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Abstract Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone‐related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl‐Ab). Here, we show that PTH and Scl‐Ab reduce the expression of microRNA‐19a and microRNA‐19b (miR‐19a/b) in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR‐19a/b expression is elevated, suggesting an inhibitory function in bone remodeling. Indeed, antagonizing miR‐19a/b in vivo increased bone mass without overt cytotoxic effects. We identified TG‐interacting factor 1 (Tgif1) as the target of miR‐19a/b in osteoblasts and essential for the increase in bone mass following miR‐19a/b inhibition. Furthermore, antagonizing miR‐19a/b augments the gain in bone mass by PTH and restores bone loss in mouse models of osteoporosis in a dual mode of action by supporting bone formation and decreasing receptor activator of NF‐κB ligand (RANKL)‐dependent bone resorption. Thus, this study identifies novel mechanisms regulating bone remodeling, which opens opportunities for new therapeutic concepts to treat bone fragility.

Abstract Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality of life. We show here that small molecule activation of the Ca2+‐permeable endolysosomal two‐pore channel 2 (TPC2) results in an amelioration of cellular phenotypes associated with LSDs such as cholesterol or lipofuscin accumulation, or the formation of abnormal vacuoles seen by electron microscopy. Rescue effects by TPC2 activation, which promotes lysosomal exocytosis and autophagy, were assessed in mucolipidosis type IV (MLIV), Niemann–Pick type C1, and Batten disease patient fibroblasts, and in neurons derived from newly generated isogenic human iPSC models for MLIV and Batten disease. For in vivo proof of concept, we tested TPC2 activation in the MLIV mouse model. In sum, our data suggest that TPC2 is a promising target for the treatment of different types of LSDs, both in vitro and in‐vivo.

The potential risk of chemicals to the human eye is assessed by adopted test guidelines (TGs) for regulatory purposes to ensure consumer safety. Over the past decade, the Organization for Economic Co-operation and Development (OECD) has approved new approach methodologies (NAMs) to predict chemical eye damage. However, existing NAMs remain associated with limitations: First, no full replacement of the in vivo Draize eye test due to limited predictability of severe/mild damage was reached. Second, the existing NAMs do not allow reliable differentiation between reversible and irreversible eye damage. Especially the prediction of tissue recovery remains challenging in vitro. Existing in vitro NAMs are based on destructive analysis with no consideration of tissue recovery. In this study, we developed a standalone eye-irritation test method based on non-invasive impedance spectroscopy (ImAi) to discriminate between damaging and irritating chemicals. Tissue effects were analyzed via transepithelial electrical resistance (TEER) measurements of human in vitro epithelial models over 14 days. The TEER was performed using a developed impedance spectrometer. For development of the EIT, a chemical reference list of 329 chemicals was compiled. The applicability of the ImAi-test was exemplified by the discrimination of Cat. 1 vs. Cat. 2 for 23 reference chemicals. Correct classification was achieved for 90.9% of Cat. 1 and 83.3% of Cat. 2 chemicals. Our non-invasive in vitro test overcomes the limitations of Cat. 2 classification of the existing in vitro methods and provides for the first time a non-animal test method that can fully replace the Draize eye test. [ABSTRACT FROM AUTHOR]

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Background: Recently, a network model of cervical dystonia (CD) has been adopted that implicates nodes and pathways involving cerebellar, basal-ganglia and cortico-cortical connections. Although functional changes in the cerebello-thalamo-cortical network in dystonia have been reported in several studies, structural information of this network remain sparse. Objective: To characterize the structural properties of the cerebellar motor network in isolated CD patients. This includes cerebellar lobules involved in motor processing, the dentate nucleus (DN), the thalamus, and the primary motor cortex (M1). Methods: Magnetic resonance imaging data of 18 CD patients and 18 healthy control subjects were acquired. In CD patients, the motor part of the Toronto Western Spasmodic Torticollis Rating Scale was assessed to evaluate motor symptom severity. The volume of cerebellar lobules I-VI and VIII, the DN and thalamus, and the cortical thickness (CT) of M1 were determined for a region of interest (ROI)-based quantitative analysis. Volumes/CT of these ROIs were compared between groups and associated with motor symptom severity in patients. Results: The volume of lobule VI and the CT of M1 were reduced in CD patients. The volumes of the other ROIs were not different between groups. No association was identified between the structural properties of lobule VI or M1 and the severity of CD motor symptoms. Conclusion: Atrophy within the cerebellum and M1 contributes to CD's complex motor network pathology. Further investigations are needed to ascertain the mechanisms underlying the local volume loss. [ABSTRACT FROM AUTHOR]

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There are numerous contradictory models concerning the reconstruction of the Palaeozoic palaeogeography of the Central European Variscides. A key region is the suture zone, the Northern Phyllite Zone, between the southern continent Gondwana including Armorica and the northern continent Laurussia including the continents Avalonia and Baltica. The Northern Phyllite Zone hosts the Silurian volcanic arc of the Rheic Ocean. This volcanic arc has been interpreted as an island arc that was accreted together with the northern part of Armorica against Laurussia in the Lower Devonian. Our results of U–Pb age dating of detrital and magmatic zircon grains give constraints on the provenance of metasedimentary rocks and the extrusion age of the volcanic rocks of the Rhenish Massif and adjacent Northern Phyllite Zone of the Central European Variscides. These help to validate the geodynamic models. U–Pb data of zircon grains indicate that the Silurian arc of the Northern Phyllite Zone is a continental arc. It received detritus from the East Avalonian basement that points to a position at the southern plate boundary of Laurussia. This Silurian arc cannot be correlated with the Silurian to Devonian magmatic arc of the Mid-German Crystalline Zone, because the host rocks of the Silurian plutons received detritus from Armorica or Baltica. The volcanic rocks of the Northern Phyllite Zone are dated with the U–Pb zircon method from 442 to 431 Ma. During the latest Silurian (Pridolian), the volcanism vanished and Devonian shelf sediments accumulated on top of the continental arc. At the same time, numerous Devonian plutons intruded into the magmatic arc of the Mid-German Crystalline Zone. Palaeogeographic reconstructions suggest that the Brabant High, the eastern most part of Avalonia, is the most obvious source area for the Devonian sediments of the Rhenohercynian Basin. The U–Pb data of the detrital zircon grains of the Rhenohercynian Basin do not fit the Avalonian age spectrum of the Brabant High, which is characterized by a high proportion of Ediacaran zircon grains. The detritus of the Rhenohercynian Basin is dominated by Mesoproterozoic zircon grains. Ediacaran zircon grains are absent. This limits the possible source area of the Rhenohercynian Basin to West Baltica and to the early Palaeozoic sediments of South Norway, Sweden and Denmark. Our data, along with published results, indicate that there was no collision between the northern part of Armorica and Laurussia during the Lower Devonian in the German part of the Rhenohercynian Zone. [ABSTRACT FROM AUTHOR]

Purpose: Disease-free survival (DFS) after neoadjuvant chemoradiotherapy (nCRT) is an important factor in affecting the quality of life and determining the subsequent treatment procedures for patients with locally advanced rectal cancer (LARC). This study aimed to develop a novel prognostic model for predicting the DFS in patients with LARC following nCRT and to verify its effectiveness. Materials and methods: Patients with LARC who underwent magnetic resonance imaging (MRI) and nCRT at our institution between November 2017 and March 2022 were enrolled in this retrospective study. Clinicopathologic data and MRI indicators of all patients were collected and evaluated. All patients were divided into DFS and non-DFS groups according to the presence or absence of local recurrence or distant metastasis. The differences in the b-value threshold (bthreshold) and apparent diffusion coefficient (ADC) values between the DFS and non-DFS groups were compared. The Cox analyses were used to determine the risk factors in predicting the DFS. A merged model was established based on the risk factors, and a nomogram was constructed. The predictive performances of the merged model were validated using the receiver-operating characteristic (ROC) and decision curve analysis (DCA). Results: Of the 524 patients enrolled, 132 who underwent surgical resection post-nCRT were included in the final analysis. The post-neoadjuvant therapy pathological N stage, extramural venous invasion (EMVI), and bthreshold were independent factors in predicting the DFS. The C-index of the model was 0.688. The area under the curve (AUC) of the nomogram in predicting the 1-, 3-, and 5-year survival rates of patients was 0.731, 0.723, and 0.779, respectively. The DCA demonstrated that the merged model had a greater advantage than either the "all" or the "none" scheme when the threshold probability was between 0.1 and 0.65. Conclusion: A merged model based on the bthreshold value and clinicopathological features showed the potential to predict the prognosis of patients with LARC after nCRT and surgery. [ABSTRACT FROM AUTHOR]

Objectives: 3D phase-resolved functional lung (PREFUL) MRI offers evaluation of pulmonary ventilation without inhalation of contrast agent. This study seeks to compare ventilation maps obtained from 3D PREFUL MRI with a direct ventilation measurement derived from 129Xe MRI in both patients with chronic obstructive pulmonary disease (COPD) and healthy volunteers. Methods: Thirty-one patients with COPD and 12 healthy controls underwent free-breathing 3D PREFUL MRI and breath-hold 129Xe MRI at 1.5 T. For both MRI techniques, ventilation defect (VD) maps were determined and respective ventilation defect percentage (VDP) values were computed. All parameters of both techniques were compared by Spearman correlation coefficient (r) and the differences between VDP values were quantified by Bland–Altman analysis and tested for significance using Wilcoxon signed-rank test. In a regional comparison of VD maps, spatial overlap and Sørensen–Dice coefficients of healthy and defect areas were computed. Results: On a global level, all 3D PREFUL VDP values correlated significantly to VDP measure derived by 129Xe ventilation imaging (all r > 0.65; all p < 0.0001). 129Xe VDP was significantly greater than 3D PREFUL derived VDPRVent (mean bias = 10.5%, p < 0.001) and VDPFVL-CM (mean bias = 11.3%, p < 0.0001) but not for VDPCombined (mean bias = 1.7%, p = 0.70). The total regional agreement of 129Xe and 3D PREFUL VD maps ranged between 60% and 63%. Conclusions: Free-breathing 3D PREFUL MRI showed a strong correlation with breath-hold hyperpolarized 129Xe MRI regarding the VDP values and modest differences in the detection of VDs on a regional level. Clinical relevance statement: 3D PREFUL MRI correlated with 129Xe MRI, unveiling regional differences in COPD defect identification. This proposes 3D PREFUL MRI as a ventilation mapping surrogate, eliminating the need for extra hardware or inhaled gases. Key Points: Current non-invasive evaluation techniques for lung diseases have drawbacks;129Xe MRI is limited by cost and availability. 3D PREFUL MRI correlated with129Xe MRI, with regional differences in identifying COPD defects. 3D PREFUL MRI can provide ventilation mapping without the need for additional hardware or inhaled gases. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity and co-existence, linked to a diverse microenvironment and worse clinical outcome. However, the underlying mechanisms remain unclear. Here, by combining preclinical models, multi-center clinical, transcriptomic, proteomic, and patient bioimaging data, we identify an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic macrophages driving subtype co-existence and an immunosuppressive microenvironment. ATAC-, ChIP-, and RNA-seq analyses reveal that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory signatures in tumor cells, antagonizing cJUN/AP1 signaling, favoring a therapy-responsive classical neoplastic state. This dichotomous regulation is amplified via regional TNF-α+ macrophages, which associates with a reactive phenotype and reduced CD8+ T cell infiltration in patients. Consequently, combined preclinical anti-TNF-α immunotherapy and chemotherapy reduces macrophages and promotes CD3+/CD8+ T cell infiltration in basal-like PDAC, improving survival. Hence, tumor cell-intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression. The mechanisms of intratumoral subtype heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, the authors analyse PDAC tumours and preclinical models using multi-omics and imaging; they demonstrate that AP1 dichotomy influences tumor plasticity, heterogeneity, and immune response, with potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Identifying flux vacua in string theory with stabilized complex structure moduli presents a significant challenge, necessitating the minimization of a scalar potential complicated by infinitely many exponential corrections. In order to obtain exact results we connect three central topics: transcendentality or algebraicity of coupling functions, emergent symmetries, and the distribution of vacua. Beginning with explicit examples, we determine the first exact landscape of flux vacua with a vanishing superpotential within F-theory compactifications on a genuine Calabi-Yau fourfold. We find that along certain symmetry loci in moduli space the generically transcendental vacuum conditions become algebraic and can be described using the periods of a K3 surface. On such loci the vacua become dense when we do not bound the flux tadpole, while imposing the tadpole bound yields a small finite landscape of distinct vacua. Away from these symmetry loci, the transcendentality of the fourfold periods ensures that there are only a finite number of vacua with a vanishing superpotential, even when the tadpole constraint is removed. These observations exemplify the general patterns emerging in the bulk of moduli space that we expose in this work. They are deeply tied to the arithmetic structure underlying flux vacua and generalize the finiteness claims about rational CFTs and rank-two attractors. From a mathematical perspective, our study is linked with the recent landmark results by Baldi, Klingler, and Ullmo about the Hodge locus that arose from connecting tame geometry and Hodge theory. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the use of intravoxel incoherent motion (IVIM) to study microperfusion and microstructural characteristics of lungs, brain, and placenta in normal and small fetuses. Methods: We retrospectively enrolled 30 small fetuses and 82 normal pregnancies who underwent a 1.5-T MRI examination using an IVIM-DWI. Small fetuses were distinguished in small for gestational age (SGA) and "true" fetal growth restriction (FGR). ROIs were placed on the brain parenchyma, lungs, and fetal/maternal placental sides. Differences in perfusion fraction f, diffusion coefficient D, and pseudo-diffusion coefficient D* and their correlation with gestational age (GA) and birth weight (BW) were investigated. Results: LUNG: f showed significantly lower values (p = 2·10–7) in small fetuses (SGA + FGR); f discriminates SGA and FGR from normal (p = 0.001; p = 1·10–6). f increases with GA (p < 0.0001) in the control group; a positive correlation was also obtained in small fetuses, although less significant. PLACENTA: FGR showed lower f values than normal ones, in both the fetal (p = 1.4·10–7) and maternal side (p = 0.001); f discriminates between SGA and FGR (p = 0.03). In small fetuses (SGA + FGR), f correlates positively with BW. BRAIN: D values in supratentorial white matter (WM) were significantly higher compared to other regions, in both normal and small fetuses. Small fetuses showed higher D values in occipital WM and pons (p = 0.041; p = 0.027) than in normal. D correlates negatively with GA in the healthy group. No correlation between D and GA was found in SGA + FGR group. Conclusions: In our study, IVIM-MRI allowed us to detect microstructural and microperfusion changes in the placenta, brain, and lung of small fetuses, noninvasively. [ABSTRACT FROM AUTHOR]

Copyright of Die Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.

This study aimed to establish and validate a multiparameter prediction model for Ki67 expression in hepatocellular carcinoma (HCC) patients while also exploring its potential to predict the one-year recurrence risk. The clinical, pathological, and imaging data of 83 patients with HCC confirmed by postoperative pathology were analyzed, and the patients were randomly divided into a training set (n = 58) and a validation set (n = 25) at a ratio of 7:3. All patients underwent a magnetic resonance imaging (MRI) scan that included multi-b value diffusion-weighted scanning before surgery, and quantitative parameters were obtained via intravoxel incoherent motion (IVIM) and diffusion kurtosis (DKI) models. Univariate and multivariate logistic regression analyses were conducted using the training set data to construct a model, which was internally validated. The area under the curve (AUC) of the receiver operating characteristics (ROC), a decision curve analysis (DCA), and a calibration analysis were used to evaluate the model's performance. Additionally, for patients with available follow-up data, the combined model was evaluated for its potential utility in predicting the one-year recurrence risk by analyzing the area under the curve (AUC) of the receiver operating characteristic (ROC) curve.The combined model outperformed the clinicaland parametric models in predicting high Ki67 expression. The nomograms based on the combined model included the neutrophil-to-lymphocyte ratio (NLR), ADCslow_Aver. The model showed strong discrimination in the training set, with an AUC of 0.836 (95% CI: 0.729–0.942) and acceptable calibration (Hosmer–Lemeshow p = 0.109). In the validation set, the model maintained moderate discrimination (AUC 0.806, 95% CI: 0.621–0.990) with good calibration (p = 0.663). DCA revealed that the combined model provided good clinical value and correction effects. Additionally, when used to predict the one-year recurrence risk, the combined model achieved moderate accuracy (AUC = 0.747), highlighting its potential utility in identifying patients at a higher risk of recurrence. A nomogram incorporating the NLR and quantitative MR diffusion parameters effectively predicts Ki67 expression in HCC patients before surgery. The model also shows promise in predicting recurrence risk, which may aid in postoperative risk stratification and patient management. Clinical Relevance Statement We established a model that incorporated the NLR and quantitative magnetic resonance diffusion parameters, which demonstrated robust performance in predicting both high Ki67 expression and the one-year recurrence risk in HCC patients. This model shows potential clinical value in guiding postoperative risk stratification and personalized treatment planning. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion Level of Evidence While public databases like Transfermarkt provide valuable data for assessing the impact of anterior cruciate ligament (ACL) injuries in professional footballers, they require robust verification methods due to accuracy concerns. We hypothesised that an artificial intelligence (AI)‐powered framework could cross‐check ACL tear‐related information from large publicly available data sets with high specificity.The AI‐powered framework uses Google Programmable Search Engine to search a curated, multilingual list of websites and OpenAI's GPT to translate search queries, appraise search results and analyse injury‐related information in search result items (SRIs). Specificity was the chosen performance metric—the AI‐powered framework's ability to accurately identify texts that do not mention an athlete suffering an ACL tear—with SRI as the evaluation unit. A database of ACL tears in male professional footballers from first‐ and second‐tier leagues worldwide (1999–2024) was collected from Transfermarkt.com, and players were randomly selected for appraisal until enough SRIs were obtained to validate the framework's specificity. Player age at injury and time until return‐to‐play (RTP) were recorded and compared with Union of European Football Associations (UEFA) Elite Club Injury Study data.Verification of 231 athletes yielded 1546 SRIs. Human analysis of the SRIs showed that 335 mentioned an ACL tear, corresponding to 83 athletes with ACL tears. Specificity and sensitivity of GPT in identifying mentions of ACL tears in a player were 99.3% and 88.4%, respectively. Mean age at rupture was 26.6 years (standard deviation: 4.6, 95% confidence interval [CI]: 25.6–27.6). Median RTP time was 225 days (interquartile range: 96, 95% CI: 209–251), which is comparable to reports using data from the UEFA Elite Club Injury Study.This study shows that an AI‐powered framework can achieve high specificity in cross‐checking ACL tear reports in male professional football from public databases, markedly reducing manual workload and enhancing the reliability of media‐based sports medicine research.Level III. [ABSTRACT FROM AUTHOR]

Diabetic polyneuropathy (DPN) shares overlapping clinical and electrodiagnostic features with chronic inflammatory demyelinating polyneuropathy (CIDP), which complicates the differential diagnosis of CIDP in diabetic patients. 32 patients with diabetes mellitus and CIDP, 68 patients with CIDP without diabetes, 83 patients with DPN, and 28 diabetic patients without polyneuropathy were examined using clinical scores (Overall Neuropathy Limitation Scale (ONLS), Neuropathy Symptom Score, Neuropathy Deficit Score), nerve conduction studies, and nerve ultrasound (Ultrasound Pattern Sum Score (UPSS)). The ONLS was significantly higher in the CIDP patients with diabetes than in DPN (median [interquartile range]: 4.0 [3.0] vs. 0 [1.0], p < 0.001) as well as the UPSS (4.0 [6.0] vs. 0 [2.9], p < 0.001). Multiple binary logistic regression revealed UPSS and ONLS as statistically significant predictors to differentiate between CIDP with diabetes and DPN. Receiver operating characteristic curve analysis showed the ONLS with an area under the curve (AUC) of 0.918 (95% CI: 0.868-0.0.967, p < 0.001). The UPSS total score had an AUC of 0.826 (95% CI: 0.743–0.909, p < 0.001). An UPSS ≥ 2.5 had a sensitivity of 77.4% and a specificity of 68.7% to detect CIDP. An ONLS ≥ 1.5 had a sensitivity of 87.1% and a specificity of 81.9% to detect CIDP. ROC curve analysis of a composite score of ONLS and UPSS revealed an AUC of 0.959 (95% CI: 0.928–0.991, p < 0.001). CIDP is an important differential diagnosis in people with diabetes mellitus. This study reports that the UPSS is well suited to differentiate between DPN and CIDP. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients. Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models. Results: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. Conclusions: Imipridones are a promising strategy for further testing and development in mUM. [ABSTRACT FROM AUTHOR]

Summary: Recently, a number of randomized controlled trials regarding the therapy of cervical cancer have been published. Thus, the aim of the current review is to provide an overview of the most recent studies that will likely have a substantial influence on clinical practice. In general, checkpoint inhibitors (CPIs) have been evaluated in a variety of clinical settings. The use of CPIs will be expanded to a variety of clinical scenarios due to a number of positive randomized clinical trials. In particular, the combination of taxane-based combination chemotherapy and pembrolizumab ± bevacizumab represents the new standard in the treatment of primary metastatic or recurrent programmed cell death ligand 1 (PD-L1)-positive cervical cancer. With respect to locally advanced cervical cancer, two new treatment escalation regimes on top of chemoradiation have been evaluated (neoadjuvant chemotherapy and adjuvant CPI therapy). Additionally, antibody–drug conjugates (ADCs), such as tisotumab vedotin (TV), could represent a promising therapeutic option in the future treatment of cervical cancer. [ABSTRACT FROM AUTHOR]

Objective: Neurological autoimmune peripheral and central nervous system disorders can be associated with anti-sulfatide antibodies. These antibodies are considered potential diagnostic biomarkers, although their additional diagnostic value in neurological fields has been increasingly questioned. Given the little evidence of anti-sulfatide antibodies' frequency and diagnostic value in neurology, we aimed to fill this knowledge gap by investigating 10 years of data. Methods: This retrospective study analyzed the results of the anti-ganglioside dot kits (GA Generic Assays GmbH) from 1318 serum samples and 462 cerebrospinal fluid (CSF) samples for the frequency, sensitivity, and specificity of anti-sulfatide antibodies in neurological disorders. Results: Although anti-sulfatide antibodies are rarely present in neurological autoimmune disorders (serum IgM 2.5%, IgG 4.6%), they are also present in non-autoimmune diseases (serum IgM 1.2%, IgG 2.5%) and lack sensitivity and specificity towards being a diagnostic marker. Furthermore, anti-sulfatide antibodies are rarely found in CSF (e.g., no positive results for IgM), and including so-called borderline results ((+)) increases sensitivity and the false-positive rate in serum and CSF. Discussion: While anti-sulfatide antibodies appear more frequently in neurological autoimmune diseases, they are rare overall and provide very limited diagnostic value in determining specific neurological diseases and—more importantly—if a neurological disease has a potential autoimmune etiology. [ABSTRACT FROM AUTHOR]

Background: Community-based coalitions are a common strategy for community engagement efforts targeting the improvement of a variety of population health outcomes. The typical processes that coalitions follow to organize efforts include steps that are sequential, slow, and time intensive. These processes also limit local decision-making to the selection of evidence-based policies or programs. Methods: We present a process control theory-based Community Action Process, Investigate-Design-Practice-Reflect (IDPR), where community hubs (i.e., coalitions) organize agile efforts in a non-sequential, rapid, and efficient manner to harness local assets and data to make decisions regarding the provision and production of population health services. Using qualitative methods, we illustrate and analyze the use of IDPR in a one community case study as part of Wellscapes, a Type 3-hybrid implementation-effectiveness community randomized controlled trial to improve children's population health physical activity. Results: We found community members followed the IDPR Community Action Process to rapidly design, organize, deliver, and receive feedback on a community-based, children's population physical activity prototype, an afterschool Play-in-the-Park opportunity for all children. Discussion: Following IDPR afforded the community coalition timely learning through feedback within a process that coordinated decisions regarding what community services met community needs (provision decisions) and how to organize the production of the population health services (production decisions). [ABSTRACT FROM AUTHOR]

From the start of life on Earth, several immune defense mechanisms have evolved to guarantee cellular integrity, homeostasis, and host survival. All these sophisticated balances as shaped by and towards the environmental needs have occurred over hundreds of millions of years. Human spaceflight involves various health hazards, such as higher levels of radiation, altered gravity, isolation and confinement, living in tight quarters, and stress associated with being away from home. A growing body of evidence points towards immunological changes in astronauts, including heightened pro-inflammatory responses, reactivation of latent viruses, and cell-mediated alterations, reflecting a dysbalanced state in astronauts. Simultaneously, enhanced pathogenicity, virulence, and drug resistance properties of microorganisms tip the scale out of favor for prolonged stay in space. As we have learned from the past, we see potential for the human immune system, forged and maintained throughout evolutionary history, to adapt to the space exposome. It is unlikely that this will happen in the short time frames set for current space exploration missions. Instead, major risks to astronaut health need to be addressed first, before humans can safely evolve into the space environment. [ABSTRACT FROM AUTHOR]

The Weyl potential, which is the sum of the spatial and temporal distortions of the Universe's geometry, provides a direct way of testing the theory of gravity and the validity of the ΛCDM (Lambda Cold Dark Matter) model. Here we present measurement of the Weyl potential at four redshifts bins using data from the first three years of observations of the Dark Energy Survey. We find that the measured Weyl potential is 2 σ, respectively 2.8 σ, below the ΛCDM predictions in the two lowest redshift bins. We show that these low values of the Weyl potential are at the origin of the tension between Cosmic Microwave Background measurements and weak lensing measurements, regarding the parameter σ8 which quantifies the clustering of matter. Interestingly, we find that the tension remains if no information from the Cosmic Microwave Background is used. Dark Energy Survey data on their own prefer a high value of the primordial fluctuations, together with a slow evolution of the Weyl potential. An important feature of our method is that the measurements of the Weyl potential are model-independent and can therefore be confronted with any theory of gravity, allowing efficient tests of models beyond General Relativity. The Weyl potential provides a direct way of testing the theory of gravity and the validity of the ΛCDM model. Here, the authors show Weyl potential measured at four redshifts bins and find that the measured values in the two lowest bins are in mild tension with the ΛCDM predictions. [ABSTRACT FROM AUTHOR]

Purpose: Large language models continue to dramatically change the medical landscape. We aimed to explore the utility of ChatGPT in providing accurate, actionable, and understandable generative medical translations in English, Spanish, and Mandarin pertaining to Otolaryngology. Methods: Responses of GPT-4 to commonly asked patient questions listed on official otolaryngology clinical practice guidelines (CPG) were evaluated with the Patient Education materials Assessment Tool-printable (PEMAT-P.) Additional critical elements were identified a priori to evaluate ChatGPT's accuracy and thoroughness in its responses. Multiple fluent speakers of English, Mandarin, and Spanish evaluated each response generated by ChatGPT. Results: Total PEMAT-P scores differed between English, Mandarin, and Spanish GPT-4 generated responses depicting a moderate effect size of language, Eta-Square 0.07 with scores ranging from 73 to 77 (P-value = 0.03). Overall understandability scores did not differ between English, Mandarin, and Spanish depicting a small effect size of language, Eta-Square 0.02 scores ranging from 76 to 79 (P-value = 0.17), nor did overall actionability scores Eta-Square 0 score ranging 66–73 (P-value = 0.44). Overall a priori procedure-specific responses similarly did not differ between English, Spanish, and Mandarin Eta-Square 0.02 scores ranging 61–78 (P-value = 0.22). Conclusion: GPT-4 produces accurate, understandable, and actionable outputs in English, Spanish, and Mandarin. Responses generated by GPT-4 in Spanish and Mandarin are comparable to English counterparts indicating a novel use for these models within Otolaryngology, and implications for bridging healthcare access and literacy gaps. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of four opioid receptor genes (Oprm1, Oprd1, Oprl1 and Oprk1) and the cannabinoid CB1 receptor (Cnr1) gene in the DRG regulate nociception. In this study, we determined the role of REST in controlling their expression in the DRG induced by spared nerve injury (SNI). SNI induced chronic pain hypersensitivity in wild-type mice and was accompanied by increased levels of Rest transcript and protein. Transcriptomic analyses of wild-type mouse DRGs suggested that SNI upregulates the expression of Rest transcripts and downregulates the transcripts of all four opioid receptor genes and the Cnr1 gene. Quantitative reverse transcription polymerase chain reaction analyses of these tissues validated these results. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated the presence of REST at these promoters. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in mouse DRG. Our results suggest that nerve injury represses the transcription of at least the Oprd1 and Cnr1 genes via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain. Thus, inhibiting REST activity could potentially reduce chronic neuropathic pain and augment opioid/cannabinoid analgesic actions by increasing the transcription of Oprd1 and Cnr1 genes in DRG neurons. [ABSTRACT FROM AUTHOR]

Copyright of Die Radiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

When reasoning about causes of sustainability problems and possible solutions, sustainability scientists rely on disciplinary-based understanding of cause–effect relations. These disciplinary assumptions enable and constrain how causal knowledge is generated, yet they are rarely made explicit. In a multidisciplinary field like sustainability science, lack of understanding differences in causal reasoning impedes our ability to address complex sustainability problems. To support navigating the diversity of causal reasoning, we articulate when and how during a research process researchers engage in causal reasoning and discuss four common ideas about causation that direct it. This articulation provides guidance for researchers to make their own assumptions and choices transparent and to interpret other researchers' approaches. Understanding how causal claims are made and justified enables sustainability researchers to evaluate the diversity of causal claims, to build collaborations across disciplines, and to assess whether proposed solutions are suitable for a given problem. [ABSTRACT FROM AUTHOR]

The effectiveness of multi-stakeholder initiatives (MSIs) in tackling grand social and environmental challenges depends on productive dialogue among diverse parties. Facilitating such dialogue in turn entails building common ground in form of joint knowledge, beliefs, and suppositions. To explore how such common ground can be built, we study the role of different facilitators and their strategies for bridging the perspectives of competing stakeholder groups in two contrasting MSIs. The German Partnership for Sustainable Textiles was launched in an initially hostile communicative environment, whereas the Fossil Free Sweden Initiative proceeded in a fertile communicative environment. We trace how the facilitators in these initiatives achieved common ground through three bridging strategies—communicative integration, temporal calibration, and process alignment—adapted to the communicative environments of these MSIs. In hostile communicative environments, facilitators achieve common ground by steering diverging stakeholder groups towards 'reconciling' their different language registers, knowledge bases, and meaning systems to 'meet in the middle' on points of agreement and shared interests. In fertile communicative environments characterised by greater mutual trust, facilitators can steer interactants to 'strategically appropriate' to the language, knowledge, and meaning system of a particular stakeholder group to win this group's support. Our analysis contributes to a better understanding of how productive multi-stakeholder dialogue can be facilitated. [ABSTRACT FROM AUTHOR]

Current culture systems available for studying hepatitis D virus (HDV) are suboptimal. In this study, we demonstrate that hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) are fully permissive to HDV infection across various tested genotypes. When co-infected with the helper hepatitis B virus (HBV) or transduced to express the HBV envelope protein HBsAg, HLCs effectively release infectious progeny virions. We also show that HBsAg-expressing HLCs support the extracellular spread of HDV, thus providing a valuable platform for testing available anti-HDV regimens. By challenging the cells along the differentiation with HDV infection, we have identified CD63 as a potential HDV co-entry factor that was rate-limiting for HDV infection in immature hepatocytes. Given their renewable source and the potential to derive hPSCs from individual patients, we propose HLCs as a promising model for investigating HDV biology. Our findings offer new insights into HDV infection and expand the repertoire of research tools available for the development of therapeutic interventions. Synopsis: This study presents human pluripotent stem cell-derived hepatocyte-like cells (HLCs) as a culture system that expands the repertoire of research tools for studying hepatitis B and D viruses (HBV/HDV) and identifies CD63 as a potential HDV co-entry factor. Co-infection with HBV or virus-mediated delivery of HBV surface proteins enables HDV to complete its life cycle in HLCs. Extracellular HDV spread in HLCs enables the evaluation of anti-HDV therapies. HDV permissiveness along HLC differentiation reveals CD63 as a novel co-factor of HDV cell entry. This study presents human pluripotent stem cell-derived hepatocyte-like cells (HLCs) as a culture system that expands the repertoire of research tools for studying hepatitis B and D viruses (HBV/HDV) and identifies CD63 as a potential HDV co-entry factor. [ABSTRACT FROM AUTHOR]

This study employed lignin-sulfonated (LS) to develop biobased carbon materials (LS-Cs) through a sulfur-doping approach to enhance their physicochemical properties, adsorption capabilities, and energy storage potentials. Various characterization techniques, including BET surface area analysis, SEM imaging, XPS, Raman spectroscopy, and elemental composition (CHNS), were employed to assess the quality of the LS-Cs adsorbent and electrode samples. Response Surface Methodology (RSM) was utilized for optimizing the two main properties (specific surface area, ABET, and mesopore area, AMESO) by evaluating three independent factors (i.e., activation temperature, ZnCl2:LS ratio, and sulfur content). According to the statistical analysis, ABET and AMESO were affected by ZnCl2 and sulfur content, while the pyrolysis temperature did not affect the responses in the studied conditions. It was found that increasing the ZnCl2 and sulfur contents led to an increment of the ABET and AMESO values. The LS-C materials exhibited very high ABETvalues up to 1993 m2 g−1 and with predominantly mesoporous features. The S-doping resulted in LS-Cs with high sulfur contents in their microstructures up to 15% (wt%). The LS-C materials were tested as adsorbents for sodium diclofenac (DCF) adsorption and reactive orange 16 dye (RO-16) and as electrodes for supercapacitors. The LS-Cs exhibited excellent adsorption capacity values for both molecules (197–372 mg g−1) for DCF, and (223–466 mg g−1) for RO-16. When tested as electrodes for supercapacitors, notably, LS-C3, which is a doped sample with sulfur, exhibited the best electrochemical performance, e.g. high specific capacitance (156 F/g at 50 mV/s), and delivered an excellent capacitance after 1000 cycles (63 F/g at 1 A/g), which denotes the noteworthy capacitive behavior of the S-doped electrode. Thus, the present work suggests an eco-friendly resource for developing effective, productive carbon materials for adsorbent and electrodes for SC application. However, further studies on the complete application of these materials as adsorbents and electrodes are needed for a deeper understanding of their behavior in environmental and energy storage applications. [ABSTRACT FROM AUTHOR]

Summary: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease that is characterized by left ventricular hypertrophy unexplained by secondary causes. Based on international epidemiological data, around 20,000–40,000 patients are expected to be affected in Austria. Due to the wide variety of clinical and morphological manifestations the diagnosis can be difficult and the disease therefore often goes unrecognized. HCM is associated with a substantial reduction in quality of life and can lead to sudden cardiac death, especially in younger patients. Early and correct diagnosis, including genetic testing, is essential for comprehensive counselling of patients and their families and for effective treatment. The latter is especially true as an effective treatment of outflow tract obstruction has recently become available in the form of a first in class cardiac myosin ATPase inhibitor, as a noninvasive alternative to established septal reduction therapies. The aim of this Austrian consensus statement is to summarize the recommendations of international guidelines with respect to the genetic background, pathophysiology, diagnostics and management in the context of the Austrian healthcare system and resources, and to present them in easy to understand algorithms. [ABSTRACT FROM AUTHOR]

Nudging individuals without obvious symptoms of non-communicable diseases (NCDs) to undergo a health screening remains a challenge, especially in middle-income countries, where NCD awareness is low but the incidence is high. We assess whether an awareness campaign implemented on Facebook can encourage individuals in Indonesia to undergo an online diabetes self-screening. We use Facebook's advertisement function to randomly distribute graphical ads related to the risk and consequences of diabetes. Depending on their risk score, participants receive a recommendation to undergo a professional screening. We were able to reach almost 300,000 individuals in only three weeks. More than 1400 individuals completed the screening, inducing costs of about US$0.75 per person. The two ads labeled "diabetes consequences" and "shock" outperform all other ads. A follow-up survey shows that many high-risk respondents have scheduled a professional screening. A cost-effectiveness analysis suggests that our campaign can diagnose an additional person with diabetes for about US$9. [ABSTRACT FROM AUTHOR]

In this paper, we tackle the widely held view that practice-oriented approaches to ethics are conservative, preserving the moral status quo, and, in particular, that they do not promote any (fundamental) change in our dealings with animals or formulate clear principles that help us to achieve such change. We shall challenge this view with reference to Wittgensteinian ethics. As a first step, we show that moral thought and action rest on basic moral certainties like: equals are to be treated equally and unequals unequally. We then explore the relations between this insight and the notion of the difficulty of reality elaborated by Cora Diamond. Our goal is to show that a Wittgensteinian-Diamondian approach to animal ethics is not necessarily morally conservative. Indeed, it offers a profound practice-oriented approach to animal ethics that is capable of promoting change in human dealings with animals because it is compatible with radical critique. [ABSTRACT FROM AUTHOR]

Background: Cerenkov luminescence imaging (CLI) is a new emerging technology that can be used for optical imaging of approved radiotracers, both in a preclinical, and even more recently, in a clinical context with rapid imaging times, low costs, and detection in real-time (Grootendorst et al. Clin Transl Imaging 4(5):353–66, 2016); Wang et al. Photonics 9(6):390, 2022). This brief review provides an overview of clinical applications of CLI with a focus on intraoperative margin assessment (IMA) to address shortcomings and provide insight for future work in this application. Methods: A literature review was performed using PubMed using the search words Cerenkov luminescence imaging (CLI), intraoperative margin assessment (IMA), and image-guided surgery. Articles were selected based on title, abstract, content, and application. Results: Original research was summarized to examine advantages and limitations of CLI compared to other modalities for IMA. The characteristics of Cerenkov luminescence (CL) are defined, and results from relevant clinical trials are discussed. Prospects of ongoing clinical trials are reviewed, along with technological advancements related to CLI. Conclusion: CLI is a proven method for molecular imaging and shows feasibility for determining intraoperative margins if future work involves establishing quantitative approaches for attenuation and scattering, depth analysis, and radiation safety for CLI at a larger scale. [ABSTRACT FROM AUTHOR]

In this paper, we explore the string theory landscape obtained from type IIB and F-theory flux compactifications. We first give a comprehensive introduction to a number of mathematical finiteness theorems, indicate how they have been obtained, and clarify their implications for the structure of the locus of flux vacua. Subsequently, in order to address finer details of the locus of flux vacua, we propose three mathematically precise conjectures on the expected number of connected components, geometric complexity, and dimensionality of the vacuum locus. With the recent breakthroughs on the tameness of Hodge theory, we believe that they are attainable to rigorous mathematical tools and can be successfully addressed in the near future. The remainder of the paper is concerned with more technical aspects of the finiteness theorems. In particular, we investigate their local implications and explain how infinite tails of disconnected vacua approaching the boundaries of the moduli space are forbidden. To make this precise, we present new results on asymptotic expansions of Hodge inner products near arbitrary boundaries of the complex structure moduli space. [ABSTRACT FROM AUTHOR]

Radioguidance that makes use of β-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of β-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of β-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation. [ABSTRACT FROM AUTHOR]

Gene replacement using adeno-associated virus (AAV) vectors is a promising therapeutic approach for many diseases1,2. However, this therapeutic modality is challenged by the packaging capacity of AAVs (approximately 4.7 kilobases)3, limiting its application for disorders involving large coding sequences, such as Duchenne muscular dystrophy, with a 14 kilobase messenger RNA. Here we developed a new method for expressing large dystrophins by utilizing the protein trans-splicing mechanism mediated by split inteins. We identified several split intein pairs that efficiently join two or three fragments to generate a large midi-dystrophin or the full-length protein. We show that delivery of two or three AAVs into dystrophic mice results in robust expression of large dystrophins and significant physiological improvements compared with micro-dystrophins. Moreover, using the potent myotropic AAVMYO4, we demonstrate that low total doses (2 × 1013 viral genomes per kg) are sufficient to express large dystrophins in striated muscles body-wide with significant physiological corrections in dystrophic mice. Our data show a clear functional superiority of large dystrophins over micro-dystrophins that are being tested in clinical trials. This method could benefit many patients with Duchenne or Becker muscular dystrophy, regardless of genotype, and could be adapted to numerous other disorders caused by mutations in large genes that exceed the AAV capacity.A method is developed for expressing large dystrophins to enhance muscle function in mouse models of muscular dystrophy, with potential clinical benefits for numerous disorders caused by mutations in large genes that exceed the adeno-associated virus capacity. [ABSTRACT FROM AUTHOR]

This article discusses the challenges faced in assessing a disease model in the NICE single technology appraisal of tirzepatide for treating type 2 diabetes. The article highlights a significant mismatch between the decision problem and UK clinical practice, as well as the evidence from clinical trials. The use of disease models is advocated, but the assessment of the PRIME T2D model in this appraisal was hindered by limited transparency, adaptability, and confidentiality concerns. The article recommends using standard modeling languages, ensuring model adaptability, and taking extra validation steps to validate specific implementations of disease models. [Extracted from the article]

Background: The aim of this study was to analyze the cleaning and disinfection of operating rooms (ORs) status quo focusing on hygiene plans in German hospitals. Methods: In 2016, a structured online survey was sent to infection prevention and control (IPC) specialists at the cost calculation hospitals of the Institute for the Hospital Remuneration System (InEK) and all university hospitals in Germany (n = 365). Results: With a response rate of 27.4%, 78% stated that written hygiene plans were available. After cleaning and disinfecting an OR with a "septic" patient, 55% waited until surfaces were dry before reusing in accordance with national recommendations, 27% waited > 30 min. Additionally, 28% of hospitals had ORs only for "septic" patients. In 56% "septic" patients were only operated on at the end of the program. Postoperative monitoring of patients with bacteria with special IPC requirements took place in the post anesthesia care unit (PACU) (29%), operating room (OR) (52%), intensive care unit (ICU) (53%), and in the intermediate care unit (IMC) (19%). Discussion and conclusions: Despite written hygiene plans in place the partly long duration of OR nonuse time following IPC measures, the consistent continued use of stratification for "septic" patients and the postoperative follow-up care of patients with colonizing/infecting bacteria with special IPC requirements in the OR and high care areas represent relevant potential for improvement. [ABSTRACT FROM AUTHOR]

Light-matter superposition states obtained via strong coupling play a decisive role in quantum information processing, but the deleterious effects of material dissipation and environment-induced decoherence inevitably destroy coherent light-matter polaritons over time. Here, we propose the use of coherent perfect absorption under near-field driving to prepare and protect the polaritonic states of a single quantum emitter interacting with a plasmonic nanocavity at room temperature. Our scheme of quantum nanoplasmonic coherent perfect absorption leverages an inherent frequency specificity to selectively initialize the coupled system in a chosen plasmon-emitter dressed state, while the coherent, unidirectional and non-perturbing near-field energy transfer from a proximal plasmonic waveguide can in principle render the dressed state robust against dynamic dissipation under ambient conditions. Our study establishes a previously unexplored paradigm for quantum state preparation and coherence preservation in plasmonic cavity quantum electrodynamics, offering compelling prospects for elevating quantum nanophotonic technologies to ambient temperatures. Quantum states are incredibly sensitive to their environment, making them perfect for ultrasensitive quantum detection—if they can be maintained long enough. Here, the authors showed that they can 'immortalize' the excited state of a coupled light-matter system using a technique called 'coherent perfect absorption'. [ABSTRACT FROM AUTHOR]

Long-acting passive immunization strategies are needed to protect immunosuppressed vulnerable groups from infectious diseases. To further explore this concept for COVID-19, we constructed Adeno-associated viral (AAV) vectors encoding the human variable regions of the SARS-CoV-2 neutralizing antibody, TRES6, fused to murine constant regions. An optimized vector construct was packaged in hepatotropic (AAV8) or myotropic (AAVMYO) AAV capsids and injected intravenously into syngeneic TRIANNI-mice. The highest TRES6 serum concentrations (511 µg/ml) were detected 24 weeks after injection of the myotropic vector particles and mean TRES6 serum concentrations remained above 100 µg/ml for at least one year. Anti-drug antibodies or TRES6-specific T cells were not detectable. After injection of the AAV8 particles, vector mRNA was detected in the liver, while the AAVMYO particles led to high vector mRNA levels in the heart and skeletal muscle. The analysis of the Fc-glycosylation pattern of the TRES6 serum antibodies revealed critical differences between the capsids that coincided with different binding activities to murine Fc-γ-receptors. Concomitantly, the vector-based immune prophylaxis led to protection against SARS-CoV-2 infection in K18-hACE2 mice. High and long-lasting expression levels, absence of anti-drug antibodies and favourable Fc-γ-receptor binding activities warrant further exploration of myotropic AAV vector-based delivery of antibodies and other biologicals. This study compares a muscle-specific and a liver-specific AAV-vector capsid for the long-term delivery of a monoclonal antibody against SARS-CoV-2 in terms of longevity, protection against infection and influence on the glycosylation profile. [ABSTRACT FROM AUTHOR]

Discrete gradients (DG) or more exactly discrete gradient methods are time integration schemes that are custom-built to preserve first integrals or Lyapunov functions of a given ordinary differential equation (ODE). In conservative molecular dynamics (MD) simulations, the energy of the system is constant and therefore a first integral of motion. Hence, discrete gradient methods seem to be a natural choice as an integration scheme in conservative molecular dynamics simulations. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review the current management of the axilla in breast cancer. Recent Findings: Axillary dissection is no longer indicated in patients with clinically node-negative axilla with 1–2 positive sentinel lymph nodes following upfront surgery or in patients with clinically node-negative axilla following neoadjuvant chemotherapy. Summary: Breast cancer has evolved away from routine axillary clearance to the less invasive sentinel lymph node biopsy to now complete omission of axillary sampling in select patients. We will review the most salient evidence that has shaped these practice changes over the last three decades. Current practice controversies are especially relevant for elderly populations and those receiving neoadjuvant therapy. Ongoing clinical trials will provide data to further guide breast cancer surgical management. [ABSTRACT FROM AUTHOR]

Copyright of Herzschrittmachertherapie und Elektrophysiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)