Search Results (42)

Background: Cabozantinib is a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor (VEGFR-TKI). These drugs are employed as therapy for several malignancies. In detail, Cabozantinib has demonstrated its efficacy against several malignancies. On the other hand, Cabozantinib and other VEGFR-TKIs can be responsible for various adverse events (AEs), in particular hepatic and dermatological AEs. Methods: To date, limited data are available in the literature regarding ocular AEs due to therapy with these drugs. In this regard, one case of corneal perforation during treatment with a VEGFR-TKI, Regorafenib, has been reported, while there are no data about Cabozantinib. In this paper, we present another clinical case of corneal perforation in a patient affected by advanced RCC and treated with Cabozantinib as a second-line therapy. The patient started Cabozantinib at the dosage of 60 mg/die although it was necessary to apply some dose reductions because of grade 2 AEs (according to CTCAE v6.0), such as asthenia, diarrhea, dysgeusia, and loss of appetite. Results: After approximately 15 months of treatment, the patient began to experience pain and vision loss in the right eye. A diagnosis of corneal perforation was made, followed by medical and surgical treatment. As regards the etiology of this pathology, all other possible causes were excluded, including a history of ocular disease, contact trauma, exposure to damaging agents (e.g., chemical agents and prolonged use of drugs such as topical NSAIDs), infections, or dry eye. Therefore, we hypothesized a correlation with Cabozantinib’s mechanisms of action and paused its administration. Conclusions: Cabozantinib may alter the ocular environment due to a lack of or imbalance in growth factors in the tear film, with a reduction in corneal epithelium proliferation. This condition might cause dry eye and a delay in corneal healing. Therefore, particular importance should be placed on ophthalmologic surveillance during treatment with these drugs in patients who develop ocular symptoms. Further in vitro and in vivo studies are necessary to deepen the knowledge about VEGFR-TKI-mediated ocular AEs. Full article

Background/Objectives: In 2019, the Italian Constitutional Court (ICC) stated that the principles of equality, dignity, and self-determination enshrined in the constitution require that assisted suicide be considered lawful under certain conditions, including that the patient is kept alive through life-sustaining treatments. In fact, since such patients could already die by refusing treatment, assisted suicide is ethical as it allows them to die more quickly and with dignity. The paper aims to analyze the requirement of life-sustaining treatments from a legal and comparative perspective. Methods: The authors performed the search on Italian legal databases as well as on Scopus and PubMed and by comparing Italian regulations with those of Spain, Portugal, and Austria, which are similar to the Italian one in their fundamentally restrictive nature. The authors have delved into the Italian legal system through an analytical method of interpretation of the normative texts and used the comparative method to investigate which of the legal systems considered is more permissive. Results: According to the ICC, continuing to prohibit assisted suicide for patients who do not require life-sustaining treatments is not discriminatory: these patients cannot be equated with others, as only in the former case does refusing treatment lead to death. From its personalist ethical framework, the ICC also rejected the claim that the patient’s self-determination is being infringed upon: self-determination must be balanced with the protection of life, which is a fundamental value. However, in 2024, the ICC clarified that life-sustaining treatments are not limited to those directly supporting vital functions through medical machines, but also include all treatments without which the person would die in a short time, such as manual bowel evacuation. Conclusions: The current Italian regulation seems inconsistent. It would be preferable to regulate assisted suicide by referencing the models of Spain, Portugal, and Austria. Full article

Every year, more than 700,000 people die by suicide worldwide, a quarter of whom are between 15 and 29 years of age. In Spain, suicide has surpassed road traffic accidents as the leading non-natural cause of death in this age group. Although its overall incidence remains low, the number of suicide attempts continues to rise, indicating an upward trend. Despite being recognized as a significant public health issue, the media often refrains from reporting on suicide to prevent the Werther effect, thereby avoiding the potential propagation of suicidal behavior. This is a form of self-censorship in the exercise of freedom of information, a right recognized by the Spanish Constitution, which also undermines the right of citizens to receive such content. The Spanish Constitutional Court has determined that public interest is a mandatory requirement to endorse the legitimacy of a news item in case of a clash with any of the rights that legally limit freedom of information. This article aims to analyze whether, in those exceptional cases in which the rule of silence is broken, the information on suicide in young people is in line with the jurisprudential concept of public interest, above privacy, honor or self-image and, especially, above the protection of children and adolescents. As a research method, this study analyzes a selection of news articles on suicides of minors, published in Spanish digital newspapers and compiled into a self-developed database. These articles are examined through the lens of the Spanish Constitutional Court’s doctrine on freedom of information. The findings indicate that public interest is unequivocally justified when news coverage focuses on aggregated data regarding suicide or suicide attempts among minors. However, when reporting on the suicide of an individual minor, the justification from the perspective of freedom of information depends on the specifics of each case, requiring a careful balance between public interest and the protection of fundamental rights. Full article

Making advanced directives is challenging in Asia. The hindering factors and perceived needs for advanced directives for people with dementia and their families have not been fully explored in Taiwan. In this study, we aimed to identify the barriers and perceived needs of people with mild dementia and the families of people with dementia within the cultural context of Taiwan for advanced directives. A qualitative descriptive design with purposive sampling and content analysis was used to collect and analyze the data. Thirteen people with mild dementia and thirty-two families of people with dementia were recruited. Our findings indicated that the hindering factors for people with mild dementia and the families of people with dementia to make advanced directives included “talking about death is a taboo”, “the timing is not right”, “cultural values of filial piety”, “male protagonist’s social status”, and “insufficient information on advanced directive”. The perceived needs for participants in making advanced directive decisions were “a wish to die without suffering”, “wanting to rely on others to make a decision”, and “an increased awareness of information”. This research offers valuable insights into the barriers and needs related to advanced directives for people with mild dementia and the families of people with dementia in Taiwan. These findings address the identified challenges and needs to develop effective solutions to help healthcare providers to better facilitate the decision-making process for advanced directives. Full article

Background/Objectives: Cardiogenic shock (CS) is associated with high mortality, particularly in women. With early intervention being a cornerstone of CS management, this study aims to explore whether sex differences exist in the utilization of critical interventions, timing of treatment, and in-hospital mortality for patients with acute myocardial infarction (AMI) and non-AMI-CS. Methods: For this retrospective cohort study, we queried the National Inpatient Sample (years 2016–2021) for CS-related hospitalizations. We assessed sex differences in utilization, timing, and outcomes of CS interventions, adjusting for demographics, comorbidities, and prior cardiac interventions via multivariate logistic regressions. Results: Of 1,052,360 weighted CS hospitalizations, 60% were for non-AMI-CS and 40% were for AMI-CS. Women with CS had lower rates of all interventions. For AMI-CS, women had higher likelihoods of in-hospital mortality after revascularization (adjusted odds ratio 1.15 [95% confidence interval 1.09–1.22]), mechanical circulatory support (MCS) (1.15 [1.08–1.22]), and right heart catheterization (RHC) (1.10 [1.02–1.19]) (all p < 0.001). Similar trends were seen in the non-AMI-CS group. Women with AMI-CS were less likely to receive early (within 24 h of admission) revascularization (0.93 [0.89–0.96]), MCS (0.76 [0.73–0.80]), or RHC (0.89 [0.84–0.95]); women with non-AMI-CS were less likely to receive early revascularization (0.78 [0.73–0.84]) or RHC (0.83 [0.79–0.88]) (all p < 0.001). Regardless of CS type, in-hospital mortality was not significantly different between men and women receiving early MCS or revascularization. Conclusions: Sex disparities in the frequency of treatment of CS persist on a national scale, with women being more likely to die following treatment and less likely to receive early treatment. However, in-hospital mortality does not differ significantly when men and women are treated equally within 24 h of admission, suggesting that early intervention should be made a priority to mitigate sex-based differences in CS outcomes. Full article

The selection of the right tool path trajectory and the corresponding machining parameters for end milling is a challenge in mold and die industries. Subsequently, the selection of appropriate tool path parameters can reduce overall machining time, improve the surface finish of the workpiece, extend tool life, reduce overall cost, and improve productivity. This work aims to establish the performance of end milling process parameters and the impact of trochoidal toolpath parameters on the surface finish of AISI D3 steel. It especially focuses on the effect of the tool tip nose radius deviation on the surface quality using precision measurement techniques. The experimental design was carried out in a systematic manner using a face-centered central composite design (FCCD) within the framework of response surface methodology (RSM). Twenty different experiment trials were conducted by changing the independent variables, such as cutting speed, feed rate, and trochoidal pitch distance. The main effects and the interactions of these parameters were determined using analysis of variance (ANOVA). The optimal conditions were identified using a multiple objective optimization method based on desirability function analysis (DFA). The developed empirical models showed statistical significance with the best process parameters, which include a feed rate of 0.05 m/tooth, a trochoidal pitch distance of 1.8 mm, and a cutting speed of 78 m/min. Further, as the trochoidal pitch distance increased, variations in the tool tip cutting edge were observed on the machined surface due to peeling off of the coating layer. The flaws on the tool tip, which alter the edge micro-geometry after machining, resulted in up to 33.83% variation in the initial nose radius. Deviations of 4.25% and 5.31% were noted between actual and predicted values of surface roughness and the nose radius, respectively. Full article

This paper reviews the process of research, development and production of a training station for the optical recognition of dice parts with machine vision. This approach is chosen due to the lack of mechanical features to allow for classical orientation approaches. The embossed dots are about 0.1–0.2 mm deep so it is impossible to design classical traps. The orientation occurs purely by visual comparison to a reference image, part of the current camera job. The sequence of parts is controlled by the programmable logic controller(PLC)program, which manages the camera job-changing process via I/O signals, thus ensuring the right face of the die is captured by the camera and achieving the right predefined order of the sequence. When the preset number of dice in the sequence is reached, they are released back to the vibratory bowl feeder by a pneumatic separator. This way, all dice parts circulate until they are recognized by the camera. There are jobs for each possible orientation of the dice and also a small HMI where the dice sequences could be adjusted by the operator(generally students). The main benefit for the students is the opportunity to program the PLC and to adjust the camera jobs for the detection of each possible orientation. This relies upon the fact that during the fall from the return conveyor to the bowl feeder, the parts flip and, thus, change their previous orientation to another side. Experiments are conducted regarding the probability of obtaining orientation “5” and all the other possible states in order to statistically express the probability. Full article

In order to understand the formability of as-received tempered commercial pure titanium grade 2 foils (CP Ti Gr2) with a thickness of 38 µm, a series of micro limited dome height (µ-LDH) tests were conducted in quasi-static speed (0.01 mm/s) at room temperature without the use of a lubricant. A technique developed at NIU was also used to create micro-circular grids (ϕ50 μm) on the as-received material. The forming limit curve (FLC) of the CP Ti Gr2 foils was obtained through the proposed µ-LDH test. For having mechanical properties of the CP Ti Gr2 foils for LS-Dyna FEA (Finite Element Analysis) simulations, a series of tensile tests in three directions were also conducted at room temperature with the same speed. The obtained FLC has been validated using a micro deep drawing case study in which both FEA simulations and experiments were conducted and compared. It has been proven in this study that the FLC obtained using the proposed µ-LDH test can be used for an extremely thin sheet-metal-forming process by the automotive, aerospace, medical, energy, and electronic industries, etc., right away for product design, forming process development, tool and die designs, and simulations, etc. Full article

Odad3 gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the Odad3 gene in mice replicates several features of PCD, such as hydrocephalus, defects in left–right body symmetry, and male infertility, with a complete absence of sperm in the reproductive tract. The majority of Odad3 knockout animals die before sexual maturation due to severe hydrocephalus and failure to thrive, which precludes fertility studies. Here, we performed the expression analysis of the Odad3 gene during gonad development and in adult testes. We showed that Odad3 starts its expression during the first wave of spermatogenesis, specifically at the meiotic stage, and that its expression is restricted to the germ cells in the adult testes, suggesting that Odad3 plays a role in spermatozoa formation. Subsequently, we conditionally deleted the Odad3 gene in adult males and demonstrated that even partial ablation of the Odad3 gene leads to asthenoteratozoospermia with multiple morphological abnormalities of sperm flagella (MMAF) in mice. The analysis of the seminiferous tubules in Odad3-deficient mice revealed defects in spermatogenesis with accumulation of seminiferous tubules at the spermiogenesis and spermiation phases. Furthermore, analysis of fertility in heterozygous Odad3^+/− knockout mice revealed a reduction in sperm count and motility as well as abnormal sperm morphology. Additionally, Odad3^+/− males exhibited a shorter fertile lifespan. Overall, these results suggest the important role of Odad3 and Odad3 gene dosage in male fertility. These findings may have an impact on the genetic and fertility counseling practice of PCD patients carrying Odad3 loss-of-function mutations. Full article

Indigenous traditional land uses, including hunting, fishing, sacred activities, and land-based education at the Red Sucker Lake First Nation (RSLFN) in Manitoba, Canada, are impacted by mining. The Red Sucker Lake First Nation (RSLFN) people want their territories’ land and water to be protected for traditional uses, culture, and ecological integrity. Towards this goal, their Island Lake Tribal Council sought support for an Indigenous-protected and conserved area (IPCA) in their territory, outside of existing mining claims, but without success. The two-eyed seeing approach was adopted in this study. Traditional land use mapping and interviews were undertaken with 21 Indigenous people from the RSLFN, showing that many traditional land uses are concentrated on greenstone belts. The interviews revealed that mining exploration has resulted in large petroleum spills, noise distress, private property destruction, wildlife die-offs, and animal population declines. These issues negatively impact RSLFN’s traditional land use practices, ecosystem integrity, and community health. Governments need to partner with Indigenous communities to reach their biodiversity targets, particularly considering northern Canada’s peatlands, including those in the RSLFN territory, surpassing Amazon forests for carbon storage. The role of critical minerals in renewable energy and geopolitics has colonial governments undermining Indigenous rights, climate stabilization, and biodiversity to prioritize extractivism. Mining at the RSLFN has environmental impacts from exploration to decommissioning and after, as well as the massive infrastructure required that includes roads, hydro, and massive energy supplies, with a proposed multimedia national Northern Corridor to export RSLFN’s resources and other resources to six ports. Full article

Spontaneous remissions (SRs) in blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are infrequent, poorly documented, and transient. We report a 40-year-old man presenting with bycitopenia and soft tissue infection. The bone marrow exhibited 3% abnormal cells. Immunophenotyping of these cells revealed the antigens CD45+ (dim), CD34+, CD117+, CD123+ (bright), HLA-DR+ (bimodal), CD56+ (bright), CD33+, CD13+, CD2+, and CD22+ (dim) and the partial expression of the CD10+, CD36+, and CD7+ antigens. All other myeloid, monocytic, and lymphoid antigens were negative. Genetic studies showed a complex karyotype and mutations in the TP53^R337C and KRAS^G12D genes. On hospital admission, the patient showed a subcutaneous nodule on the right hand and left lower limb. Flow cytometry multiparameter (FCM) analysis showed the presence of 29% abnormal cells with the previously described immunophenotype. The patient was diagnosed with BPDCN. The patient was treated with broad-spectrum antibiotics for soft tissue infection, which delayed therapy for BPDCN. No steroids or chemotherapeutic or hypomethylating agents were administered. His blood cell counts improved and skin lesions disappeared, until the patient relapsed five months after achieving spontaneous remission. About 60% of abnormal cells were identified. No changes in immunophenotype or the results of genetic studies were observed. The patient underwent a HyperCVAD chemotherapy regimen for six cycles. Consolidation therapy was performed via allogeneic bone marrow transplantation with an HLA-unrelated donor. One year after the bone marrow transplant, the patient died due to the progression of his underlying disease, coinciding with a respiratory infection caused by SARS-CoV-2. In the available literature, SRs are often linked to infections or other stimulators of the immune system, suggesting that powerful immune activation could play a role in controlling the leukemic clone. Nevertheless, the underlying mechanism of this phenomenon is not clearly understood. We hypothesize that the immune system would force the leukemic stem cell (LSC) to undergo a state of quiescence. This loss of replication causes the LSC progeny to die off, resulting in the SR of BPDCN. Full article

This essay presents a certain defense of Hegel’s doctrine of Incarnation. For Hegel, the logic of the Incarnation constitutes not only the highest insight of religion and theology but, arguably, the key to philosophy itself, as the perfected self-knowledge of the absolute. Such knowledge is what Hegel calls “absolute knowing”, and marks the absolute reconciliation of the knowing subject and its object, substance, or in other words: of the domains of, as it were, historical knowledge and eternal truth. Hegel discovers in the Christian doctrine of Incarnation the logic of this very reconciliation of history and eternity: truth, or the absolute, coincides with the subject’s knowledge of it, which not only includes but privileges the historical “dismemberment” involved in such knowing. Only in Christianity does God dismember himself, or become historical—sacrifice himself, die—in order to know and become himself. But this “death of God” is for Hegel the very meaning of modern subjectivity. For this reason, or if Hegel is right, the Hegelian subject constitutes the sole way in which the desire of philosophy—namely, for the other that truth is—can keep itself from becoming incoherent after the death of God. It is not merely that Hegel’s doctrine of the subject remains valid despite the death of God; rather, the Hegelian subject, whose logic is incarnational and for this reason founds itself on the “death of God”, stands as the sole coherent articulation of this event, even and especially in its Nietzschean guise. Full article

Isolated deep infiltrating endometriosis (DIE) of sacral nerve roots or major pelvic nerves, including the sciatic nerve, is considered to be extremely rare. Due to the overlap with sciatica symptoms, the diagnosis of sciatica DIE is difficult yet crucial, as it results in permanent neural damage if left untreated. We report a case of a 45-year-old woman who experienced a three-year-long and recently exacerbating pain in her right leg, accompanied by a tingling sensation and weakness in her right leg and foot, with difficulty walking. In between regular menstrual bleedings, when her aforementioned symptoms worsened, she had been experiencing mild 10-day extra-cyclical bleeding. Her neurologist’s, orthopedist’s, and gynecological examinations were unremarkable. Magnetic resonance imaging (MRI) showed an infiltrative lesion on the right sciatic nerve that was immunohistochemically confirmed to be endometriosis. The patient was treated with gonadotropin-releasing hormone analogues (GnRHa), which led to a significantly diminished size of the lesion on the control MRI, and endometriosis remission was obtained. For persistent mild, but cyclical, pain and muscle weakness, continuous progestagnes were administered, with advice for physical therapy provided for her neuro-muscle rehabilitation and a scheduled check-up in 6 months. Full article

Since the legalization of medical assistance in dying (MAiD) in Canada in 2016, volitional non-participation in MAiD on the part of some healthcare institutions has revealed ethical uncertainties, potential access problems, and policy gaps. The problem has remained much neglected in the literature base, with no comprehensive studies on the subject so far. We analyzed print media articles and grey literature on institutional objections to and non-participation in MAiD. Thematic analyses were performed on all data to better understand the diverse stakeholder arguments and positions that characterize this important public health debate. Our search yielded 89 relevant media articles and 22 legislative, policy, and other relevant documents published since 2016 in the English language. We identified four main themes about institutional refusals to participate in MAiD, articulated as the following questions: (1) Who has the right to conscience? (2) Can MAiD be considered a palliative practice? (3) Are there imbalances across diverse stakeholder rights and burdens? and (4) Where are the gaps being felt in MAiD service implementation? Stakeholder views about institutional conscience with respect to MAiD are varied, complex, and evolving. In the absence of substantial systematic evidence, public domain materials constitute a key resource for understanding the implications for service access and determining the relevance of this contentious issue for future MAiD research and policy. Full article

According to the World Health Organisation, falling is a major health problem with potentially fatal implications. Each year, thousands of people die as a result of falls, with seniors making up 80% of these fatalities. The automatic detection of falls may reduce the severity of the consequences. Our study focuses on developing a vision-based fall detection system. Our work proposes a new feature descriptor that results in a new fall detection framework. The body geometry of the subject is analyzed and patterns that help to distinguish falls from non-fall activities are identified in our proposed method. An AlphaPose network is employed to identify 17 keypoints on the human skeleton. Thirteen keypoints are used in our study, and we compute two additional keypoints. These 15 keypoints are divided into five segments, each of which consists of a group of three non-collinear points. These five segments represent the left hand, right hand, left leg, right leg and craniocaudal section. A novel feature descriptor is generated by extracting the distances from the segmented parts, angles within the segmented parts and the angle of inclination for every segmented part. As a result, we may extract three features from each segment, giving us 15 features per frame that preserve spatial information. To capture temporal dynamics, the extracted spatial features are arranged in the temporal sequence. As a result, the feature descriptor in the proposed approach preserves the spatio-temporal dynamics. Thus, a feature descriptor of size $[m\times 15]$ is formed where m is the number of frames. To recognize fall patterns, machine learning approaches such as decision trees, random forests, and gradient boost are applied to the feature descriptor. Our system was evaluated on the UPfall dataset, which is a benchmark dataset. It has shown very good performance compared to the state-of-the-art approaches. Full article