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Objective: Perampanel (PER) is indicated as adjunctive antiseizure medication (ASM) in adolescents and adults with epilepsy. Data from clinical trials show good efficacy and tolerability, while limited information is available on the routine clinical use of PER, especially when used as only add-on treatment. Methods: We performed an observational, retrospective, multicenter study on people with focal or generalized epilepsy aged >12 years, consecutively recruited from 52 Italian epilepsy centers. All patients received PER as the only add-on treatment to a background ASM according to standard clinical practice. Retention rate, seizure frequency, and adverse events were recorded at 3, 6, and 12months after PER introduction. Subanalyses by early or late use of PER and by concomitant ASM were also conducted. Results: Five hundred and three patients were included (age 36.5 ± 19.9 years). Eighty-one percent had focal epilepsy. Overall, the retention rate was very high in the whole group (89% at 12months) according with efficacy measures. No major differences were observed in the subanalyses, although patients who used PER as early add-on, as compared with late add-on, more often reached early seizure freedom at 3-month follow-up (66% vs 53%, P=.05). Treatment-emergent adverse events occurred in 25%, far less commonly than in PER randomized trials. Significance: This study confirms the good efficacy and safety of PER for focal or generalized epilepsy in real-life conditions. We provide robust data about its effectiveness as only add-on treatment even in patients with a long-standing history of epilepsy and previously treated with many ASMs.

Inositol is a natural sugar-like compound, commonly present in many plants and foods. It is involved in several biochemical pathways, most of them controlling vital cellular mechanisms, such as cell development, signaling and nuclear processes, metabolic and endocrine modulation, cell growth, signal transduction, etc. In this narrative review, we focused on the role of inositol in human brain physiology and pathology, with the aim of providing an update on both potential applications and current limits in its use in psychiatric disorders. Overall, imaging and biomolecular studies have shown the role of inositol levels in the pathogenesis of mood disorders. However, when administered as monotherapy or in addition to conventional drugs, inositol did not seem to influence clinical outcomes in both mood and psychotic disorders. Conversely, more encouraging results have emerged for the treatment of panic disorders. We concluded that, despite its multifaceted neurobiological activities and some positive findings, to date, data on the efficacy of inositol in the treatment of psychiatric disorders are still controversial, partly due to the heterogeneity of supporting studies. Therefore, systematic use of inositol in routine clinical practice cannot be recommended yet, although further basic and translational research should be encouraged.

Frailty indexes (FIs) provide quantitative measurements of nonspecific health decline and are particularly useful as longitudinal monitors of morbidity in aging studies. For mouse studies, frailty assessments can be taken noninvasively, but they require handling and direct observation that is labor-intensive to the scientist and stress inducing to the animal. Here, we implement, evaluate, and provide a refined digital FI composed entirely of computational analyses of home-cage video and compare it to manually obtained frailty scores in both C57BL/6 and genetically heterogeneous Diversity Outbred mice. We show that the frailty scores assigned by our digital index correlate with both manually obtained frailty scores and chronological age. Thus, we provide an automated tool for frailty assessment that can be collected reproducibly, at scale, without substantial labor cost.

Inference carried out on pre-trained deep neural networks (DNNs) is particularly effective as it does not require re-training and entails no loss in accuracy. Unfortunately, resource-constrained devices such as those in the Internet of Things may need to offload the related computation to more powerful servers, particularly, at the network edge. However, edge servers have limited resources compared to those in the cloud; therefore, inference offloading generally requires dividing the original DNN into different pieces that are then assigned to multiple edge servers. Related approaches in the state of the art either make strong assumptions on the system model or fail to provide strict performance guarantees. This article specifically addresses these limitations by applying distributed assignment to deep neural network inference at the edge. In particular, it devises a detailed model of DNN-based inference, suitable for realistic scenarios involving edge computing. Optimal inference offloading with load balancing is also defined as a multiple assignment problem that maximizes proportional fairness. Moreover, a distributed algorithm for DNN inference offloading is introduced to solve such a problem in polynomial time with strong optimality guarantees. Finally, extensive simulations employing different datasets and DNN architectures establish that the proposed solution significantly improves upon the state of the art in terms of inference time (1.14 to 2.62 times faster), load balance (with a Jain’s fairness index of 0.9), and convergence (one order of magnitude less iterations).

The direct etherification of wheat straw lignin and lignin model compounds using alcohols as reagents and zirconocene triflate as moisture-tolerant Lewis acidic catalyst is herein described.

We present BISTRO Survey 850 {\mu}m dust emission polarisation observations of the L1495A-B10 region of the Taurus molecular cloud, taken at the JCMT. We observe a roughly triangular network of dense filaments. We detect 9 of the dense starless cores embedded within these filaments in polarisation, finding that the plane-of-sky orientation of the core-scale magnetic field lies roughly perpendicular to the filaments in almost all cases. We also find that the large-scale magnetic field orientation measured by Planck is not correlated with any of the core or filament structures, except in the case of the lowest-density core. We propose a scenario for early prestellar evolution that is both an extension to, and consistent with, previous models, introducing an additional evolutionary transitional stage between field-dominated and matter-dominated evolution, observed here for the first time. In this scenario, the cloud collapses first to a sheet-like structure. Uniquely, we appear to be seeing this sheet almost face-on. The sheet fragments into filaments, which in turn form cores. However, the material must reach a certain critical density before the evolution changes from being field-dominated to being matter-dominated. We measure the sheet surface density and the magnetic field strength at that transition for the first time and show consistency with an analytical prediction that had previously gone untested for over 50 years (Mestel 1965)., Comment: 14 pages, 5 figures. ApJ accepted

Future wireless networks should meet heterogeneous service requirements of diverse applications, including interactive multimedia, augmented reality, and autonomous driving. The fog radio access network (Fog-RAN) is a novel architecture that enables efficient and flexible allocation of network resources to end users. However, guaranteeing application-specific service requirements while maximizing resource utilization is an open challenge in Fog-RANs. This article proposes a multi-resource Fog-RAN slicing scheme that maximizes network resource utilization and satisfies important economic properties: Pareto optimality, envy-freeness, and sharing incentive. The proposed solution considers both heterogeneous resources (i.e., bandwidth, storage and computing) and the different service levels defined in 5G networks. Accordingly, a two-level resource scheduling mechanism is devised to jointly allocate Fog-RAN resources to slices in two stages: a broker allocates resources to slices at fog nodes over a given time window; a slice hypervisor then allocates slice-specific resources at each fog node to users with a much shorter time scale. An extensive evaluation based on real-world datasets demonstrates that the proposed solution significantly increases the monetary gain of service providers, namely, by 32% to 60% compared to the state of the art, including dynamic hierarchical resource allocation and dynamic slicing with proportional allocation.

El presente trabajo propone una lectura analítica de historias de vida, en clave de narrativas, de experiencias de maestrandos y egresados que incursionan durante el período 2020-2021 en la investigación educativa. Se funda en un enfoque interpretativo con herramientas metodológicas biográfico-narrativas de investigación en ciencias sociales. De este modo, la historia de vida se inscribe tanto como perspectiva socioantropológica de registro de diversa información proporcionada por los sujetos cuanto como género documental, aspecto este desde el cual se ponen de manifiesto sus caracteres discursivos. Los textos ofrecen en primera persona el recorte de un momento vital que -en el marco de la pandemia COVID-19- no solo se hace eco de este suceso de alto valor condicionante de futuras transformaciones, sino que además permite la posibilidad de reflexionar sobre las vivencias, contradicciones, interrogantes y aprendizajes que la experiencia del ingreso al equipo de investigación les permite construir como registro subjetivo.

A population‐level analysis is proposed to address data sparsity when building predictive models for engineering infrastructure. Utilizing an interpretable hierarchical Bayesian approach and operational fleet data, domain expertise is naturally encoded (and appropriately shared) between different subgroups, representing (1) use‐type, (2) component, or (3) operating condition. Specifically, domain expertise is exploited to constrain the model via assumptions (and prior distributions) allowing the methodology to automatically share information between similar assets, improving the survival analysis of a truck fleet (15% and 13% increases in predictive log‐likelihood of hazard) and power prediction in a wind farm (up to 82% reduction in the standard deviation of maximum output prediction). In each asset management example, a set of correlated functions is learnt over the fleet, in a combined inference, to learn a population model. Parameter estimation is improved when subfleets are allowed to share correlated information at different levels in the hierarchy; the (averaged) reduction in standard deviation for interpretable parameters in the survival analysis is 70%, alongside 32% in wind farm power models. In turn, groups with incomplete data automatically borrow statistical strength from those that are data‐rich. The statistical correlations enable knowledge transfer via Bayesian transfer learning, and the correlations can be inspected to inform which assets share information for which effect (i.e., parameter). Successes in both case studies demonstrate the wide applicability in practical infrastructure monitoring, since the approach is naturally adapted between interpretable fleet models of different in situ examples.

Understanding the chemical processes during starless core and prestellar core evolution is an important step in understanding the initial stages of star and disk formation. This project is a study of deuterated ammonia, o-NH$_2$D, in the L1251 star-forming region toward Cepheus. Twenty-two dense cores (twenty of which are starless or prestellar, and two of which have a protostar), previously identified by p-NH$_3$ (1,1) observations, were targeted with the 12m Arizona Radio Observatory telescope on Kitt Peak. o-NH$_2$D J$_{\rm{K_a} \rm{K_c}}^{\pm} =$ $1_{11}^{+} \rightarrow 1_{01}^{-}$ was detected in 13 (59\%) of the NH$_3$-detected cores with a median sensitivity of $\sigma_{T_{mb}} = 17$ mK. All cores detected in o-NH$_2$D at this sensitivity have p-NH$_3$ column densities $> 10^{14}$ cm$^{-2}$. The o-NH$_2$D column densities were calculated using the constant excitation temperature (CTEX) approximation while correcting for the filling fraction of the NH$_3$ source size. The median deuterium fraction was found to be 0.11 (including 3$\sigma$ upper limits). However, there are no strong, discernible trends in plots of deuterium fraction with any physical or evolutionary variables. If the cores in L1251 have similar initial chemical conditions, then this result is evidence of the cores physically evolving at different rates., Comment: 18 pages, 14 figures, MNRAS, in press

BACKGROUND The current curative approaches for ischemia/reperfusion injury on liver transplantation are still under debate for their safety and efficacy in patients with end-stage liver disease. We present the SIMVA statin donor treatment before Liver Transplants study. METHODS SIMVA statin donor treatment before Liver Transplants is a monocentric, double-blind, randomized, prospective tial aiming to compare the safety and efficacy of preoperative brain-dead donors' treatment with the intragastric administration of 80 mg of simvastatin on liver transplant recipient outcomes in a real-life setting. Primary aim was incidence of patient and graft survival at 90 and 180 d post-transplant; secondary end-points were severe complications. RESULTS The trial enrolled 58 adult patients (18-65 y old). The minimum follow-up was 6 mo. No patient or graft was lost at 90 or 180 d in the experimental group (n = 28), whereas patient/graft survival were 93.1% (P = 0.016) and 89.66% (P = 0.080) at 90 d and 86.21% (P = 0.041) and 86.2% (P = 0.041) at 180 d in the control group (n = 29). The percentage of patients with severe complications (Clavien-Dindo ≥IIIb) was higher in the control group, 55.2% versus 25.0% in the experimental group (P = 0.0307). The only significant difference in liver tests was a significantly higher gamma-glutamyl transferase and alkaline phosphatase at 15 d (P = 0.017), (P = 0.015) in the simvastatin group. CONCLUSIONS Donor simvastatin treatment is safe, and may significantly improve early graft and patient survival after liver transplantation, although further research is mandatory.

In this paper, we propose a new model to address the problem of negative interest rates that preserves the analytical tractability of the original Cox–Ingersoll–Ross (CIR) model without introducing a shift to the market interest rates, because it is defined as the difference of two independent CIR processes. The strength of our model lies within the fact that it is very simple and can be calibrated to the market zero yield curve using an analytical formula. We run several numerical experiments at two different dates, once with a partially sub-zero interest rate and once with a fully negative interest rate. In both cases, we obtain good results in the sense that the model reproduces the market term structures very well. We then simulate the model using the Euler–Maruyama scheme and examine the mean, variance and distribution of the model. The latter agrees with the skewness and fat tail seen in the original CIR model. In addition, we compare the model’s zero coupon prices with market prices at different future points in time. Finally, we test the market consistency of the model by evaluating swaptions with different tenors and maturities.

BackgroundAcute myocardial infarction (MI) frequently leads to consciousness disturbance following hemodynamic collapse. Therefore, MI can occur together with upper cervical spine trauma. Herein, we report the successful treatment of complex C1/C2 fractures in a patient with concomitant three-vessel coronary artery disease (CAD).Case presentationA 70-year-old patient presented in our emergency outpatient clinic after a hemodynamic collapse without neurological deficits or heart-related complaints. Computed tomography (CT) scan of the cervical spine revealed a dislocated odontoid fracture Anderson and D'Alonzo type II and an unstable Gehweiler type III injury (Jefferson's fracture). An intradiploic arachnoid cyst in the posterior wall of the posterior fossa was a coincident radiological finding. Furthermore, coronary angiography confirmed three-vessel CAD with high-grade coronary artery stenosis. Indication for upper cervical spine surgery and bypass surgery was given. An interdisciplinary team of neurosurgeons, cardiothoracic surgeons and anesthesiologists evaluated the patient's case to develop the most suitable therapy concept and alternative strategies. Finally, in first step, C1-C2 fusion was performed by Harms technique under general anesthesia with x-ray guidance, spinal neuronavigation, Doppler ultrasound and cardiopulmonary monitoring. Cardiothoracic surgeons were on standby. One month later bypass surgery was performed uneventfully. Follow-up CT scan of cervical spine revealed intraosseous screw positioning and beginning fusion of the fractures. The patient did not develop neurological deficits and recovered completely from both surgeries.ConclusionsTreating complex C1/C2 fractures with concomitant severe CAD requiring treatment is challenging and carries a high risk of complications. To our knowledge, the literature does not provide any guidelines regarding therapy of this constellation. To receive upper cervical spine stability and to prevent both, spinal cord injury and cardiovascular complications, an individual approach is required. Interdisciplinary cooperation to determine optimal therapeutic algorithms is needed.

Background: Hepatic interstitial T-lymphocytes (T-Li), Natural Killer (NK) and NK-T cells play an important role in both innate and adaptive immunity and contribute to the regulation of ischemia/reperfusion injury (IRI) after transplantation of abdominal organ. Methods: The cellular concentrations and phenotypes of NK, T-Li, NK-T were analyzed retrospectively in a consecutive series of hepatic perfusates after surgical removal of whole livers on the bench previously collected from adult multi-organ donors after brain death. (DBD), and compared with the demographic and pathological characteristics of the patients transplanted at our Institute with kidneys taken from the same donors. The liver interstitial cells were purified from the perfusate by density gradient centrifugation and the phenotype was determined by flow cytometric investigation using the following immunological markers: CD3, CD4, CD8 and CD56 in order to determine the relative percentage of T-Li, NK-T and NK cells. Results: The perfusates of 42 DBDs, and the related clinical outcome of kidney transplant recipients from 2010 to 2020, were analyzed. T-Li were significantly associated with the time in days of delayed functional recovery of transplanted kidneys (DGF) (p = 0.02), to onset of secondary infection from Cytomegalovirus (p = 0.03). On COX analysis, percent cell concentration of T-Li and time to DGF were significantly associated with an increased relative risk (HR) of organ survival (HR = 1.038, p = 0.04; and HR = 1.029, p = 0.01, respectively). The specificity of the NK and NK-T cell proportions were not associated with any relevant clinical outcomes in kidney transplant patients. Conclusions: The present study points to a new potential role of T-Li cells detected in the context of liver perfusate DBD, and could detect potential impacts in organ allocation, surgical harvesting techniques and in the analysis of IRI pathophysiological events after kidney transplants from multi-organ DBDs.

Haemorrhagic enteritis is an economically significant disease reported in the majority of the countries where turkeys are raised intensively; it is caused by turkey adenovirus 3 (TAdV-3). The aim of this study was to analyse and compare the ORF1 gene 3′ region from turkey haemorrhagic enteritis virus (THEV) vaccine-like and field strains in order to develop a molecular diagnostic method to differentiate the strains from each other. Eighty samples were analysed by sequencing and phylogenetic analyses using a new set of polymerase chain reaction (PCR) primers targeting a genomic region spanning the partial ORF1, hyd and partial IVa2 gene sequences. A commercial live vaccine was also included in the analysis. The results showed that 56 of the 80 sequences obtained in this study showed ³99.8% nucleotide identity with the homologous vaccine strain sequence. Three non-synonymous mutations – ntA1274G (aaI425V), ntA1420C (aaQ473H) and ntG1485A (aaR495Q) – were detected in the THEV field strains but not in the vaccine strain. Phylogenetic analysis confirmed the clustering of the field and vaccine-like strains in different phylogenetic branches. In conclusion, the method employed in this study could be a useful tool towards making a correct diagnosis. The data could contribute to the knowledge of field distribution of THEV strains and increase the limited existing information available on native isolates around the world.

Table S1, Table S2, Table S3, Table S4, Figure S1 - S21, Supplementary Figure Legends

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.Significance:These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.

We study the mathematical theory of second order systems with two species, arising in the dynamics of interacting particles subject to linear damping, to nonlocal forces and to external ones, and resulting into a nonlocal version of the compressible Euler system with linear damping. Our results are limited to the 1 space dimensional case but allow for initial data taken in a Wasserstein space of probability measures. We first consider the case of smooth nonlocal interaction potentials, not subject to any symmetry condition, and prove existence and uniqueness. The concept of solutions relies on a stickiness condition in case of collisions, in the spirit of previous works in the literature. The result uses concepts from classical Hilbert space theory of gradient flows (cf. Brezis, Operateurs maximaux monotones et semi-groupes de contractions dans les espaces de Hilbert, 1973) and a trick used in Brenier et al. (J. Math. Pures Appl. 99(5):577–617, 2013). We then consider a large-time and large-damping scaled version of our system and prove convergence to solutions to the corresponding first order system. Finally, we consider the case of Newtonian potentials - subject to symmetry of the cross-interaction potentials - and external convex potentials. After showing existence in the sticky particles framework in the spirit of Brenier et al. (J. Math. Pures Appl. 99(5):577–617, 2013), we prove convergence for large times towards Dirac delta solutions for the two densities. All the results share a common technical framework in that solutions are considered in a Lagrangian framework, which allows to estimate the behavior of solutions via $L^{2}$ L 2 estimates of the pseudo-inverse variables corresponding to the two densities. In particular, due to this technique, the large-damping result holds under a rather weak condition on the initial data, which does not require well-prepared initial velocities. We complement the results with numerical simulations.

We present and analyze observations of polarized dust emission at 850 μm toward the central 1 × 1 pc hub-filament structure of Monoceros R2 (Mon R2). The data are obtained with SCUBA-2/POL-2 on the James Clerk Maxwell Telescope (JCMT) as part of the B-fields in Star-forming Region Observations survey. The orientations of the magnetic field follow the spiral structure of Mon R2, which are well described by an axisymmetric magnetic field model. We estimate the turbulent component of the magnetic field using the angle difference between our observations and the best-fit model of the underlying large-scale mean magnetic field. This estimate is used to calculate the magnetic field strength using the Davis–Chandrasekhar–Fermi method, for which we also obtain the distribution of volume density and velocity dispersion using a column density map derived from Herschel data and the C18O (J = 3 − 2) data taken with HARP on the JCMT, respectively. We make maps of magnetic field strengths and mass-to-flux ratios, finding that magnetic field strengths vary from 0.02 to 3.64 mG with a mean value of 1.0 ± 0.06 mG, and the mean critical mass-to-flux ratio is 0.47 ± 0.02. Additionally, the mean Alfvén Mach number is 0.35 ± 0.01. This suggests that, in Mon R2, the magnetic fields provide resistance against large-scale gravitational collapse, and the magnetic pressure exceeds the turbulent pressure. We also investigate the properties of each filament in Mon R2. Most of the filaments are aligned along the magnetic field direction and are magnetically subcritical.

The recent paleoproteomic studies, including paleo-metaproteomic analyses, improved our understanding of the dietary of ancient populations, the characterization of past human diseases, the reconstruction of the habitat of ancient species, but also provided new insights into the phylogenetic relationships between extant and extinct species. In this respect, the present work reports the results of the metaproteomic analysis performed on the middle part of a trunk, and on the portion of a trunk tip tissue of two different woolly mammoths some 30,000 years old. In particular, proteins were extracted by applying EVA (Ethylene–Vinyl Acetate studded with hydrophilic and hydrophobic resins) films to the surface of these tissues belonging to two Mammuthus primigenus specimens, discovered in two regions located in the Russian Far East, and then investigated via a shotgun MS-based approach. This approach allowed to obtain two interesting results: (i) an indirect description of the habitat of these two mammoths, and (ii) an improved characterization of the collagen type I, alpha-1 and alpha-2 chains (col1a1 and col1a2). Sequence characterization of the col1a1 and col1a2 highlighted some differences between M. primigenius and other Proboscidea together with the identification of three (two for col1a1, and one for col1a2) potentially diagnostic amino acidic mutations that could be used to reliably distinguish the Mammuthus primigenius with respect to the other two genera of elephantids (i.e., Elephas and Loxodonta), and the extinct American mastodon (i.e., Mammut americanum). The results were validated through the level of deamidation and other diagenetic chemical modifications of the sample peptides, which were used to discriminate the “original” endogenous peptides from contaminant ones. The data have been deposited to the ProteomeXchange with identifier .

Prestellar cores are generally spheroidal, some of which appear oblate while others appear prolate. Very few of them appear circular in projection. Little, however, is understood about the processes or the physical conditions under which prolate/oblate cores form. We find that an initially sub-critical filament experiencing relatively low pressure ($\lesssim 10^{4}$ K cm$^{-3}$) forms prolate cores (i.e., those with axial ratios in excess of unity) via gradual accumulation of gas in density crests. Meanwhile, a filament that is initially transcritical and experiences pressure similar to that in the Solar neighbourhood (between $\mathrm{few}\ \times 10^{4}$ K cm$^{-3}$ - $\mathrm{few}\ \times 10^{5}$ K cm$^{-3}$) forms oblate cores (i.e., those with axial ratios less than unity) via \emph{Jeans like} fragmentation. At higher pressure, however, fragments within the filament do not tend to survive as they rebound soon after formation. We also argue that quasi-oscillatory features of velocity gradient observed along the filament axis, and in the direction orthogonal to the axis, are integral to the filament evolution process and arise due to the growth of corrugations on its surface. The axial component of the velocity gradient, in particular, traces the gas-flow along the filament length. We therefore posit that it could be used to constrain the filament-formation mechanism. The magnitude of the respective components of velocity gradients increases with increasing external pressure., 20 pages; 15 figures; Accepted for publication in MNRAS Low resolution figures have been deliberately included here to make the article compatible with Arxiv submission rules

Il gioco d'azzardo, fenomeno sociale di massa, è legalmente e socialmente accettato, incentivato dall'illusione di una grande occasione in grado di garantire un'esistenza di ludico disimpegno. Comoda scorciatoia per aumentare la fiscalità erariale dello Stato, l'azzardo entra ambiguamente nell'ambiente domestico, in senso fisico e virtuale. Il giocatore, attore inconsapevole del rischio, viene proiettato in una dimensione apparentemente priva di limiti spazio temporali in cui la percezione del danno viene sublimata, anche fisicamente, nell'esaltazione del proprio piacere.

Neuroblastoma is a biologically heterogeneous extracranial tumor, derived from the sympathetic nervous system, that affects most often the pediatric population. Therapeutic strategies relying on aggressive chemotherapy, surgery, radiotherapy, and immunotherapy have a negative outcome in advanced or recurrent disease. Here, spherical polymeric nanomedicines (SPN) are engineered to co-deliver a potent combination therapy, including the cytotoxic docetaxel (DTXL) and the natural wide-spectrum anti-inflammatory curcumin (CURC). Using an oil-in-water emulsion/solvent evaporation technique, four SPN configurations were engineered depending on the therapeutic payload and characterized for their physico-chemical and pharmacological properties. All SPN configurations presented a hydrodynamic diameter of ∼185nm with a narrow size distribution. A biphasic release profile was observed for all the configurations, with almost 90% of the total drug mass released within the first 24hours. SPN cytotoxic potential was assessed on a panel of human neuroblastoma cells, returning IC

IntroductionHepatocellular carcinoma (HCC) accounts for nearly 90% of primary liver cancers, with estimates of over 1 million people affected by 2025. We aimed to explore the impacting role of an iterative surgical treatment approach in a cohort of HCC patients within the Milan criteria, associated with clinical risk factors for tumor recurrence (RHCC) after liver transplant (LT) and loco-regional therapies (LRT), as well as liver resection (LR) and/or microwave thermal ablation (MWTA).MethodsWe retrospectively analyzed our experience performed during an 8-year period between January 2013 and December 2021 in patients treated for HCC, focusing on describing the impact on preoperative end-stage liver disease severity, oncologic staging, tumor characteristics, and surgical treatments. The Cox model was used to evaluate variables that could predict relapse risks. Relapse risk curves were calculated according to the Kaplan–Meier method, and the log-rank test was used to compare them.ResultsThere were 557 HCC patients treated with a first-line approach of LR and/or LRTs (n = 335) or LT (n = 222). The median age at initial transplantation was 59 versus 68 for those whose first surgical approach was LR and/or LRT. In univariate analysis with the Cox model, nodule size was the single predictor of recurrence of HCC in the posttreatment setting (HR: 1.61, 95% CI: 1.05–2.47, p = 0.030). For the LRT group, we have enlightened the following clinical characteristics as significantly associated with RHCC: hepatitis B virus infection (which has a protective role with HR: 0.34, 95% CI: 0.13–0.94, p = 0.038), number of HCC nodules (HR: 1.54, 95% CI: 1.22–1.94, p < 0.001), size of the largest nodule (HR: 1.06, 95% CI: 1.01–1.12, p = 0.023), serum bilirubin (HR: 1.57, 95% CI: 1.03–2.40, p = 0.038), and international normalized ratio (HR: 16.40, 95% CI: 2.30–118.0, p = 0.006). Among the overall 111 patients with RHCC in the LRT group, 33 were iteratively treated with further curative treatment (12 were treated with LR, two with MWTA, three with a combined LR-MWTA treatment, and 16 underwent LT). Only one of 18 recurrent patients previously treated with LT underwent LR. For these RHCC patients, multivariable analysis showed the protective roles of LT for primary RHCC after IDLS (HR: 0.06, 95% CI: 0.01–0.36, p = 0.002), of the time relapsed between the first and second IDLS treatments (HR: 0.97, 95% CI: 0.94–0.99, p = 0.044), and the impact of previous minimally invasive treatment (HR: 0.28, 95% CI: 0.08–1.00, p = 0.051).ConclusionThe coexistence of RHCC with underlying cirrhosis increases the complexity of assessing the net health benefit of ILDS before LT. Minimally invasive surgical therapies and time to HCC relapse should be considered an outcome in randomized clinical trials because they have a relevant impact on tumor-free survival.

In recent years, the Choosing Wisely and Less is More campaigns have gained growing attention in the medical scientific community. Several projects have been launched to facilitate confrontation among patients and physicians, to achieve better and harmless patient-centered care. Such initiatives have paved the way to a new "way of thinking." Embracing such a philosophy goes through a cognitive process that takes into account several issues. Medicine is a highly inaccurate science and physicians should deal with uncertainty. Evidence from the literature should not be accepted as it is but rather be translated into practice by medical practitioners who select treatment options for specific cases based on the best research, patient preferences, and individual patient characteristics. A wise choice requires active effort into minimizing the chance that potential biases may affect our clinical decisions. Potential harms and all consequences (both direct and indirect) of prescribing tests, procedures, or medications should be carefully evaluated, as well as patients' needs and preferences. Through such a cognitive process, a patient management shift is needed, moving from being centered on establishing a diagnosis towards finding the best management strategy for the right patient at the right time. Finally, while "thinking wisely," physicians should also "act wisely," being among the leading actors in facing upcoming healthcare challenges related to environmental issues and social discrepancies.

Hypothesis Polymeric anisotropic soft microparticles show interesting behavior in biological environments and hold promise for drug delivery and biomedical applications. However, self-assembly and substrate-based lithographic techniques are limited by low resolution, batch operation or specific particle geometry and deformability. Two-photon polymerization in microfluidic channels may offer the required resolution to continuously fabricate anisotropic micro-hydrogels in sub-10 µm size-range. Experiments Here, a pulsed laser source is used to perform two-photon polymerization under microfluidic flow of a poly(ethylene glycol) diacrylate (PEGDA) solution with the objective of realizing anisotropic micro-hydrogels carrying payloads of various nature, including small molecules and nanoparticles. The fabrication process is described via a reactive-convective-diffusion system of equations, whose solution under proper auxiliary conditions is used to corroborate the experimental observations and sample the configuration space. Findings By tuning the flow velocity, exposure time and pre-polymer composition, anisotropic PEGDA micro-hydrogels are obtained in the 1–10 μm size-range and exhibit an aspect ratio varying from 1 to 5. Furthermore, 200 nm curcumin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and 100 nm ssRNA-encapsulating lipid nanoparticles were entrapped within square PEGDA micro-hydrogels. The proposed approach could support the fabrication of micro-hydrogels of well-defined morphology, stiffness, and surface properties for the sustained release of therapeutic agents.

Indigenous knowledge provides valuable information on wildlife health and ecology, contributing to a broader understanding of the patterns and phenomena observed. Muskoxen (Ovibos moschatus), an important species for the subsistence and culture of Inuit communities in the Arctic, are increasingly exposed to diverse stressors linked to rapid climate change and other anthropogenic changes. Identifying and understanding these stressors and their impacts on muskoxen will inform management, health monitoring, and future research. To achieve this understanding, we documented Indigenous knowledge through seven semi-structured small group interviews, each involving two to three purposely chosen muskox harvesters in Kugluktuk, Nunavut, Canada to (1) establish the characteristics of healthy muskoxen, (2) determine the factors considered to impact muskoxen, and (3) understand, from an Indigenous knowledge perspective, the results from a study on the sex, seasonal, and annual patterns of glucocorticoids (described as “stress hormones” for the purposes of the interviews) in muskox hair. Key outcomes include (1) a more holistic understanding of muskox health and what it encompasses, (2) recognition and exploration of a rich One Health perspective expressed by participants around factors influencing muskoxen in a changing world and highlighting the multiple socioecological connections, and (3) a broader comprehension of the glucocorticoid (stress) patterns measured in muskox hair, the various factors that influence them, and their interrelations. This study represents a meaningful advancement in the process of actively involving communities at all steps of the research and highlights the important contributions Indigenous knowledge can offer to the complex field of wildlife endocrinology research.

Supplementary Materials and Methods Supplementary References Tables S1 to S3 and legends Figures S1 to S4 and legends

Increased TLS Formation, Macrophage Infiltration and Proinflammatory TAM Activation in HCCs from Gadd45b-/- Mice

Gadd45b Loss Enhances Proinflammatory Macrophage Activation by Upregulating p38 Signalling

Supplemental Figure Legends and Supplementary Materials and Methods

Supplementary Fig. S3 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Supplementary Fig. S1 from Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Germline Transmission of the Gadd45bF Allele

Host Reconstitution with BM-Derived Cells of Donor Origin

Reduced DEN-induced HCC Development in 129/SvJxC57BL/6J Gadd45b-/- Mice

Increased Immune Infiltration, Proinflammatory TAM Activation and Effects of CD8+ T-Cell Depletion in Fibrosarcomas and/or Ovarian Tumours from Gadd45b-/- mice