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OBJECTIVE Resection of brain metastases (BMs) may be associated with increased risk of leptomeningeal disease (LMD). This study examined rates and predictors of LMD, including imaging subtypes, in patients who underwent resection of a BM followed by postoperative radiation. METHODS A retrospective, single-center study was conducted examining overall LMD, classic LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression, Cox proportional hazards, and random forest analyses were performed to identify risk factors associated with LMD. RESULTS Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD, with 19 cases (8.8%) of cLMD and 28 cases (12.9%) of nLMD. Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from the date of LMD diagnosis compared with nLMD (median 2.4 vs 6.9 months, p = 0.02, log-rank test). Cox proportional hazards analysis identified cerebellar/insular/occipital location (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.73–6.11, p = 0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27–4.88, p = 0.008), and ventricle contact (HR 2.82, 95% CI 1.5–5.3, p = 0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an area under the receiver operating characteristic curve of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. CONCLUSIONS Tumor location, absence of extracranial disease at the time of surgery, ventricle contact, and increased tumor volume were associated with LMD. Further work is needed to determine whether escalating therapies in patients at risk of LMD prevents disease dissemination.

PurposeIn this article, the authors aim to achieve a deeper understanding of the aspects that influence academic faculty's subjective well-being (SWB). For this purpose, the authors focus on scholars who work in a business school that not only is located in Latin America, but is in a transition process, changing from being solely a teaching-oriented to a research-oriented model due to Association to Advance Collegiate Schools of Business (AACSB) accreditation purposes.Design/methodology/approachTwenty in-depth semi-structured interviews were conducted with professors at a private business school in Mexico. The interviews took place between November 2018 and late 2020.FindingsScholars of business schools who are transitioning from being teaching-oriented to becoming research-oriented in order to comply with AACSB requirements face heightened institutional pressures that can generate negative effects on professors' SWB; especially on three dimensions: health, a sense of lack of self-efficacy and apprehension due to the lack of resources.Research limitations/implicationsThis paper studied a particular context; however, even when the findings of this article are relevant, they cannot be generalized, as each context will have its own peculiarities.Originality/valueMore attention needs to be given to scholars' SWB, particularly of those working in business schools located in the Global South. This is especially relevant since faculty members of business schools in emerging economies are aiming to compete in the international arena; therefore, they face heightened institutional pressures since they need to be more academically productive without neglecting teaching and administrative tasks and despite having less access to resources than their counterparts working in business schools in developed economies. The authors believe that hearing researchers' stories about their concerns and desires can raise awareness and lead to better work conditions.

Purpose of Review Recent advances in donor heart preservation have allowed the utilization of hearts that would typically be discarded due to prolonged ischemic times or donation via the circulatory death pathway. This review will discuss recent advances in donor heart preservation including optimization of machine perfusion technologies and future strategies of potential benefit for the donor heart and transplant outcomes. Recent Findings Improvements in organ preservation strategies have enabled retrieval of donor hearts that were not ideal for static cold storage. Machine perfusion (normothermic and hypothermic) and normothermic regional perfusion have ultimately expanded the donor pool for adult heart transplantation. Xenotransplantation has also incorporated machine perfusion for porcine donor heart preservation. Summary Traditional static cold storage is feasible for non-complex donors and transplants. Machine perfusion has enabled increased donor heart utilization however optimal preservation strategies are dependent on the donor criteria, predicted ischemic times and surgical complexity.

Poly(3-hydroxybutyrate), PHB, is a hydrophobic biopolymer with good mechanical and barrier properties. However, neat PHB is a semicrystalline polymer with a relative high degree of crystallinity and poor film properties. In this work, this biopolymer was plasticized with glycerol tributyrate and functionalized with copper (II) sulfate, allowing us to obtain biodegradable antimicrobial flexible films. Films with the minimum inhibitory concentration (MIC) of copper (II) sulfate presented a higher roughness than neat PHB films. The presence of plasticizer significantly improved the copper sulfate diffusion process, which was evidenced by a greater inhibition halo for plasticized materials compared to unplasticized ones, at the same salt concentration. Plasticized PHB with 2.5% copper (II) sulfate inhibited both Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomona aeruginosa) bacteria, as determined by the bacterial inhibition halo. In addition, neat PHB films and PHB containing copper (II) sulfate did not show in vitro cytotoxicity in the L-929 cell line. Thus, plasticized PHB functionalized with copper (II) sulfate can be used as biodegradable antimicrobial flexible films for different applications.

Estrone-3-sulfate (E3S) uptake mediated by organic anion transporting polypeptide 1B3 (OATP1B3) can be activated by epigallocatechin gallate (EGCG). In this study, by using chimeric transporters and site-directed mutagenesis, we found that Val386 in transmembrane domain 8 (TM8) is essential for OATP1B3’s activation by EGCG. Kinetic studies showed that the loss of activation of 1B3-TM8 and 1B3-V386F in the presence of EGCG is due to their decreased substrate binding affinity and reduced maximal transport rate. The overall transport efficiency of OATP1B3, 1B3-TM8, and 1B3-V386F in the absence and presence of EGCG were 8.6 ± 0.7 vs 15.9 ± 1.4 (p < 0.05), 11.2 ± 2.1 vs 2.7 ± 0.3 (p < 0.05), and 10.2 ± 1.0 vs 2.5 ± 0.3 (p < 0.05), respectively. While 1B3-V386F cannot be activated by EGCG, its transport activity for EGCG is also diminished. OATP1B3’s activation by EGCG is substrate-dependent as EGCG inhibits OATP1B3-mediated pravastatin uptake. Furthermore, the activation of OATP1B3-mediated E3S uptake by quercetin 3-O-α-L-arabinopyranosyl(1→2)-α-L-rhamnopyranoside is not affected by TM8 and V386F. Taken together, the activation of OATP1B3 by small molecules is substrate- and modulator-dependent and V386 in TM8 plays a critical role in the activation of OATP1B3-mediated E3S uptake by EGCG.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

Today’s lifespan of companies tends to be low in the so-called micro-, small-, and medium-sized enterprises (MSMEs). Organizational life cycle (OLC) theory indicates that organizational aging is related, but not determined, by the firm chronological age or its size. Therefore, a firm’s aging should be analyzed by other factors such as flexibility. The literature considers flexibility as an essential capability, a source of competitive advantage, and an enabler of long-term growth for MSMEs. However, little attention in emerging economies has been paid to examine the nuances of this concept in relation to the OLC in this type of companies. Additionally, studies tend to analyze flexibility as a general term, ignoring that it is a polymorphic concept. That is why there is a need to research the different categories of flexibility. Drawing on a quantitative approach conducting a factor analysis, a two-step cluster, and decision tree analysis to interrogate data from 257 MSMEs in Mexico, this study provides evidence of different dimensions of strategic and structural flexibility that help to characterize and predict the growth, maturity, and declining stages of MSMEs. Our results show that mature firms present more strategic and structural flexible characteristics than those involved in growth or decline stages. The flexible factors that help classify and predict an MSME in the maturity stage include open communication, decentralized decision making, and formalization. We provide a model with these results to illuminate unaddressed issues regarding the broad term of flexibility and its relationship to OLC., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. There is no funding for this article

Objectives To evaluate whether combining fast acquisitions with deep-learning reconstruction can provide diagnostically useful images and quantitative assessment comparable to standard-of-care acquisitions for lumbar spine MRI. Methods Eighteen patients were imaged with both standard protocol and fast protocol using reduced signal averages, each protocol including sagittal fat-suppressed T2-weighted, sagittal T1-weighted, and axial T2-weighted 2D fast spin-echo sequences. Fast-acquisition data was additionally reconstructed using vendor-supplied deep-learning reconstruction with three different noise reduction factors. For qualitative analysis, standard images as well as fast images with and without deep-learning reconstruction were graded by three radiologists on five different categories. For quantitative analysis, convolutional neural networks were applied to sagittal T1-weighted images to segment intervertebral discs and vertebral bodies, and disc heights and vertebral body volumes were derived. Results Based on noninferiority testing on qualitative scores, fast images without deep-learning reconstruction were inferior to standard images for most categories. However, deep-learning reconstruction improved the average scores, and noninferiority was observed over 24 out of 45 comparisons (all with sagittal T2-weighted images while 4/5 comparisons with sagittal T1-weighted and axial T2-weighted images). Interobserver variability increased with 50 and 75% noise reduction factors. Deep-learning reconstructed fast images with 50% and 75% noise reduction factors had comparable disc heights and vertebral body volumes to standard images (r2 ≥ 0.86 for disc heights and r2 ≥ 0.98 for vertebral body volumes). Conclusions This study demonstrated that deep-learning-reconstructed fast-acquisition images have the potential to provide noninferior image quality and comparable quantitative assessment to standard clinical images.

IntroductionChagas disease, caused by chronic infection with the protozoan parasite Trypanosoma cruzi, affects 6-7 million people worldwide. The major clinical manifestation of Chagas disease is chronic Chagasic cardiomyopathy (CCC), which encompasses a spectrum of symptoms including arrhythmias, hypertrophy, dilated cardiomyopathy, heart failure, and sudden death. Current treatment is limited to two antiparasitic drugs, benznidazole (BNZ) and nifurtimox, but both have limited efficacy to halt the progression of CCC. We developed a vaccine-linked chemotherapy strategy using our vaccine consisting of recombinant Tc24-C4 protein and a TLR-4 agonist adjuvant in a stable squalene emulsion, in combination with low dose benznidazole treatment. We previously demonstrated in acute infection models that this strategy parasite specific immune responses, and reduced parasite burdens and cardiac pathology. Here, we tested our vaccine-linked chemotherapy strategy in a mouse model of chronic T. cruzi infection to evaluate the effect on cardiac function.MethodsFemale BALB/c mice infected with 500 blood form T. cruzi H1 strain trypomastigotes were treated beginning 70 days after infection with a low dose of BNZ and either low or high dose of vaccine, in both sequential and concurrent treatments streams. Control mice were untreated, or administered only one treatment. Cardiac health was monitored throughout the course of treatment by echocardiography and electrocardiograms. Approximately 8 months after infection, endpoint histopathology was performed to measure cardiac fibrosis and cellular infiltration.ResultsVaccine-linked chemotherapy improved cardiac function as evidenced by amelioration of altered left ventricular wall thickness, left ventricular diameter, as well as ejection fraction and fractional shortening by approximately 4 months of infection, corresponding to two months after treatment was initiated. At study endpoint, vaccine-linked chemotherapy reduced cardiac cellular infiltration, and induced significantly increased antigen specific IFN-γ and IL-10 release from splenocytes, as well as a trend toward increased IL-17A.DiscussionThese data suggest that vaccine-linked chemotherapy ameliorates changes in cardiac structure and function induced by infection with T. cruzi. Importantly, similar to our acute model, the vaccine-linked chemotherapy strategy induced durable antigen specific immune responses, suggesting the potential for a long lasting protective effect. Future studies will evaluate additional treatments that can further improve cardiac function during chronic infection.