV) in people living with HIV have been described. We describe a case of AEV in a 36-year-old HIV-positive man with an history of stable optimal CD4 cell count and undetectable HIV viral load. The AEV significantly deteriorated after the administration of the second dose of the quadrivalent anti-HPV vaccine and did not improve despite local treatment, anti-HPV vaccination completion, and persistently optimal combined antiretroviral treatment adherence. To the best of our knowledge, this is the first report of an AEV deterioration with a clinical and temporal pattern mimicking an immune reconstitution inflammatory syndrome (IRIS) following anti-HPV vaccination, instead of low CD4 count restoration. After reviewing the current literature, we have hypothesized a vaccine-mediated IRIS-like phenomenon in the pathogenesis of the disease.
Mental health of adults in Ireland during the first year of the COVID-19 pandemic: results from a nationally representative, longitudinal study

Objective: Emerging evidence indicates that the mental health consequences of COVID-19 may not be as deleterious as initially feared. We analyzed the levels of symptom expression and rates of Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), and COVID-19 related Posttraumatic Stress Disorder (C19-PTSD) in the adult population of Ireland at different points during the first year of the pandemic.Methods: Data were collected from a nationally representative sample of 1041 adults across five waves from March/April 2020 to March/April 2021. New participants were recruited at follow-up waves to maintain nationally representative cross-sectional estimates. Cross-sectional estimates of each and any disorder were calculated, and longitudinal changes in means and prevalence estimates of MDD, GAD, and C19-PTSD were assessed using structural equation modelling.Results: Cross-sectional estimates of meeting criteria for MDD, GAD, or C19-PTSD were 34.7% in March/April 2020 (Wave 1) and 33.7% in March/April 2021 (Wave 5). Longitudinal analyses revealed no significant change in symptoms of MDD, a significant decrease in GAD symptoms, and a significant increase in C19-PTSD symptoms. There were significant decreases in prevalence estimates of MDD (by 4.9%) and GAD (by 6.3%), and no significant change in C19-PTSD. Overall, 4.7% fewer people met criteria for any disorder at Wave 5 than at Wave 1. Conclusion: There was no evidence of an increase in mental health problems in the adult population during the first year of the pandemic in Ireland. Analyses of longitudinal data indicated a small but significant decrease in the proportion of people suffering from a mental health disorder.