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Abstract Purpose To investigate in a feasibility study the combination of [18F]FDG whole-body (WB) positron emission tomography-magnetic resonance (PET-MR), including an integrated breast MR within a single protocol for locoregional and distant staging in breast cancer patients. Methods Consecutive patients with breast cancer diagnoses according to conventional imaging modalities (full-field digital mammography (FFDM) and ultrasound (US)) were prospectively included. All patients underwent [18F]FDG WB PET-MR, including an integrated dedicated breast MR (prone position) and WB PET-MR (supine position) protocol. Results of [18F]FDG WB PET-MR, including integrated breast MR, versus conventional imaging modalities were compared. Results From April 2021–April 2022, 28 patients were included. On conventional imaging, cT1-2 breast cancer was present in 22 (FFDM) and 23 (US) out of 28 patients. With regard to clinical nodal status, eight patients were considered cN0, eighteen cN1 (1-3 suspicious lymph nodes), and two patients were cN2 (four suspicious axillary lymph nodes/internal mammary lymph node metastasis). [18F]FDG WB PET-MR, including an integrated breast MR protocol, upstaged clinical tumor status in two patients and clinical nodal status in nine patients according to both [18F]FDG WB PET-MR and breast MR findings. In addition, distant metastases were detected in three patients (liver/bone), and another patient was diagnosed with a synchronous primary tumor (lung cancer). Conclusion [18F]FDG WB PET-MR, including an integrated breast MR within a single protocol in breast cancer patients, is feasible and provides a promising new approach in breast cancer patients with regard to locoregional and distant staging. Critical relevance statement [18F]FDG whole-body PET-MR, including an integrated breast MR protocol, is feasible and allows locoregional and distant staging within a single imaging exam in breast cancer patients. Key Points [18F]FDG PET-MR allows the combination of breast MR and whole-body staging. Therefore, a single protocol of whole-body [18F]FDG PET-MR, including an integrated breast MRI, is investigated. [18F]FDG PET-MR, including an integrated breast MR is feasible and can be considered in daily clinical practice. Graphical Abstract

Abstract Background Wound healing complications are a major challenge following the extended lateral approach in calcaneal fractures. Soft-tissue microcirculation plays an important role via the delivery of oxygen, nutrients, and the regulation of a local milieu. The aim of this clinical study was to examine the effect of intraoperative pneumatic tourniquet application on skin and subcutaneous microcirculation, and its impact on wound healing progression. Methods Patients with calcaneal fractures were randomly assigned to two groups defined by a surgery conducted either with use or without use of a tourniquet. Blood flow (BF [AU]), tissue oxygen saturation (SO 2 [%]) and the relative amount of haemoglobin (rHb[AU]) were intraoperatively measured at two depths (2 and 8 mm) non-invasively by spectrophotometry (Micro-Lightguide O2C ® , LEA Medizintechnik, Giessen, Germany). Time points were before and after inflation of the pneumatic tourniquet and also at the end of surgery before deflation. A linear mixed model (LMM) was fitted for statistical analysis. Results Thirty-four patients (3 women and 31 men) with 37 calcaneal fractures were included. In 22 of them, the surgery was conducted with a tourniquet and in the other 15 without its use. A significant decrease of microcirculation, characterized by decreases in blood flow (p = 0.011) and tissue oxygenation (p = 0.023) was measured in 8 mm depth after inflating the tourniquet. However, these changes did not influence the time of postoperative wound healing. Conclusion The use of a pneumatic tourniquet reduces deep microcirculation without affecting postoperative wound healing. Trial registration The study was registered in www.ClinicalTrials.gov (NCT01264146).

Abstract The P2X1 receptor is a trimeric ligand-gated ion channel that plays an important role in urogenital and immune functions, offering the potential for new drug treatments. However, progress in this area has been hindered by limited structural information and a lack of well-characterised tool compounds. In this study, we employ cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in an ATP-bound desensitised state and an NF449-bound closed state. NF449, a potent P2X1 receptor antagonist, engages the receptor distinctively, while ATP, the endogenous ligand, binds in a manner consistent with other P2X receptors. To explore the molecular basis of receptor inhibition, activation, and ligand interactions, key residues involved in ligand and metal ion binding were mutated. Radioligand binding assays with [3H]-α,β-methylene ATP and intracellular calcium ion influx assays were used to evaluate the effects of these mutations. These experiments validate key ligand-receptor interactions and identify conserved and non-conserved residues critical for ligand binding or receptor modulation. This research expands our understanding of the P2X1 receptor structure at a molecular level and opens new avenues for in silico drug design targeting the P2X1 receptor.

Abstract Brucella melitensis is a major livestock bacterial pathogen and zoonosis, causing disease and infection-related abortions in small ruminants and humans. A considerable burden to animal-based economies today, the presence of Brucella in Neolithic pastoral communities has been hypothesised but we lack direct genomic evidence thus far. We report a 3.45X B. melitensis genome preserved in an ~8000 year old sheep specimen from Menteşe Höyük, Northwest Türkiye, demonstrating that the pathogen had evolved and was circulating in Neolithic livestock. The genome is basal with respect to all known B. melitensis and allows the calibration of the B. melitensis speciation time from the primarily cattle-infecting B. abortus to approximately 9800 years Before Present (BP), coinciding with a period of consolidation and dispersal of livestock economies. We use the basal genome to timestamp evolutionary events in B. melitensis, including pseudogenization events linked to erythritol response, the supposed determinant of the pathogen’s placental tropism in goats and sheep. Our data suggest that the development of herd management and multi-species livestock economies in the 11th–9th millennium BP drove speciation and host adaptation of this zoonotic pathogen.

El proceso de carbonización hidrotérmica ha llamado la atención de la comunidad académica y científica como una tecnología emergente y ecológica para la transformación de los residuos lignocelulósicos urbanos en fuente de bioenergía en forma sólida (hidrocarbón), líquida y gaseosa. Esta revisión aborda la comprensión de las propiedades y el potencial uso de estos residuos como fuente de bioenergía. Se analizan las propiedades fisicoquímicas y energéticas de estos residuos, así como los parámetros de operación que influyen en su transformación. Además, se presentan nuevas perspectivas sobre los desafíos futuros relacionados con el uso potencial de estos residuos y el proceso de carbonización. La conversión sostenible de estos residuos urbanos en una fuente de bioenergía contribuirá a reducir la dependencia de los combustibles fósiles, minimizar las emisiones de gases de efecto invernadero, garantizar una gestión eficiente de los residuos urbanos y desarrollar una bioeconomía circular.

Wilms tumour (WT) is the fourth leading cause of cancer death in children. Elucidating modifiable risk factors is crucial in identifying venues for primary prevention of the disease. This study aimed to review literature and synthesize environmental risk factors for WT. We conducted a systematic review and meta-analysis of epidemiological studies using PubMed, Web of Science, and Embase databases. Studies were included if they were case-control or cohort studies of children under the age of 20 years at diagnosis and reported Relative Risks (RRs) with 95 % confidence intervals (CIs). Pooled effect sizes (ES) and 95 % CIs for risk factors associated with WT were estimated using random-effects models. We included 58 eligible studies from Asia, Europe, Latin and North America, and Oceania totalling approximately10000 cases of WT diagnosed between 1953 and 2019. We confirmed an association between high birthweight ((>4000 g) ES 1.54, CI 1.20–1.97) and WT. Similarly, consistent associations were suggested for Caesarean section (ES 1.23, CI 1.07–1.42), gestational age

Objective: To help healthcare professionals (HCP) act with more confidence when communicating about approaching death, we sought to develop a communication model for HCP to facilitate conversations with dying patients and family caregivers (FC) in nonemergency situations. Methods: We used a four-phase integrative approach: (1) creation of a preliminary model based on a systematic literature review and expert knowledge, (2) review of the model draft by international palliative care experts, (3) review by key stakeholders, and (4) final appraisal by communication experts. Results: After the clinical recognition of dying, the communication model provides a structure and practical communication aids for navigating the conversation based on three phases. It describes the content and relational level as core dimensions of effective conversations about approaching death and highlights the importance of HCP self-awareness and self-care when caring for the dying. Conclusion: Based on systematic involvement of key stakeholders, the model supports clinicians navigating challenging conversations about approaching death with dying patients and their FC successfully and with more confidence. Innovation: This study expands the theoretical basis for communication about approaching death and offers a pragmatic model for educational interventions and clinical use.

Urban lignocellulosic biomass (ULB), derived from the maintenance of public and private green spaces, such as parks, gardens, sports facilities, and areas along roads, emerges as a solid alternative to replace fossil sources. These resources stand out due to their abundance, low cost, and availability. Hydrothermal carbonization (HTC) emerged as an efficient technology to process this biomass that has a high moisture and ash content, eliminating the need for prior drying. This article reviews the conversion of ULB to solid biofuels through the HTC process, addressing the physicochemical and energetic properties of ULB and the resulting hydrochar, as well as the HTC process and the influence of the operating variables that affect the energetic quality of hydrochar. The carbonization temperature (180 to 280 °C) has a very significant influence more than the residence time (0.5 to 24 h) on the increase in the higher heating value (17.83 to 30.12 MJ kg-1) and the fuel ratio, the decrease in the H/C and O/C ratios, the decrease in the combustibility index, the increase in the ignitability index (? 14.5 MJ kg-1), and the carbon range. However, high carbonization temperatures and long residence times in the reactor are unsuitable because they require large amounts of energy to perform HTC. Therefore, biofuel prices, biomass logistics, optimization of HTC process variables, and reduction of energy consumption are challenges for the HTC process to generate a solid biofuel with excellent energy properties.

# Background Little is known about the challenges of stoma care and potential solutions for patients in low- and middle-income countries (LMICs). This study aimed to assess the outcomes and experience of care for patients with stomas in LMICs using a mixed methods approach. # Methods A cross-sectional survey of hospitals assessed health system characteristics relevant to stoma care. A six-month retrospective audit collected data on all patients undergoing new stoma formation, and postoperative complications. Semi-structured interviews with stoma patients and informal caregivers, and key informant interviews with healthcare providers were conducted to gather information on experiences, challenges and coping strategies relating to stoma care. The results were triangulated to develop a questionnaire-based tool to assess patients’ and carers’ knowledge and attitudes towards stoma and stoma care. # Results Six hospitals from the Philippines, Malawi, Nigeria and India participated in the study. Data from 446 patients demonstrated diversity case mix, outcomes and postoperative stoma counselling. Interview data from the Philippines highlighted the lack of knowledge on stoma care of the patients and carers, poor access to stoma care and resources and the lack of affordable stoma care supplies. Triangulating these inputs, a 33-item questionnaire was developed to facilitate task sharing of expert stoma care to non-expert nurses and caregivers. # Conclusions This study highlighted gaps in capacity to provide stoma counselling and poor access to and affordability of stoma care supplies for patients in LMICs. This novel questionnaire can help close these gaps and improve care for new ostomates in resource limited settings. # Registration The study is registered in the Philippine Health Research Registry PHRR No.210805-003783 (https://registry.healthresearch.ph/index.php/registry)

Abstract Introduction Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [177Lu]Lu-PSMA-I&T. This study aimed to assess and compare the therapeutic efficacy of a single dose with a fractionated dose of [177Lu]Lu-PSMA-I&T in an orthotopic model of TNBC. Methods Rj:NMRI-Foxn1 nu/nu mice were used as recipients of MDA-MB-231 xenografts. The single dose group was treated with 1 × 60 ± 5 MBq dose of [177Lu]Lu-PSMA-I&T, while the fractionated dose group received 4 × a 15 ± 2 MBq dose of [177Lu]Lu-PSMA-I&T at 7 day intervals. The control group received 0.9% NaCl. Tumor progression was monitored using [18F]FDG-PET/CT. Ex vivo analysis encompassed immunostaining, TUNEL staining, H&E staining, microautoradiography, and autoradiography. Results Tumor volumes were significantly smaller in the single dose (p

Printed mathematical expression recognition (MER) models are usually trained and tested using LaTeX-generated mathematical expressions (MEs) as input and the LaTeX source code as ground truth. As the same ME can be generated by various different LaTeX source codes, this leads to unwanted variations in the ground truth data that bias test performance results and hinder efficient learning. In addition, the use of only one font to generate the MEs heavily limits the generalization of the reported results to realistic scenarios. We propose a data-centric approach to overcome this problem, and present convincing experimental results: Our main contribution is an enhanced LaTeX normalization to map any LaTeX ME to a canonical form. Based on this process, we developed an improved version of the benchmark dataset im2latex-100k, featuring 30 fonts instead of one. Second, we introduce the real-world dataset realFormula, with MEs extracted from papers. Third, we developed a MER model, MathNet, based on a convolutional vision transformer, with superior results on all four test sets (im2latex-100k, im2latexv2, realFormula, and InftyMDB-1), outperforming the previous state of the art by up to 88.3%.

Literature reviews on artificial intelligence (AI) have focused on the different applications of AI in higher education, the AI techniques used, and the benefits/risks of the use of AI. One of the greatest potentials of AI is to personalize higher education to the needs of students and offer timely feedback. This could benefit students with disabilities tremendously if their needs are also considered in the development of new AI educational technologies (EdTech). However, current reviews have failed to address the perspective of students with disabilities, which prompts ethical concerns. For instance, AI could treat people with disabilities as outliers in the data and end up discriminating against them. For that reason, this systematic literature review raises the following two questions: To what extent are ethical concerns considered in articles presenting AI applications assessing students (with disabilities) in higher education? What are the potential risks of using AI that assess students with disabilities in higher education? This scoping review highlights the lack of ethical reflection on AI technologies and an absence of discussion and inclusion of people with disabilities. Moreover, it identifies eight risks associated with the use of AI EdTech for students with disabilities. The review concludes with suggestions on how to mitigate these potential risks. Specifically, it advocates for increased attention to ethics within the field, the involvement of people with disabilities in research and development, as well as careful adoption of AI EdTech in higher education.

Abstract We continue the study of random matrix universality in two-dimensional conformal field theories. This is facilitated by expanding the spectral form factor in a basis of modular invariant eigenfunctions of the Laplacian on the fundamental domain. The focus of this paper is on the discrete part of the spectrum, which consists of the Maass cusp forms. Both their eigenvalues and Fourier coefficients are sporadic discrete numbers with interesting statistical properties and relations to analytic number theory; this is referred to as ‘arithmetic chaos’. We show that the near-extremal spectral form factor at late times is only sensitive to a statistical average over these erratic features. Nevertheless, complete information about their statistical distributions is encoded in the spectral form factor if all its spin sectors exhibit universal random matrix eigenvalue repulsion (a ‘linear ramp’). We ‘bootstrap’ the spectral correlations between the cusp form basis functions that correspond to a universal linear ramp and show that they are unique up to theory-dependent subleading corrections. The statistical treatment of cusp forms provides a natural avenue to fix the subleading corrections in a minimal way, which we observe leads to the same correlations as those described by the [torus]×[interval] wormhole amplitude in AdS3 gravity.

The purpose of this paper is to explain at the simplest possible level why finite mathematics based on a finite ring of characteristic p is more general (fundamental) than standard mathematics. The belief of most mathematicians and physicists that standard mathematics is the most fundamental arose for historical reasons. However, simple mathematical arguments show that standard mathematics (involving the concept of infinities) is a degenerate case of finite mathematics in the formal limit p→∞; standard mathematics arises from finite mathematics in the degenerate case when operations modulo a number are discarded. Quantum theory based on a finite ring of characteristic p is more general than standard quantum theory because the latter is a degenerate case of the former in the formal limit p→∞.

Gliomas are the most common type of cerebral tumors; they occur with increasing incidence in the last decade and have a high rate of mortality. For efficient treatment, fast accurate diagnostic and grading of tumors are imperative. Presently, the grading of tumors is established by histopathological evaluation, which is a time-consuming procedure and relies on the pathologists’ experience. Here we propose a supervised machine learning procedure for tumor grading which uses quantitative phase images of unstained tissue samples acquired by digital holographic microscopy. The algorithm is using an extensive set of statistical and texture parameters computed from these images. The procedure has been able to classify six classes of images (normal tissue and five glioma subtypes) and to distinguish between gliomas types from grades II to IV (with the highest sensitivity and specificity for grade II astrocytoma and grade III oligodendroglioma and very good scores in recognizing grade III anaplastic astrocytoma and grade IV glioblastoma). The procedure bolsters clinical diagnostic accuracy, offering a swift and reliable means of tumor characterization and grading, ultimately the enhancing treatment decision-making process.

Antimicrobial resistance (AMR) is a growing problem in African cattle production systems, posing a threat to human and animal health and the associated economic value chain. However, there is a poor understanding of the resistomes in small-holder cattle breeds in East African countries. This study aims to examine the distribution of antimicrobial resistance genes (ARGs) in Kenya, Tanzania, and Uganda cattle using a metagenomics approach. We used the SqueezeMeta-Abricate (assembly-based) pipeline to detect ARGs and benchmarked this approach using the Centifuge-AMRplusplus (read-based) pipeline to evaluate its efficiency. Our findings reveal a significant number of ARGs of critical medical and economic importance in all three countries, including resistance to drugs of last resort such as carbapenems, suggesting the presence of highly virulent and antibiotic-resistant bacterial pathogens (ESKAPE) circulating in East Africa. Shared ARGs such as aph(6)-id (aminoglycoside phosphotransferase), tet (tetracycline resistance gene), sul2 (sulfonamide resistance gene) and cfxA_gen (betalactamase gene) were detected. Assembly-based methods revealed fewer ARGs compared to read-based methods, indicating the sensitivity and specificity of read-based methods in resistome characterization. Our findings call for further surveillance to estimate the intensity of the antibiotic resistance problem and wider resistome classification. Effective management of livestock and antibiotic consumption is crucial in minimizing antimicrobial resistance and maximizing productivity, making these findings relevant to stakeholders, agriculturists, and veterinarians in East Africa and Africa at large.

The ICH S1B carcinogenicity global testing guideline has been recently revised with a novel addendum that describes a comprehensive integrated Weight of Evidence (WoE) approach to determine the need for a 2-year rat carcinogenicity study. In the present work, experts from different organizations have joined efforts to standardize as much as possible a procedural framework for the integration of evidence associated with the different ICH S1B(R1) WoE criteria. The framework uses a pragmatic consensus procedure for carcinogenicity hazard assessment to facilitate transparent, consistent, and documented decision-making and it discusses best-practices both for the organization of studies and presentation of data in a format suitable for regulatory review. First, it is acknowledged that the six WoE factors described in the addendum form an integrated network of evidence within a holistic assessment framework that is used synergistically to analyze and explain safety signals. Second, the proposed standardized procedure builds upon different considerations related to the primary sources of evidence, mechanistic analysis, alternative methodologies and novel investigative approaches, metabolites, and reliability of the data and other acquired information. Each of the six WoE factors is described highlighting how they can contribute evidence for the overall WoE assessment. A suggested reporting format to summarize the cross-integration of evidence from the different WoE factors is also presented. This work also notes that even if a 2-year rat study is ultimately required, creating a WoE assessment is valuable in understanding the specific factors and levels of human carcinogenic risk better than have been identified previously with the 2-year rat bioassay alone.

Abstract The structural process of bone and periodontal ligament (PDL) remodeling during long-term orthodontic tooth movement (OTM) has not been satisfactorily described yet. Although the mechanism of bone changes in the directly affected alveolar bone has been deeply investigated, detailed knowledge about specific mechanism of PDL remodeling and its interaction with alveolar bone during OTM is missing. This work aims to provide an accurate and user-independent analysis of the alveolar bone and PDL remodeling following a prolonged OTM treatment in mice. Orthodontic forces were applied using a Ni–Ti coil-spring in a split-mouth mice model. After 5 weeks both sides of maxillae were scanned by high-resolution micro-CT. Following a precise tooth movement estimation, an extensive 3D analysis of the alveolar bone adjacent to the first molar were performed to estimate the morphological and compositional parameters. Additionally, changes of PDL were characterized by using a novel 3D model approach. Bone loss and thinning, higher connectivity as well as lower bone mineral density were found in both studied regions. Also, a non-uniformly widened PDL with increased thickness was observed. The extended and novel methodology in this study provides a comprehensive insight about the alveolar bone and PDL remodeling process after a long-duration OTM.

Abstract Intraseasonal variation of rainfall extremes within boreal summer in the Indo-Pacific region is driven by the Boreal Summer Intraseasonal Oscillation (BSISO), a quasi-periodic north-eastward movement of convective precipitation from the Indian Ocean to the Western Pacific. Predicting the spatiotemporal location of the BSISO is essential for subseasonal prediction of rainfall extremes but still remains a major challenge due to insufficient understanding of its propagation pathway. Here, using unsupervised machine learning, we characterize how rainfall extremes travel within the region and reveal three distinct propagation modes: north-eastward, eastward-blocked, and quasi-stationary. We show that Pacific sea surface temperatures modulate BSISO propagation — with El Niño-like (La Niña-like) conditions favoring quasi-stationary (eastward-blocked) modes—by changing the background moist static energy via local overturning circulations. Finally, we demonstrate the potential for early warning of rainfall extremes in the region up to four weeks in advance.

Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather than depending on the engagement of a single activating receptor, their activation involves a delicate balance between inhibitory and activating signals mediated through an array of surface molecules. Only when this cumulative balance surpasses a specific threshold do NK cells initiate their activity. Remarkably, the activation threshold of NK cells remains robust even when cells express vastly different repertoires of inhibitory and activating receptors. These threshold values seem to be influenced by NK cell interactions with their environment during development and after release from the bone marrow. Understanding how NK cells integrate this intricate pattern of stimuli is an ongoing area of research, particularly relevant for cellular therapies seeking to harness the anti-cancer potential of these cells by modifying surface receptor expression. In this review, we will explore some of the current dogmas regarding NK cell activation and discuss recent literature addressing advances in our understanding of this field.

Background: Identifying the cause of recurrent or persisting pain after posterior lumbar interbody fusion (PLIF) is essential for establishing optimal treatment. In this study, we evaluate patients after PLIF surgery by 18F-fluoride PET/CT scans and patient-reported outcome measures (PROMs). Methods: A total of 36 PLIF patients were included. Sixty minutes after intravenous injection of 18F-fluoride, PET/CT scanning was performed. Bone graft ingrowth, subsidence, screw loosening and damage of facet joints were scored by quantifying the level of bone metabolism of the vertebral endplates in the disc spaces, around screws and around the facet joints on the PET scans. Results: In contrast to asymptomatic patients, symptomatic patients showed abnormal PET values around pedicle screws and/or facet joints and at the lower endplates of the disc spaces, identifying a possible source of pain. On CT, no significant differences between these two groups were found. Conclusion: The PET/CT findings appeared to correlate better with symptoms on PROMs compared to CT findings alone. When interpreting 18F-fluoride PET/CT findings after PLIF surgery, one should realize bone metabolism in the disc spaces of the operated segments and around pedicle screws or facet joint changes during follow-up, reflecting natural recovery.

Abstract When two particles collide in an asymptotically AdS spacetime with high enough energy and small enough impact parameter, they can form a black hole. Motivated by dual quantum circuit considerations, we propose a threshold condition for black hole formation. Intuitively the condition can be understood as the onset of overlap of the butterfly cones describing the ballistic spread of the effect of the perturbations on the boundary systems. We verify the correctness of the condition in three bulk dimensions. We describe a six-point correlation function that can diagnose this condition and compute it in two-dimensional CFTs using eikonal resummation.

Abstract Background Canine prostheses have been commercially available for many years but are still in early stages of research, development, and clinical application. Objective To prospectively investigate mid‐term clinical outcomes of partial limb amputation with a socket prosthesis (PLASP) in canine patients via a descriptive prospective clinical case series and to describe a clinical protocol for PLASP. Methods Client‐owned dogs (n = 12) with distal limb pathology for which total limb amputation was recommended were enrolled. Partial limb amputation was performed and a socket prosthesis was moulded and fitted to the limb. Complications, clinical follow‐up, and objective gait analysis (OGA) were recorded for at least 6 months. An online survey was completed by owners after study completion. Results Ten dogs with thoracic limb pathology and two with pelvic limb pathology were included. The most common site of amputation was mid‐radius (n = 5). Eleven of 12 dogs demonstrated quadrupedal gait on OGA with mean per cent body weight distribution (%BWD) of 26% on thoracic limb prostheses and a %BWD of 16% for the one pelvic limb prosthesis that OGA data were available for. Complications included prosthesis suspension difficulties (n = 5), pressure sores (4), bursitis (4), postoperative infection (3), prosthesis aversion (2), dermatitis (1), and owner noncompliance (1). Two owners elected to discontinue prosthesis use. Conclusions PLASP allowed restoration of quadrupedal gait patterns in most patients. Owners reported overall positive satisfaction, though a high complication rate was observed. PLASP should be considered in select cases as an alternative to total limb amputation for dogs with distal limb pathology.

Abstract Pancreatic neuroendocrine tumors (PanNETs) are a rare tumor entity with largely unpredictable progression and increasing incidence in developed countries. Molecular pathways involved in PanNETs development are still not elucidated, and specific biomarkers are missing. Moreover, the heterogeneity of PanNETs makes their treatment challenging and most approved targeted therapeutic options for PanNETs lack objective responses. Here, we applied a systems biology approach integrating dynamic modeling strategies, foreign classifier tailored approaches, and patient expression profiles to predict PanNETs progression as well as resistance mechanisms to clinically approved treatments such as the mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We set up a model able to represent frequently reported PanNETs drivers in patient cohorts, such as Menin-1 (MEN1), Death domain associated protein (DAXX), Tuberous Sclerosis (TSC), as well as wild-type tumors. Model-based simulations suggested drivers of cancer progression as both first and second hits after MEN1 loss. In addition, we could predict the benefit of mTORC1 inhibitors on differentially mutated cohorts and hypothesize resistance mechanisms. Our approach sheds light on a more personalized prediction and treatment of PanNET mutant phenotypes.

Abstract Heterogeneous chemical cycles of pyrogenic nitrogen and halides influence tropospheric ozone and affect the stratosphere during extreme Pyrocumulonimbus (PyroCB) events. We report field‐derived N2O5 uptake coefficients, γ(N2O5), and ClNO2 yields, φ(ClNO2), from two aircraft campaigns observing fresh smoke in the lower and mid troposphere and processed/aged smoke in the upper troposphere and lower stratosphere (UTLS). Derived φ(ClNO2) varied across the full 0–1 range but was typically

In a companion paper, we present the first spatially resolved polarized image of Sagittarius A* on event horizon scales, captured using the Event Horizon Telescope, a global very long baseline interferometric array operating at a wavelength of 1.3 mm. Here we interpret this image using both simple analytic models and numerical general relativistic magnetohydrodynamic (GRMHD) simulations. The large spatially resolved linear polarization fraction (24%–28%, peaking at ∼40%) is the most stringent constraint on parameter space, disfavoring models that are too Faraday depolarized. Similar to our studies of M87*, polarimetric constraints reinforce a preference for GRMHD models with dynamically important magnetic fields. Although the spiral morphology of the polarization pattern is known to constrain the spin and inclination angle, the time-variable rotation measure (RM) of Sgr A* (equivalent to ≈46° ± 12° rotation at 228 GHz) limits its present utility as a constraint. If we attribute the RM to internal Faraday rotation, then the motion of accreting material is inferred to be counterclockwise, contrary to inferences based on historical polarized flares, and no model satisfies all polarimetric and total intensity constraints. On the other hand, if we attribute the mean RM to an external Faraday screen, then the motion of accreting material is inferred to be clockwise, and one model passes all applied total intensity and polarimetric constraints: a model with strong magnetic fields, a spin parameter of 0.94, and an inclination of 150°. We discuss how future 345 GHz and dynamical imaging will mitigate our present uncertainties and provide additional constraints on the black hole and its accretion flow.

The Event Horizon Telescope observed the horizon-scale synchrotron emission region around the Galactic center supermassive black hole, Sagittarius A* (Sgr A*), in 2017. These observations revealed a bright, thick ring morphology with a diameter of 51.8 ± 2.3 μ as and modest azimuthal brightness asymmetry, consistent with the expected appearance of a black hole with mass M ≈ 4 × 10 ^6 M _⊙ . From these observations, we present the first resolved linear and circular polarimetric images of Sgr A*. The linear polarization images demonstrate that the emission ring is highly polarized, exhibiting a prominent spiral electric vector polarization angle pattern with a peak fractional polarization of ∼40% in the western portion of the ring. The circular polarization images feature a modestly (∼5%–10%) polarized dipole structure along the emission ring, with negative circular polarization in the western region and positive circular polarization in the eastern region, although our methods exhibit stronger disagreement than for linear polarization. We analyze the data using multiple independent imaging and modeling methods, each of which is validated using a standardized suite of synthetic data sets. While the detailed spatial distribution of the linear polarization along the ring remains uncertain owing to the intrinsic variability of the source, the spiraling polarization structure is robust to methodological choices. The degree and orientation of the linear polarization provide stringent constraints for the black hole and its surrounding magnetic fields, which we discuss in an accompanying publication.

The host immune system plays a significant role in managing and clearing pathogen material during an infection, but this complex process presents numerous challenges from a modeling perspective. There are many mathematical and statistical models for these kinds of processes that take into account a wide range of events that happen within the host. In this work, we present a Bayesian joint model of longitudinal and time-to-event data of Leishmania infection that considers the interplay between key drivers of the disease process: pathogen load, antibody level, and disease. The longitudinal model also considers approximate inflammatory and regulatory immune factors. In addition to measuring antibody levels produced by the immune system, we adapt data from CD4+ and CD8+ T cell proliferation, and expression of interleukin 10, interferon-gamma, and programmed cell death 1 as inflammatory or regulatory factors mediating the disease process. The model is developed using data collected from a cohort of dogs naturally exposed to Leishmania infantum. The cohort was chosen to start with healthy infected animals, and this is the majority of the data. The model also characterizes the relationship features of the longitudinal outcomes and time-to-death due to progressive Leishmania infection. In addition to describing the mechanisms causing disease progression and impacting the risk of death, we also present the model's ability to predict individual trajectories of Canine Leishmaniosis (CanL) progression. The within-host model structure we present here provides a way forward to address vital research questions regarding the understanding of the progression of complex chronic diseases such as Visceral Leishmaniasis, a parasitic disease causing significant morbidity worldwide.

IntroductionTranscranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) – a Dopamine receptor-antagonist – the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured.Methods23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen).ResultsVerum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session.ConclusionResults suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression.

Background: Peripheral arterial disease (PAD) reduces functional capacity and raises cardiovascular risks, but underdiagnosis is common, resulting in less comprehensive care than other cardiovascular conditions. While diabetes has long been viewed as a key risk factor for PAD, recent studies indicate that its impact is influenced by the presence of concurrent cardiovascular risk factors. The aim of this study is to elucidate the intricate relationship between the prevalence of PAD, diabetic complications, and cardiovascular risk factors among asymptomatic patients with type 2 diabetes mellitus (T2DM). Methods: Ninety-one patients with T2DM and no symptoms or previous diagnosis of PAD were recruited from the outpatient diabetic clinic. Clinical data were extracted from electronic medical records, and the screening for PAD was conducted using MESI mTABLET. Results: Screening for PAD among asymptomatic individuals with T2DM revealed that 5.49 % of patients exhibit a low ankle-brachial index (ABI). Patients who had previously experienced major adverse cardiovascular events or exhibited albuminuria displayed lower ABI values. Furthermore, a striking 45.05 % of the participants displayed an abnormally high carotid-femoral pulse wave velocity (cfPWV) value, with elevated PWV values correlating with advanced age and longer diabetes duration. Conclusions: The prevalence of elevated cfPWV is more pronounced than that of decreased ABI in T2DM patients with asymptomatic PAD and is associated with older age and longer diabetes duration, therefore measurement of both ABI and PWV is crucial for the cardiovascular risk assessment protocol for patients with T2DM and timely PAD diagnosis.

Abstract It has been proposed that the exponential decay and subsequent power law saturation of out-of-time-order correlation functions can be universally described by collective ‘scramblon’ modes. We develop this idea from a path integral perspective in several examples, thereby establishing a general formalism. After reformulating previous work on the Schwarzian theory and identity conformal blocks in two-dimensional CFTs relevant for systems in the infinite coupling limit with maximal quantum Lyapunov exponent, we focus on theories with sub-maximal chaos: we study the large-q limit of the SYK quantum dot and chain, both of which are amenable to analytical treatment at finite coupling. In both cases we identify the relevant scramblon modes, derive their effective action, and find bilocal vertex functions, thus constructing an effective description of chaos. The final results can be matched in detail to stringy corrections to the gravitational eikonal S-matrix in holographic CFTs, including a stringy Regge trajectory, bulk to boundary propagators, and multi-string effects that are unexplored holographically.

IntroductionResearch on the neural mechanisms of perceptual decision-making has typically focused on simple categorical choices, say between two alternative motion directions. Studies on such discrete alternatives have often suggested that choices are encoded either in a motor-based or in an abstract, categorical format in regions beyond sensory cortex.MethodsIn this study, we used motion stimuli that could vary anywhere between 0° and 360° to assess how the brain encodes choices for features that span the full sensory continuum. We employed a combination of neuroimaging and encoding models based on Gaussian process regression to assess how either stimuli or choices were encoded in brain responses.ResultsWe found that single-voxel tuning patterns could be used to reconstruct the trial-by-trial physical direction of motion as well as the participants’ continuous choices. Importantly, these continuous choice signals were primarily observed in early visual areas. The tuning properties in this region generalized between choice encoding and stimulus encoding, even for reports that reflected pure guessing.DiscussionWe found only little information related to the decision outcome in regions beyond visual cortex, such as parietal cortex, possibly because our task did not involve differential motor preparation. This could suggest that decisions for continuous stimuli take can place already in sensory brain regions, potentially using similar mechanisms to the sensory recruitment in visual working memory.

This work shows the physicochemical properties and assessment energetic quality assessments on the ignitability index and the emission factor of pruning from urban Ficus benjamina tree (Fb). Seven samples with different proportions and parts of the pruning were used. Such as; branches of different diameters, leaves, and their mixture. Proximate analysis, elemental analysis, and higher heating value analysis were conducted. From this information, the ignitability index and emission factor were estimated. The results showed that pruning of Fb has an average of 8.1 wt.% moisture, 75.15 wt.% volatile matter, 5.87 wt.% ash, 10.87 wt.% fixed carbon, 42.81 wt.% of carbon, 5.86 wt.% hydrogen, 1.01 wt.% nitrogen, 0.05 wt.% sulfur, and a higher heating value of 17.05 MJ kg-1. Pruning of Fb has shown an ignitability index of 38.44, high CO and CO2 emissions, and low levels of NOx and SO2 emissions. When comparing the results obtained with the literature, pruning of Fb show potential to be explored as biofuels and energy generation systems.

ABSTRACT: Growth performance, gizzard weight, ceca digesta short-chain fatty acids (SCFA), and apparent retention (AR) of components were investigated in broilers and turkeys in response to cereal grain type, fiber level, and multienzyme supplement (MES) fed from hatch to 28 d of life. 480-day-old male broiler chicks and equal number of turkeys were placed separately in metabolism cages (10 birds/cage) and allocated to 8 diets. The species-specific diets were a corn or wheat-based basal diet without (LF) or with 10% corn DDGS or wheat middlings (HF) and fed without or with MES. This effectively created a 2 (grain types) × 2 (fiber levels) × 2 (MES) factorial arrangement of treatments. The diets had TiO2 as an indigestible marker. Body weight, feed intake, and mortalities were recorded to calculate body weight gain (BWG) and feed conversion ratio (FCR). Excreta samples were collected on d 25 to 27 for AR, and all birds were necropsied for gizzard weight and ceca digesta on d 28. The interaction between grain and MES in broilers was such that wheat diets with MES had the lowest (P = 0.005) FCR. In broilers, LF diets had better (P = 0.010) FCR than HF diets. The wheat diets had the highest (P = 0.006) concentration of butyric acid in broilers. Broilers fed HF and corn diets had heavier gizzard than broilers-fed LF and wheat diets. The MES improved (P < 0.05) AMEn in HF, corn, and wheat diets in broilers. The turkeys fed wheat diets had the lowest (P = 0.019) FCR. Turkeys fed HF wheat diets had the heaviest (P < 0.001) gizzard. In turkeys, the MES improved AMEn in HF and LF corn diets, and only in LF wheat diets compared to respective controls. Treatments had no effect on turkeys cecal SCFA. In conclusion, grain type, fiber, and MES did not affect growth in both species. However, species exhibited differing FCR, gizzard, and energy utilization to fiber and MES.

ObjectiveThe treatment with 177Lutetium PSMA (177Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC) has recently been approved by the FDA and EMA. Since treatment success is highly variable between patients, the prediction of treatment response and identification of short- and long-term survivors after treatment could help tailor mCRPC diagnosis and treatment accordingly. The aim of this study is to investigate the value of radiomic parameters extracted from pretreatment 68Ga-PSMA PET images for the prediction of treatment response.MethodsA total of 45 mCRPC patients treated with 177Lu-PSMA-617 from two university hospital centers were retrospectively reviewed for this study. Radiomic features were extracted from the volumetric segmentations of metastases in the bone. A random forest model was trained and validated to predict treatment response based on age and conventionally used PET parameters, radiomic features and combinations thereof. Further, overall survival was predicted by using the identified radiomic signature and compared to a Cox regression model based on age and PET parameters.ResultsThe machine learning model based on a combined radiomic signature of three features and patient age achieved an AUC of 0.82 in 5-fold cross-validation and outperformed models based on age and PET parameters or radiomic features (AUC, 0.75 and 0.76, respectively). A Cox regression model based on this radiomic signature showed the best performance to predict overall survival (C-index, 0.67).ConclusionOur results demonstrate that a machine learning model to predict response to 177Lu-PSMA treatment based on a combination of radiomics and patient age outperforms a model based on age and PET parameters. Moreover, the identified radiomic signature based on pretreatment 68Ga-PSMA PET images might be able to identify patients with an improved outcome and serve as a supportive tool in clinical decision making.

IntroductionThe fMRI BOLD response to emotional stimuli highlighting the role of the medial prefrontal cortex (MPFC) has been thoroughly investigated. Recently, the relationship between emotion processing and GABA levels has been studied using MPFC proton magnetic resonance spectroscopy (1H-MRS). However, the role of GABAA receptors in the MPFC during emotion processing remains unexplored.MethodsUsing [11C]flumazenil PET, we investigated the relationship between the binding potential of GABAA receptors and emotion processing as measured using simultaneous fMRI BOLD. We hypothesized a correlation between the percent signal change in the BOLD signal and the binding potential of GABAA receptors in the MPFC. In a combined simultaneous fMRI and [11C]flumazenil-PET study, we analyzed the data from 15 healthy subjects using visual emotional stimuli. Our task comprised two types of emotional processing: passive viewing and appraisal. Following the administration of a bolus plus infusion protocol, PET and fMRI data were simultaneously acquired in a hybrid 3 T MR-BrainPET.ResultsWe found a differential correlation of BOLD percent signal change with [11C]flumazenil binding potential in the MPFC. Specifically, [11C]flumazenil binding potential in the ventromedial prefrontal cortex (vMPFC) correlated with passive viewing of emotionally valenced pictures. In contrast, the [11C]flumazenil binding potential and the BOLD signal induced by picture appraisal did show a correlation in the paracingulate gyrus.ConclusionOur data deliver first evidence for a relationship between MPFC GABAA receptors and emotion processing in the same region. Moreover, we observed that GABAA receptors appear to play different roles in emotion processing in the vMPFC (passive viewing) and paracingulate gyrus (appraisal).

Summary: Boolean networks are commonly used in systems biology to dynamically model gene regulatory interactions. Here, we present a protocol for implementing Boolean network dynamics as quantum circuits. We describe steps for accessing cloud-based quantum processing units offered by IBM and IonQ and downloading and parsing logic for gene regulatory networks. We then detail procedures for performing simulations of quantum circuits on local devices and visualizing measurement results.For complete details on the use and execution of this protocol, please refer to Weidner et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Multiple trauma patients with severe chest trauma are at increased risk for tracheostomy. While the risk factors associated with the need for tracheostomy are well established in the general critical care population, they have not yet been validated in a cohort of patients suffering severe thoracic trauma. This retrospective cohort study analysed data on patients aged 18 years or older who were admitted to one of the six participating academic level I trauma centres with multiple injuries, including severe thoracic trauma (AISThorax ≥ 3) between 2010 and 2014. A multivariable binary regression was used to identify predictor variables for tracheostomy and to develop the Tracheostomy in Thoracic Trauma Prediction Score (T3P-Score). The study included 1019 adult thoracic trauma patients, of whom 165 underwent tracheostomy during their intensive care unit (ICU) stay. Prehospital endotracheal intubation (adjusted OR [AOR]: 2.494, 95% CI [1.412; 4.405]), diagnosis of pneumonia during the ICU stay (AOR: 4.374, 95% CI [2.503; 7.642]), duration of mechanical ventilation (AOR: 1.008/hours of intubation, 95% CI [1.006; 1.009]), and an AISHead ≥ 3 (AOR 1.840, 95% CI [1.039; 3.261]) were independent risk factors for tracheostomy. Patients with sepsis had a lower risk of tracheostomy than patients without sepsis (AOR 0.486, 95% CI [0.253; 0.935]). The T3P-Score had high predictive validity for tracheostomy (ROCAUC = 0.938, 95% CI [0.920, 0.956]; Nagelkerke’s R2 was 0.601). The T3P-Score’s specificity was 0.68, and the sensitivity was 0.96. The severity of thoracic trauma did not predict the need for tracheostomy. Follow-up studies should validate the T3P-Score in external data sets and study the reasons for the reluctant use of tracheostomy in patients with severe thoracic trauma and subsequent sepsis. Trial registration : The study was applied for and registered a priori with the respective ethics committees.

Introduction: Clinical data on the differences in presentation and outcome of admitted COVID-19 patients in Nigeria are limited. This study aimed to compare the first and second waves of the COVID-19 pandemic in a Tertiary Hospital in Lagos and describe the clinical differences between the waves, the severity of COVID-19, and the mortality differences. Methods: The study was a retrospective review of the medical records of all children and adults admitted to the Lagos University Teaching Hospital (LUTH) COVID-19 Isolation and Treatment Centre during the first wave (from April 2020 to October 2020) and second wave (from December 2020 to April 2021). The clinical characteristics (including COVID severity) and outcome among admitted patients during the two waves were compared. Results: Between April 2020 and April 2021, 602 patients were admitted to LUTH for COVID-19. Patients in the first wave were significantly younger (43 vs. 54.5 years), more in number (53.8% vs. 46.2%), and had a higher proportion of health-care workers than those in the second wave (14.5% vs. 6.5%). Comorbidities were present in more than half of the patients hospitalized for COVID-19 infection (51.0%). This proportion was much higher during the pandemic's second wave (41.7% vs. 61.9%, P < 0.001). The most common comorbidity found in hospitalized patients was hypertension (37.0%). Patients admitted during the second wave had shorter stays (11 vs. 7 days) and similar mortality rates (10.2% vs. 10.8%). Conclusion: The first and second waves had comparable mortality rates though patients in the first wave were younger and there were more healthcare providers in the cohort. Patients admitted to the second wave however had more comorbidities but shorter lengths of stay which may suggest a better understanding of the infection and better outcome.

Abstract Purpose Metastatic bone disease (MBD) is the most common form of metastases, most frequently deriving from prostate cancer. MBD is screened with bone scintigraphy (BS), which have high sensitivity but low specificity for the diagnosis of MBD, often requiring further investigations. Deep learning (DL) - a machine learning technique designed to mimic human neuronal interactions- has shown promise in the field of medical imaging analysis for different purposes, including segmentation and classification of lesions. In this study, we aim to develop a DL algorithm that can classify areas of increased uptake on bone scintigraphy scans. Methods We collected 2365 BS from three European medical centres. The model was trained and validated on 1203 and 164 BS scans respectively. Furthermore we evaluated its performance on an external testing set composed of 998 BS scans. We further aimed to enhance the explainability of our developed algorithm, using activation maps. We compared the performance of our algorithm to that of 6 nuclear medicine physicians. Results The developed DL based algorithm is able to detect MBD on BSs, with high specificity and sensitivity (0.80 and 0.82 respectively on the external test set), in a shorter time compared to the nuclear medicine physicians (2.5 min for AI and 30 min for nuclear medicine physicians to classify 134 BSs). Further prospective validation is required before the algorithm can be used in the clinic.

Abstract Background To quantify the relationship between [18F]FDG uptake of the primary tumour measured by PET-imaging with immunohistochemical (IHC) expression of ER, PR, HER2, Ki-67, and clinical subtypes based on these markers in breast cancer patients. Methods PubMed and Embase were searched for studies that compared SUVmax between breast cancer patients negative and positive for IHC expression of ER, PR, HER2, Ki-67, and clinical subtypes based on these markers. Two reviewers independently screened the studies and extracted the data. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were estimated by using DerSimonian-Laird random-effects models. P values less than or equal to 5% indicated statistically significant results. Results Fifty studies were included in the final analysis. SUVmax is significantly higher in ER-negative (31 studies, SMD 0.66, 0.56–0.77, P

Does automation adoption mitigate the COVID-19 infection rate of employees? What resources and internal and external factors need to be configured with automation to mitigate COVID-19 contagion from employees successfully? According to the type of automation. What resources efficiently complement to mitigate the contagion rate from employers? From a fuzzy-set qualitative comparative analysis (fsQCA) approach, we analyzed 759 manufacturing firms in Finland, drawn from the World Bank 2020 Enterprise Survey; this study addresses the multiple configurations that drive pandemic risk mitigation and management. We find that configurations under automation reduce the risk of employee infection. Our results show the critical role of automation in employee safety. We argue that access to government support and the development of technological innovation are necessary conditions for implementing measures to prevent and mitigate the risk of contagion in the employee. In addition, the first configuration states that manufacturing firms employing soft automation can successfully mitigate employee exposure. The second configuration states that high human resource flexibility successfully complements firms with complex automation to achieve high mitigation. Finally, the third configuration shows those manufacturing firms that employ low-tech automation (manual processes); in this manner, digitization enables successfully mitigating pandemic contagion. Moreover, it suggests recommendations for policymakers and managers.

Abstract Background Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCAmut). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125I. Methods TNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm3, [123I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [125I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction. Results SPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [125I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid. Conclusion Considering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [125I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application.

Abstract We study collisions between localized shockwaves inside a black hole interior. We give a holographic boundary description of this process in terms of the overlap of two growing perturbations in a shared quantum circuit. The perturbations grow both exponentially as well as ballistically. Due to a competition between different physical effects, the circuit analysis shows dependence on the transverse locations and exhibits four regimes of qualitatively different behaviors. On the gravity side we study properties of the post-collision geometry, using exact calculations in simple setups and estimations in more general circumstances. We show that the circuit analysis offers intuitive and surprisingly accurate predictions about gravity computations involving non-linear features of general relativity.

IntroductionExtracorporeal shockwave therapy (ESWT) is used as a treatment option for several musculoskeletal pathologies in dogs. When performing ESWT using electrohydraulic devices, sedation is commonly recommended due to the noise and discomfort associated with the treatment. The aim of this study was to compare the tolerance of ESWT delivered by a standard or novel trode in awake canine patients with musculoskeletal disease.Materials and methodsThis was a prospective, blinded clinical trial in which dogs with musculoskeletal disease received awake treatment with ESWT with a gradually increasing energy protocol using both standard and novel trodes with an electrohydraulic generator in a randomized fashion. Noise reactivity and tolerance to treatment as measured in number of shocks and energy level achieved were recorded.ResultsForty client-owned dogs with pathology affecting the hips, stifles, elbows, or shoulders were enrolled. Thirty-three dogs completed all three treatment sessions, three dogs completed two sessions, and four dogs completed one session. There was evidence of improved patient tolerability with the novel trode, based on an increased average number of shocks delivered (n ± SD = 848 ± 334 for novel trode; n ± SD = 767 ± 358 for standard trode; p = 0.0384) and higher average treatment energy level achieved (E ± SD = 6.5 ± 2.5 for novel trode; E ± SD = 5.3 ± 2.8 for standard trode; p = < 0.001). Decreased noise reactivity was found to be positively correlated with tolerability of shockwave treatment (energy level: p = 0.0168; number of shocks: p = 0.0097).DiscussionAdministration of electrohydraulic ESWT is feasible in select awake patients using a gradually increasing energy protocol, and the tested novel shockwave trode is better tolerated than the standard trode. Further studies are required to determine the efficacy of the novel trode, and if gradually increasing energy protocols are clinically equivalent to current standard protocols that employ a consistent energy level.

Natural killer (NK) cells play an important role in the early defense against tumors and virally infected cells. Their function is thought to be controlled by the balance between activating and inhibitory receptors, which often compete for the same ligands. Several activating receptors expressed on virtually all NK cells lack an inhibitory partner, most notably CD16, NCR1 and NKG2D. We therefore hypothesized that a signal through at least one of these receptors is always required for full NK cell activation. We generated animals lacking all three receptors (TKO) and analyzed their NK cells. In vitro, TKO NK cells did not show reduced ability to kill tumor targets but displayed hyperresponsiveness to NK1.1 stimulation. In vivo, TKO animals had a minor reduction in their ability to control non-hematopoietic tumors and cytomegalovirus infection, which was the result of reduced NK cell activity. Together, our findings show that activating NK cell receptors without an inhibitory partner do not provide a ‘master’ signal but are integrated in the cumulative balance of activating and inhibitory signals. Their activity is controlled through regulation of the responsiveness and expression of other activating receptors. Our findings may be important for future development of NK cell-based cancer immunotherapy.

We solve the particle-antiparticle and cosmological constant problems proceeding from quantum theory, which postulates that: various states of the system under consideration are elements of a Hilbert space H with a positive definite metric; each physical quantity is defined by a self-adjoint operator in H; symmetry at the quantum level is defined by a representation of a real Lie algebra A in H such that the representation operator of any basis element of A is self-adjoint. These conditions guarantee the probabilistic interpretation of quantum theory. We explain that in the approaches to solving these problems that are described in the literature, not all of these conditions have been met. We argue that fundamental objects in particle theory are not elementary particles and antiparticles but objects described by irreducible representations (IRs) of the de Sitter (dS) algebra. One might ask why, then, experimental data give the impression that particles and antiparticles are fundamental and there are conserved additive quantum numbers (electric charge, baryon quantum number and others). The reason is that, at the present stage of the universe, the contraction parameter R from the dS to the Poincare algebra is very large and, in the formal limit R→∞, one IR of the dS algebra splits into two IRs of the Poincare algebra corresponding to a particle and its antiparticle with the same masses. The problem of why the quantities (c,ℏ,R) are as are does not arise because they are contraction parameters for transitions from more general Lie algebras to less general ones. Then the baryon asymmetry of the universe problem does not arise. At the present stage of the universe, the phenomenon of cosmological acceleration (PCA) is described without uncertainties as an inevitable kinematical consequence of quantum theory in semiclassical approximation. In particular, it is not necessary to involve dark energy the physical meaning of which is a mystery. In our approach, background space and its geometry are not used and R has nothing to do with the radius of dS space. In semiclassical approximation, the results for the PCA are the same as in General Relativity if Λ=3/R2, i.e., Λ>0 and there is no freedom for choosing the value of Λ.

In this paper, I attempt to describe Mark Burgin’s results in non-Diophantine mathematics, which are important for the foundation of mathematics and its application in quantum field theory. In particular, the elimination of divergences in quantum electrodynamics is described.