Miracle-dz/UniFAR-FTUs huggingface dataset:
Is it a chimera? A systematic review of the economic evaluations of CAR-T cell therapy - an update

ABSTRACT Introduction The new class of chimeric antigen receptor T-cell has emboldened health-care professionals and patients for a more effective treatment of hematological malignancies, indicatively lymphoma, acute lymphoblastic leukemia, and myeloma. Nevertheless, their burgeoning procurement costs comprise a litmus stress for health systems across the globe. In this context, this systematic review aims to update the current body of evidence assessing CAR-T economic evaluations and elucidate their financial efficiency. Areas covered A systematic review of the economic evaluations of tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel and brexucabtagene autoleucel was performed. Expert opinion The updated results corroborated the previously reported favorable cost–effectiveness ratio of CAR-T. They also pointed out differences among CAR-T agents. However, their budget impact emerges as a significant barrier in the reimbursement process. Any proposed Managed Entry Agreement must integrate the ingrained uncertainty of long-term efficacy and precede reimbursement decisions.
A Numerical Approach for Interfacial Motion and its Application to viscous effects in the Benjamin-Feir instability

The evolution of the free interface between two incompressible viscous fluid flows occurs in many physical problems. The numerical simulation of these free surfaces presents great difficulties in scientific computing, especially when the Reynolds number is very large. In this thesis, a new numerical approach is introduced to simulate the twodimensional viscous incompressible fluid flows with free interface. A mapped coordinate system is used to transform the curved geometry into a rectangular region so that a standard grid can be applied to the region. The Navier-Stocks equations using the stream function and vorticity are solved together with the interface conditions between two fluids. The second-order backward difference formula is used for time evolution. An implicit/explicit method is used to avoid iterative procedure when handling the nonlinear terms. A periodic boundary condition is assumed in the horizontal direction and spectral methods are applied. The equations are then written as a first order ODE system in the vertical direction. In order to achieve a stable numerical method for calculations with huge Reynolds number as well as a high accuracy, a forth-order boundary value problem solver is introduced to solve this ODE system. In order to get the initial conditions for the simulation, linear stability analysis with the interface is performed within the mapped geometry. The non-linear
Treatment Strategies for Cardiomyopathy in Children: A Scientific Statement From the American Heart Association

This scientific statement from the American Heart Association focuses on treatment strategies and modalities for cardiomyopathy (heart muscle disease) in children and serves as a companion scientific statement for the recent statement on the classification and diagnosis of cardiomyopathy in children. We propose that the foundation of treatment of pediatric cardiomyopathies is based on these principles applied as personalized therapy for children with cardiomyopathy: (1) identification of the specific cardiac pathophysiology; (2) determination of the root cause of the cardiomyopathy so that, if applicable, cause-specific treatment can occur (precision medicine); and (3) application of therapies based on the associated clinical milieu of the patient. These clinical milieus include patients at risk for developing cardiomyopathy (cardiomyopathy phenotype negative), asymptomatic patients with cardiomyopathy (phenotype positive), patients with symptomatic cardiomyopathy, and patients with end-stage cardiomyopathy. This scientific statement focuses primarily on the most frequent phenotypes, dilated and hypertrophic, that occur in children. Other less frequent cardiomyopathies, including left ventricular noncompaction, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy, are discussed in less detail. Suggestions are based on previous clinical and investigational experience, extrapolating therapies for cardiomyopathies in adults to children and noting the problems and challenges that have arisen in this experience. These likely underscore the increasingly apparent differences in pathogenesis and even pathophysiology in childhood cardiomyopathies compared with adult disease. These differences will likely affect the utility of some adult therapy strategies. Therefore, special emphasis has been placed on cause-specific therapies in children for prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments. Current investigational strategies and treatments not in wide clinical practice, including future direction for investigational management strategies, trial designs, and collaborative networks, are also discussed because they have the potential to further refine and improve the health and outcomes of children with cardiomyopathy in the future.
A large travel-associated outbreak of iatrogenic botulism in four European countries following intragastric botulinum neurotoxin injections for weight reduction, Türkiye, February to March 2023

In March 2023, 34 associated cases of iatrogenic botulism were detected in Germany (30 cases), Switzerland (two cases), Austria (one case), and France (one case). An alert was rapidly disseminated via European Union networks and communication platforms (Food- and Waterborne Diseases and Zoonoses Network, EpiPulse, Early Warning and Response System) and the International Health Regulation mechanism; the outbreak was investigated in a European collaboration. We traced sources of the botulism outbreak to treatment of weight loss in Türkiye, involving intragastric injections of botulinum neurotoxin. Cases were traced using a list of patients who had received this treatment. Laboratory investigations of the first 12 German cases confirmed nine cases. The application of innovative and highly sensitive endopeptidase assays was necessary to detect minute traces of botulinum neurotoxin in patient sera. The botulism notification requirement for physicians was essential to detect this outbreak in Germany. The surveillance case definition of botulism should be revisited and inclusion of cases of iatrogenic botulism should be considered as these cases might lack standard laboratory confirmation yet warrant public health action. Any potential risks associated with the use of botulinum neurotoxins in medical procedures need to be carefully balanced with the expected benefits of the procedure.
Shorter Tours by Nicer Ears

1 Extremely Nice Ears Suppose we have a graph G = (V,E) with an ear decomposition with the following properties (after deleting the trivial ears): 1. all short (consisting of 3 edges or less) ears are pendant (having no other ear attached to an interior node of the ear). 2. all ears are odd (have an odd number of edges) 3. the graph induced by all short ears is acyclic 4. all ears are open. Then we can find a tour of length at most 75 |V |. Proof. We take the best result of two algorithms. The first algorithm is the following: 1. take the edges of all short ears 2. add a minimal set of edges so that all nodes not in the interior of pending ears are connected 3. add all edges of remaining pendant ears 4. find a minimal T -join, where T is the set of nodes that have odd degree in current solution. The number of edges in the solution for each step is: 1. 3 2 |V3|, where V3 is the set of nodes that are interior nodes of 3-ears, since 3 edges are added for every 3-ear, and each 3-ear has 2 interior nodes 2. |V0| − π3 − 1, where π3 is the number of 3-ears, and V0 is the set of nodes that is not in the interior of pending ears, since we can view this as the number of edges in a tree connecting |V0| − π3 nodes, after contracting the 3-ears of the first step; the fact that the graph induced by all short pendant ears is acyclic means that every contraction reduces the number of nodes by 1 3. ≤ 54 |Vp,≥5|, where Vp,≥5 is the set of nodes that are interior nodes of pendant ears of size 5 or larger, since x edges are added for every x− 1 nodes in the interior, and x ≥ 5 1To do: add subsection explaining how the case with closed ears can be handled, add algorithms for 2-connected subgraph problem and connected T -join problem, add section about notation and terminology in paper, which I don’t follow here.
Remarkable fungal biodiversity on northern Belgium bats and hibernacula

ABSTRACT Bats can be affected by fungal pathogens such as Pseudogymnoascus destructans, the causative agent of the white-nose syndrome. Their body surface can also be colonized by fungal commensals or carry transient fungal species and participate in their dispersal. In this study, 114 bat specimens belonging to seven species were sampled from various locations in northern Belgium. Culture-based methods revealed an important mycological diversity, with a total of 209 different taxa out of the 418 isolates. Overall, a mean of 3.7 taxa per bat was recorded, but significant differences were observed between sampling sites and seasons. The mycobiomes were dominated by cosmopolitan and plant-associated species, in particular from the genera Cladosporium, Penicillium, and Aspergillus. Other species known to be related to bats or their environment, such as Apiotrichum otae, were also retrieved. Sampling of hibernacula indicated that diverse fungal species can inhabit these sites, including a yet undescribed Pseudogymnoascus species, distinct from Ps. destructans, namely, Ps. cavicola.
CONSTRUCTING PHYLOGENETIC TREE USING SVDS OF FLATTENINGS

Phylogenetic algebraic geometry is concerned with certain complex projective algebraic varieties derived from finite trees. This paper gives a self-contained introduction to this subject and introduces a new, statistically consistent algorithm for phylogenetic tree construction that uses the singular value decompositions of flattenings of statistical models. We use rank condition of flattenings determining a partition of phylogenetic tree to be a split. Starting with an mutiple sequence alignment of n DNA sequences, we show that SVD gives us to decide whether a split of the taxa occurs in their phylogenetic tree, assuming only that evolution follows a tree model. Using this fact, we have developed an algorithm to construct a phylogenetic tree by computing only O(n²) SVDs relating to the hierarchy of flattenings. Furthermore we have obtained more efficient algorithm comparing to the previous one which Eriksson has got. Also we could save computing time for SVDs of flattenings.
A high-performance electrochemical biosensor using an engineered urate oxidase

We constructed a high-performance biosensor for detecting uric acid by immobilizing an engineered urate oxidase on gold nanoparticles deposited on a carbon-glass electrode. This biosensor showed a low limit-of-detection (9.16 nM), a high sensitivity (14 μA/μM), a wide range of linearity (50 nM–1 mM), and more than 28 days lifetime.
A study on data confidentiality in early detection of Alzheimer's disease

The rapidly aging population causes long hospital waiting time, expensive hospital stays and increases the workload of doctors and medical practitioners. Managing the cost and quality of treatment and caring for seniors are important in all countries. This phenomenon has a demand for electronic healthcare (e-healthcare). A Bluetooth enabled in-home patient monitoring system facilitates early detection of Alzheimer's disease. With the help of short-range Bluetooth communications, the location and movement pattern of a patient can be tracked and recorded in a local database. Thus a medical practitioner is able to perform remote diagnosis via the internet. This system is not suitable for long-range outdoor environments. The e-healthcare solution has a number of issues like security and privacy that are hard to accomplish in an effective way. The proposed e-healthcare solution can be enhanced for long range outdoor environments with location tracking technology like GPS (Global Positioning System). Data security issues can be considered with two important aspects like secure and dependable distributed data storage and fine-grained distributed data access control for sensitive and private patient medical data. Different methods are analyzed to improve the security and efficiency of data sharing. This work facilitates better medical treatments, improve the quality of treatments and reduce healthcare costs.
Cryo-Electron Microscopy Structures of a Campylobacter Multidrug Efflux Pump Reveal a Novel Mechanism of Drug Recognition and Resistance

Campylobacter jejuni has emerged as one of the most problematic and highly antibiotic-resistant pathogens, worldwide. The Centers for Disease Control and Prevention have designated antibiotic-resistant C. jejuni as a serious antibiotic resistance threat in the United States. ABSTRACT Campylobacter jejuni is a bacterium that is commonly present in the intestinal tracts of animals. It is also a major foodborne pathogen that causes gastroenteritis in humans. The most predominant and clinically important multidrug efflux system in C. jejuni is the CmeABC (Campylobacter multidrug efflux) pump, a tripartite system that includes an inner membrane transporter (CmeB), a periplasmic fusion protein (CmeA), and an outer membrane channel protein (CmeC). This efflux protein machinery mediates resistance to a number of structurally diverse antimicrobial agents. A recently identified CmeB variant, termed resistance enhancing CmeB (RE-CmeB), can increase its multidrug efflux pump activity, likely by influencing antimicrobial recognition and extrusion. Here, we report structures of RE-CmeB in its apo form as well as in the presence of four different drugs by using single-particle cryo-electron microscopy (cryo-EM). Coupled with mutagenesis and functional studies, this structural information allows us to identify critical amino acids that are important for drug resistance. We also report that RE-CmeB utilizes a somewhat unique subset of residues to bind different drugs, thereby optimizing its ability to accommodate different compounds with distinct scaffolds. These findings provide insights into the structure-function relationship of this newly emerged antibiotic efflux transporter variant in Campylobacter. IMPORTANCE Campylobacter jejuni has emerged as one of the most problematic and highly antibiotic-resistant pathogens, worldwide. The Centers for Disease Control and Prevention have designated antibiotic-resistant C. jejuni as a serious antibiotic resistance threat in the United States. We recently identified a C. jejuni resistance enhancing CmeB (RE-CmeB) variant that can increase its multidrug efflux pump activity and confers an exceedingly high-level of resistance to fluoroquinolones. Here, we report the cryo-EM structures of this prevalent and clinically important C. jejuni RE-CmeB multidrug efflux pump in both the absence and presence of four antibiotics. These structures allow us to understand the action mechanism for multidrug recognition in this pump. Our studies will ultimately inform an era in structure-guided drug design to combat multidrug resistance in these Gram-negative pathogens.
Conformal symmetry breaking differential
 operators on differential forms

We study conformal symmetry breaking differential operators which map differential forms on $\mathbb{R}^n$ to differential forms on a codimension one subspace $\mathbb{R}^{n-1}$. These operators are equivariant with respect to the conformal Lie algebra of the subspace $\mathbb{R}^{n-1}$. They correspond to homomorphisms of generalized Verma modules for ${\mathfrak so}(n,1)$ into generalized Verma modules for ${\mathfrak so}(n+1,1)$ both being induced from fundamental form representations of a parabolic subalgebra. We apply the F-method to derive explicit formulas for such homomorphisms. In particular, we find explicit formulas for the generators of the intertwining operators of the related branching problems restricting generalized Verma modules for ${\mathfrak so}(n+1,1)$ to ${\mathfrak so}(n,1)$. As consequences, we find closed formulas for all conformal symmetry breaking differential operators in terms of the first-order operators $d$, $\delta$, $\bar{d}$ and $\bar{\delta}$ and certain hypergeometric polynomials. A dominant role in these studies will be played by two infinite sequences of symmetry breaking differential operators which depend on a complex parameter $\lambda$. These will be termed the conformal first and second type symmetry breaking operators. Their values at special values of $\lambda$ appear as factors in two systems of factorization identities which involve the Branson-Gover operators of the Euclidean metrics on $\mathbb{R}^n$ and $\mathbb{R}^{n-1}$ and the operators $d$, $\delta$, $\bar{d}$ and $\bar{\delta}$ as factors, respectively. Moreover, they are shown to naturally recover the gauge companion and $Q$-curvature operators of the Euclidean metric on the subspace $\mathbb{R}^{n-1}$, respectively.
NFX1‐123: A potential therapeutic target in cervical cancer

NFX1‐123 is a splice variant isoform of the NFX1 gene. It is highly expressed in cervical cancers caused by HPV, and NFX1‐123 is a protein partner with the HPV oncoprotein E6. Together, NFX1‐123 and E6 affect cellular growth, longevity, and differentiation. The expression status of NFX1‐123 in cancers beyond cervical and head and neck cancers, and its potential as therapeutic target, have not been investigated. TSVdb of TCGA was used to quantify NFX1‐123 expression in 24 cancers compared with normal tissues. The NFX1‐123 protein structure was predicted and then submitted to retrieve suitable drug molecules. The top four compounds, found to bind in silico to NFX1‐123, were tested experimentally to determine their effects on NFX1‐123‐related cellular growth, survival, and migration. 46% of cancers (11 of 24 had significant differences in NFX1‐123 expression, with nine having had greater NFX1‐123 expression, when compared with adjacent normal tissues. Bioinformatics and proteomic predictive analysis modeled the three‐dimensional structure of NFX1‐123, and drug libraries were screened for high‐binding affinity compounds using this modeled structure. Seventeen drugs with binding energies ranging from −1.3 to −10 Kcal/mol were identified. The top four compounds were used to treat HPV‐ and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1‐123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1‐123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1‐123 a potential novel therapeutic target.
Immune-Related Adverse Events and Clinical Outcomes in Advanced Urothelial Cancer Patients Treated With Immune Checkpoint Inhibitors

Abstract Background In advanced urothelial cancers (UC), immune checkpoint inhibitors (ICI) show promise as a durable therapy. Immune-related adverse events (irAEs), a side effect of ICIs, may serve as an indicator of beneficial response. We investigated the relationship between irAEs and clinical outcomes in patients with advanced UC who received ICI. Materials and Methods In this retrospective study, we investigated 70 patients with advanced UC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on patients were collected through chart review. Cox’s proportional hazard model and logistic regression were applied to estimate the association with overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). The possible lead-time bias was handled in extended Cox regression models. Results The median age of the cohort was 68. Over one-third (35%) of patients experienced an irAE, with skin being the most frequent organ involved (12.9%). Patients that experienced at least one irAE had significantly enhanced OS (HR: 0.38, 95% CI, 0.18-0.79, P = .009), PFS (HR: 0.27, 95% CI, 0.14-0.53, P < .001), and CB (OR: 4.20, 95% CI, 1.35-13.06, P = .013). Patients who experienced dermatologic irAEs also had significantly greater OS, PFS, and CB. Conclusion Of patients with advanced UC that had undergone ICI therapy, those who had irAEs, especially dermatologic irAEs, had significantly greater OS, PFS, and CB. These results may suggest that irAE’s may serve as an important marker of durable response to ICI therapy in urothelial cancer. The findings of this study need to be validated with larger cohort studies in the future.
A core component of psychological therapy causes adaptive changes in computational learning mechanisms.

BACKGROUND Cognitive distancing is an emotion regulation strategy commonly used in psychological treatment of various mental health disorders, but its therapeutic mechanisms are unknown. METHODS 935 participants completed an online reinforcement learning task involving choices between pairs of symbols with differing reward contingencies. Half (49.1%) of the sample was randomised to a cognitive self-distancing intervention and were trained to regulate or 'take a step back' from their emotional response to feedback throughout. Established computational (Q-learning) models were then fit to individuals' choices to derive reinforcement learning parameters capturing clarity of choice values (inverse temperature) and their sensitivity to positive and negative feedback (learning rates). RESULTS Cognitive distancing improved task performance, including when participants were later tested on novel combinations of symbols without feedback. Group differences in computational model-derived parameters revealed that cognitive distancing resulted in clearer representations of option values (estimated 0.17 higher inverse temperatures). Simultaneously, distancing caused increased sensitivity to negative feedback (estimated 19% higher loss learning rates). Exploratory analyses suggested this resulted from an evolving shift in strategy by distanced participants: initially, choices were more determined by expected value differences between symbols, but as the task progressed, they became more sensitive to negative feedback, with evidence for a difference strongest by the end of training. CONCLUSIONS Adaptive effects on the computations that underlie learning from reward and loss may explain the therapeutic benefits of cognitive distancing. Over time and with practice, cognitive distancing may improve symptoms of mental health disorders by promoting more effective engagement with negative information.