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The ethnoracial future of the United States has been framed as a demographic binary: Whites vs. people of color. The argument here is that this binary distorts by failing to take into adequate account the rapidly growing group of Americans who have been raised in mixed minority and White families, the great majority of the total mixed population. The members of this group generally have distinctive social characteristics: socioeconomic advantages compared to minorities and social integration into milieus with many Whites, as revealed by relatively high rates of marriage to them. However, their identities often encompass their minority heritage. Accordingly, they straddle the society's major ethnoracial fracture line, creating an in-between social space and connecting, through kinship and other close social relations, both of its sides. However, their numbers are distorted in public national population data, such as census data and population projections; and they are typically counted as part of the non-White population. The recently announced revision of the race/ethnic data standards for the census offers an opportunity to refashion public data in a way that illuminates the important role this mixed group is likely to play in the nation's demographic future., Competing Interests: Competing interests statement:The author declares no competing interest.

Chronic kidney disease (CKD) patients can benefit from personalized education on lifestyle and nutrition management strategies to enhance healthcare outcomes. The potential use of chatbots, introduced in 2022, as a tool for educating CKD patients has been explored. A set of 15 questions on lifestyle modification and nutrition, derived from a thorough review of three specific KDIGO guidelines, were developed and posed in various formats, including original, paraphrased with different adverbs, incomplete sentences, and misspellings. Four versions of AI were used to answer these questions: ChatGPT 3.5 (March and September 2023 versions), ChatGPT 4, and Bard AI. Additionally, 20 questions on lifestyle modification and nutrition were derived from the NKF KDOQI guidelines for nutrition in CKD (2020 Update) and answered by four versions of chatbots. Nephrologists reviewed all answers for accuracy. ChatGPT 3.5 produced largely accurate responses across the different question complexities, with occasional misleading statements from the March version. The September 2023 version frequently cited its last update as September 2021 and did not provide specific references, while the November 2023 version did not provide any misleading information. ChatGPT 4 presented answers similar to 3.5 but with improved reference citations, though not always directly relevant. Bard AI, while largely accurate with pictorial representation at times, occasionally produced misleading statements and had inconsistent reference quality, although an improvement was noted over time. Bing AI from November 2023 had short answers without detailed elaboration and sometimes just answered "YES". Chatbots demonstrate potential as personalized educational tools for CKD that utilize layman's terms, deliver timely and rapid responses in multiple languages, and offer a conversational pattern advantageous for patient engagement. Despite improvements observed from March to November 2023, some answers remained potentially misleading. ChatGPT 4 offers some advantages over 3.5, although the differences are limited. Collaboration between healthcare professionals and AI developers is essential to improve healthcare delivery and ensure the safe incorporation of chatbots into patient care.

Gradenigo's syndrome (GS) presents with the classical triad of otitis media, facial pain, and abducens nerve palsy as a complication of petrous apicitis. However, in the era of increased antibiotic use, complications of petrous apicitis have become infrequent and cases of GS are not frequently seen in clinical practice. We present the case of a 76-year-old man with uncontrolled diabetes mellitus presented with a two-month history of worsening right-sided headache, right-sided facial pain and weakness, along with dysphagia, hearing loss, and right otalgia with intermittent otorrhea following a right upper molar extraction. Imaging identified the inflammatory changes and indications of petrous apicitis. Although GS has become quite rare in recent years, this case highlights the importance of the responsible use of antibiotics in treating a seemingly innocuous infection., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Assi et al.)

Large-vessel vasculitides (LVV) comprise a group of chronic inflammatory diseases of the aorta and its major branches. The most common forms of LVV are giant cell arteritis (GCA) and Takayasu arteritis (TAK). Both GCA and TAK are characterized by granulomatous inflammation of the vessel wall accompanied by a maladaptive immune and vascular response that promotes vascular damage and remodeling. The inflammatory process in LVV starts in the adventitia where fibroblasts constitute the dominant cell population. Fibroblasts are traditionally recognized for synthesizing and renewing the extracellular matrix thereby being major players in maintenance of normal tissue architecture and in tissue repair. More recently, fibroblasts have emerged as a highly plastic cell population exerting various functions, including the regulation of local immune processes and organization of immune cells at the site of inflammation through production of cytokines, chemokines and growth factors as well as cell-cell interaction. In this review, we summarize and discuss the current knowledge on fibroblasts in LVV. Furthermore, we identify key questions that need to be addressed to fully understand the role of fibroblasts in the pathogenesis of LVV., Competing Interests: Declaration of competing interest Kornelis S.M. van der Geest received speaking fee from Roche, and research support from AbbVie and Siemens Healthineers. Other authors had no conflicts of interest to declare. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Kornelis S.M. van der Geest reports a relationship with Roche that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A spinal epidural abscess is a rare condition characterized by the accumulation of pus between the dura mater and vertebral column, often caused by hematogenous spread from a distant site or local spread from infection in nearby structures. The abscess leads to compression of the spinal cord and can result in neurological damage, including dysfunction or permanent neurological deficits. Treatment of spinal epidural abscesses should not be delayed and requires a combination of decompression by surgical drainage and antibiotic therapy. The authors present a rare case in which a spinal epidural abscess developed from a hospital-acquired pressure ulcer, further complicated by bacteremia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Carlson et al.)

Vascular smooth muscle cells (VSMCs) have been shown to play a role in the pathogenesis of giant cell arteritis (GCA) through their capacity to produce chemokines recruiting T cells and monocytes in the arterial wall and their ability to migrate and proliferate in the neointima where they acquire a myofibroblast (MF) phenotype, leading to vascular stenosis. This study aimed to investigate if MFs could also impact T-cell polarization. Confocal microscopy was used to analyze fresh fragments of temporal artery biopsies (TABs). Healthy TAB sections were cultured to obtain MFs, which were then treated or not with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and analyzed by immunofluorescence and RT-PCR. After peripheral blood mononuclear cells and MFs were co-cultured for seven days, T-cell polarization was analyzed by flow cytometry. In the neointima of GCA arteries, we observed a phenotypic heterogeneity among VSMCs that was consistent with a MF phenotype (α-SMA + CD90 + desmin + MYH11 + ) with a high level of STAT1 phosphorylation. Co-culture experiments showed that MFs sustain Th1/Tc1 and Th17/Tc17 polarizations. The increased Th1 and Tc1 polarization was further enhanced following the stimulation of MFs with IFN-γ and TNF-α, which induced STAT1 phosphorylation in MFs. These findings correlated with increases in the production of IL-1β, IL-6, IL-12 and IL-23 by MFs. Our study showed that MFs play an additional role in the pathogenesis of GCA through their ability to maintain Th17/Tc17 and Th1/Tc1 polarizations, the latter being further enhanced in case of stimulation of MF with IFN-γ and TNF-α., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The pathogenesis of Giant Cell Arteritis (GCA) relies on vascular inflammation and vascular remodeling, the latter being poorly controlled by current treatments., Methods: This study aimed to evaluate the effect of a novel cell therapy, Human Monocyte-derived Suppressor Cells (HuMoSC), on inflammation and vascular remodeling to improve GCA treatment. Fragments of temporal arteries (TAs) from GCA patients were cultured alone or in the presence of HuMoSCs or their supernatant. After five days, mRNA expression was measured in the TAs and proteins were measured in culture supernatant. The proliferation and migration capacity of vascular smooth muscle cells (VSMCs) were also analyzed with or without HuMoSC supernatant., Results: Transcripts of genes implicated in vascular inflammation ( CCL2 , CCR2 , CXCR3 , HLADR ), vascular remodeling ( PDGF , PDGFR ), angiogenesis (VEGF) and extracellular matrix composition ( COL1A1 , COL3A1 and FN1 ) were decreased in arteries treated with HuMoSCs or their supernatant. Likewise, concentrations of collagen-1 and VEGF were lower in the supernatants of TAs cultivated with HuMoSCs. In the presence of PDGF, the proliferation and migration of VSMCs were both decreased after treatment with HuMoSC supernatant. Study of the PDGF pathway suggests that HuMoSCs act through inhibition of mTOR activity. Finally, we show that HuMoSCs could be recruited in the arterial wall through the implication of CCR5 and its ligands., Conclusion: Altogether, our results suggest that HuMoSCs or their supernatant could be useful to decrease vascular in flammation and remodeling in GCA, the latter being an unmet need in GCA treatment., Competing Interests: MS: Roche–Chugai consulting, AbbVie consulting, Boehringer Ingelheim consulting, Novartis consulting and research grant, VIFOR Pharma consulting; BB: Roche–Chugai personal fees for consulting, Boehringer Ingelheim consulting; CC-G: Horus and Bayer grant, Novartis and Bayer honoraria and Novartis, Bayer, Thea, Horus, Alcon and Allergan medical advisory board; P-HG: Allergan, Bayer and Novartis travel expenses, Novartis and Bayer honoraria; MCC: GlaxoSmithKline consulting, CSL Vifor consulting, AbbVie consulting, Janssen consulting, Astrazeneca consulting, Kiniksa Pharmaceuticals research grant; GE-F: GlaxoSmithKline consulting, Janssen consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Samson, Genet, Corbera-Bellalta, Greigert, Espígol-Frigolé, Gérard, Cladière, Alba-Rovira, Ciudad, Gabrielle, Creuzot-Garcher, Tarris, Martin, Saas, Audia, Bonnotte and Cid.)

Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, EXT1 and EXT2. In this work, we report a cross-sectional study including 35 index patients and 20 affected family members. Clinical phenotyping of all 55 affected cases was obtained, but genetic studies were performed only in 35 indexes. Of these, a total of 40% ( n = 14) had a family history of MO. Clinical severity scores were class I in 34% ( n :18), class II in 24.5% ( n :13) and class III in 41.5% ( n :22). Pathogenic variants were identified in 83% (29/35) probands. We detected 18 (62%) in EXT1 and 11 (38%) in EXT2 . Patients with EXT1 variants showed a height z-score of 1.03 SD lower than those with EXT2 variants and greater clinical severity (II-III vs. I). Interestingly, three patients showed intellectual impairment, two patients showed a dual diagnosis, one Turner Syndrome and one hypochondroplasia. This study improves knowledge of MO, reporting new pathogenic variants and forwarding the worldwide collaboration necessary to promote the inclusion of patients into future biologically based therapeutics.

This paper presents the roadmap of the main materials to be used for ITER and DEMO class reactors as well as an overview of the most relevant innovations that have been made in recent years. The main idea in the EUROfusion development program for the FW (first wall) is the use of low-activation materials. Thus far, several candidates have been proposed: RAFM and ODS steels, SiC/SiC ceramic composites and vanadium alloys. In turn, the most relevant diagnostic systems and PFMs (plasma-facing materials) will be described, all accompanied by the corresponding justification for the selection of the materials as well as their main characteristics. Finally, an outlook will be provided on future material development activities to be carried out during the next phase of the conceptual design for DEMO, which is highly dependent on the success of the IFMIF-DONES facility, whose design, operation and objectives are also described in this paper.

Most people lack direct experience with wildlife and form their risk perception primarily on information provided by the media. The way the media frames news may substantially shape public risk perception, promoting or discouraging public tolerance towards wildlife. At the onset of the COVID-19 pandemic, bats were suggested as the most plausible reservoir of the virus, and this became a recurrent topic in media reports, potentially strengthening a negative view of this ecologically important group. We investigated how media framed bats and bat-associated diseases before and during the COVID-19 pandemic by assessing the content of 2651 online reports published across 26 countries, to understand how and how quickly worldwide media may have affected the perception of bats. We show that the overabundance of poorly contextualized reports on bat-associated diseases likely increased the persecution towards bats immediately after the COVID-19 outbreak. However, the subsequent interventions of different conservation communication initiatives allowed pro-conservation messages to resonate across the global media, likely stemming an increase in bat persecution. Our results highlight the modus operandi of the global media regarding topical biodiversity issues, which has broad implications for species conservation. Knowing how the media acts is pivotal for anticipating the propagation of (mis)information and negative feelings towards wildlife. Working together with journalists by engaging in dialogue and exchanging experiences should be central in future conservation management., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Elsevier Ltd. All rights reserved.)

Introduction: Hereditary osteochondromatosis is an uncommon, autosomal, dominant condition characterized by the presence of multiple bone growths., Objective: To analyze factors associated with health-related quality of life (HRQoL) among children > 2 years and adults receiving follow-up at a tertiary care children's hospital in Argentina., Population and Methods: Cross-sectional study of a follow-up cohort. HRQoL was measured using the Pediatric Quality of Life Inventory® (PedsQL) and the Short Form Health Survey (SF- 36). Sex, age, sociodemographic characteristics, height, radiology, axis alteration and limb function, presence of pain, and malignant change were recorded. Severity was classified as per Pedrini et al. Parametric and non-parametric tests and regression analysis were done., Results: A total of 66 cases (47 children and 19 adults) were included. Male/female ratio: 1.7/1. Median age: 13.4 years (r: 2.21-55.3). Pain was observed in 30/47 children and in 17/19 adults. Considering the adult bone age (or epiphyseal closure) as the cutoff point to define adult status, 11/37 children and 18/27 adults had a severe disease and 2/38 children and 9/27 adults had short stature. The average value of the physical component of HRQoL in children was 65.9 (SD: 22.5) and, in adults, 27.2 (IQR: 18.5- 34.7). The presence of pain and clinical severity were significantly associated with a lower HRQoL, both in children and adults., Conclusions: This study found that pain and disease severity had a negative effect on HRQoL., Competing Interests: None., (Sociedad Argentina de Pediatría.)

Background: Effective and safe therapies are needed for the treatment of patients with giant cell arteritis (GCA). Emerging as a key cytokine in inflammation, granulocyte-macrophage colony stimulating factor (GM-CSF) may play a role in promoting inflammation in GCA., Objectives: To investigate expression of GM-CSF and its receptor in arterial lesions from patients with GCA. To analyse activation of GM-CSF receptor-associated signalling pathways and expression of target genes. To evaluate the effects of blocking GM-CSF receptor α with mavrilimumab in ex vivo cultured arteries from patients with GCA., Methods: Quantitative real time PCR, in situ RNA hybridisation, immunohistochemistry, immunofluorescence and confocal microscopy, immunoassay, western blot and ex vivo temporal artery culture., Results: GM-CSF and GM-CSF receptor α mRNA and protein were increased in GCA lesions; enhanced JAK2/STAT5A expression/phosphorylation as well as increased expression of target genes CD83 and Spi1/PU.1 were observed. Treatment of ex vivo cultured GCA arteries with mavrilimumab resulted in decreased transcripts of CD3ε, CD20, CD14 and CD16 cell markers, and reduction of infiltrating CD16 and CD3ε cells was observed by immunofluorescence. Mavrilimumab reduced expression of molecules relevant to T cell activation (human leukocyte antigen-DR [HLA-DR]) and Th1 differentiation (interferon-γ), the pro-inflammatory cytokines: interleukin 6 (IL-6), tumour necrosis factor α (TNFα) and IL-1β, as well as molecules related to vascular injury (matrix metalloprotease 9, lipid peroxidation products and inducible nitric oxide synthase [iNOS]). Mavrilimumab reduced CD34 + cells and neoangiogenesis in GCA lesions., Conclusion: The inhibitory effects of mavrilimumab on multiple steps in the GCA pathogenesis cascade in vitro are consistent with the clinical observation of reduced GCA flares in a phase 2 trial and support its development as a therapeutic option for patients with GCA., Competing Interests: Competing interests: SM, AJ and AD’A report employment by Kiniksa Pharmaceuticals Corp. during development of the manuscript. KB and JFP report current employment by Kiniksa Pharmaceuticals Corp. MCC reports consulting fees from GSK, Abbvie, Vifor and Janssen, and a research grant from Kiniksa Pharmaceuticals Corp. GE-F reports consulting fees from Janssen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

SignificanceThe contemporary intellectual landscape, dominated by theories about race and racism, has engendered the majority-minority conception of the American future, in which White people are outnumbered by Americans of color by midcentury. But assimilation, as a set of processes with societal ramifications, is still potent, driven by demographic dynamics that generate opportunities for minority mobility, and is linked to increasing family mixing between White and non-White people. The children of these families offer the best window into ongoing assimilation. The binary vision of the majority-minority society needs major modification because of the emergence and growing size of this bridging group. In addition, racism-focused theories need to be complemented by assimilation ideas to grasp the implications of demographic change.

Background: Healthcare systems advocate for quality care and humanized relations in routine birth care, and have therefore created the Birth Plan, a document available to pregnant women to state their preferences in relation to the birth process., Methods: This qualitative research with a phenomenological design was carried out to record the experiences of women who presented a Birth Plan. Sample selection was carried out using non-probabilistic, intentional and convenience sampling, selecting seven participants who were willing to participate and share their experiences., Results: After analyzing the content of the interviews, four categories emerged: "respecting the woman's wishes: humanizing the birth process", "information and primary Care", "expectations regarding the care received" and "results of using the birth plan", with their corresponding subcategories., Conclusion: Women consider it beneficial to present a Birth Plan, because it informs them about the process and gives them the opportunity to have a better experience, which takes into account their preferences for making the delivery less instrumental. In addition, they state the importance of having trained professionals involved, and call for more attention to be paid to the birth process in general.

Purpose: Age, sex, and type of fracture have traditionally been described as prognostic factors for proximal humeral fractures (PHFs). Some non-medical patient-related factors may play a role in the outcome. This paper evaluates the association of comorbidities and socioeconomic factors with clinical outcomes for PHF., Methods: A total of 217 patients with PHF were evaluated according to Neer's classification with X-ray. Comorbidities were assessed through the Charlson comorbidity index and, non-medical patient-related factors were determined with a 52-item questionnaire concerning personal behaviors such as social activities, family support, economic solvency, and leisure-time activities. The clinical outcome was assessed with the Constant-Murley Score (CMS), with a minimum 1-year follow-up. The minimal clinically relevant difference for the CMS was set at 10 points. A multivariable analysis was performed to adjust for comorbidities and non-medical patient-related factors, such as age, sex, fracture classification, and treatment., Results: One hundred and eighty-three patients completed the initial research protocol, while 126 of them completed the 1-year follow-up. The mean age was 71.6 years (SD ± 13.3), and 79.3% of the patients were women. In the bivariable analysis, age and comorbidities were correlated with the CMS (correlation coefficient: - 0.34 [- 0.49, 0.17] and 0.35 [0.18, 0.50], respectively), as well as non-medical patient-related factors and the fracture pattern (p value ANOVA < 0.001). In the multivariable regression model, the effects of considering oneself socially active, without economic problems, and self-sufficient were associated with a higher CMS than the effect of the fracture pattern (beta coefficient: 11.69 [6.09-17.30], 15.54 [8.32-22.75], and 10.61 [3.34-17.88], respectively)., Conclusion: Socioeconomic status had a higher impact on functional outcomes than fracture pattern in patients with PHF., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Clinical practice suggests that rheumatic heart disease (RHD) represents a significant public health challenge in the Caribbean region where advanced disease appears early often leading to surgical intervention. We aimed to determine the burden of RHD and type of procedure among patients undergoing valve surgery in the Dominican Republic (DR)., Methods: Demographic, clinical and procedural data of all subjects intervened between January 2014 and December 2018 were obtained including valve disorder, anatomic location and type of surgery. Correlation coefficients were used to assess yearly trends of RHD among the 7 cardiovascular surgical centers in the country., Results: Of 1626 valvular surgeries performed, 733 (45%) corresponded to RHD; 55% female patients, age 50 ± 11 (6-72) years; involving mitral 458 (63%); mitral + aortic 139 (19%); aortic 105 (14%); mitral + tricuspid 31 (4%); 95% prosthetic replacement and 5% mitral/tricuspid repairs. Mean proportion of RHD valve procedures per center for the study period was 53 ± 34%. Age-adjusted analysis showed an overall upwards trend in RHD valvular surgery (mean annual increment of 50 ± 40%, P = 0.01)., Conclusions: Despite inter-center variability, rates of surgical RHD in the DR increased during the last 5 years affecting a relatively young population. Mitral involvement was the predominant lesion and prosthetic replacement the leading procedure. These data may guide local and regional institutions and policy makers towards the implementation of cost-effective initiatives against RHD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been recently reported that rats' optimal behavior in the "suboptimal choice" procedure is eliminated when the duration of the terminal links is increased to 30 s or more (Cunningham & Shahan, 2019). The main goal of the present study is to analyze the generality of such results, via a procedure that has been extensively used in the study of rats' performance in this task. In Experiment 1, nine rats were exposed to a procedure that presented levers as discriminative stimuli, varying the duration of their presentation from 10 s to 50 s across conditions. The results showed that rats preferred the optimal alternative in all conditions. To further analyze the relationship between rats' preferences and the duration of the terminal links, in Experiment 2 we contrasted the performance of two groups that differed in the configuration of the stimuli associated to the terminal links. For one of them, the stimuli were the same as in the Cunningham and Shahan's (2019) experiment (Tone + Light); for the other, the stimulus was light only. The results show that rats were suboptimal in the former group, and optimal in the latter. We discuss our results in terms of the prevalence of rats' optimal behavior when confronted with the manipulation of different variables and the necessity of improving the knowledge about the relationship between optimal/suboptimal choice and the salience of the discriminative stimuli. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors., Objective: Starting from our previous observations that PP2A (protein phosphatase 2) regulates the HIF (hypoxia-inducible factor)/PHD-2 (prolyl hydroxylase 2)-constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion, and oxygen restoration., Methods and Results: We show that the PP2A regulatory subunit B55α is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55α counter cell stress conditions and thrive for stabilization and maturation. When B55α is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55α/PP2A complex restrains PHD-2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55α deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55α-deficient vessels., Conclusions: Our data underline a unique role of the B55α/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent antiangiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF-R (vascular endothelial growth factor receptor)-targeted therapies. Graphical Abstract: A graphical abstract is available for this article.

In the suboptimal choice procedure, pigeons systematically choose an alternative associated with stimuli that indicate the presence or absence of a reward and with a smaller probability of reinforcement, over another option associated with noninformative stimuli, and a higher probability of reinforcement. In contrast, rats generally show the opposite preference. A recent hypothesis for explaining this difference suggests that both species would prefer the discriminative alternative in situations in which the stimuli have incentive salience. However, this hypothesis has not been confirmed in rats. The null relationship between incentive salience and performance in the suboptimal choice procedure stands in contrast to the strong influence that incentive salience has been shown to have in other choice protocols. A possible explanation for this difference is that in the suboptimal choice procedure, the incentive salience is normally shared by both alternatives and subjects attribute the same incentive salience to them. To analyze this possibility, we presented an asymmetrical arrangement of the incentive salience between the discriminative and the non-discriminative alternatives in order to evaluate its impact on suboptimal choice. We also examined whether rats classified as sign-trackers are more influenced by this asymmetrical arrangement. The results showed that the alternative with higher incentive salience attracted more preference and that this effect was stronger for sign-tracking subjects. These results suggest a strong relationship between preference in the suboptimal choice procedure and the incentive salience attributed to the different alternatives., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: To determine the safety and clinical benefit of therapeutic plasma exchange (TPE) as rescue therapy in children with acute inflammatory demyelinating CNS syndromes and to identify baseline prognostic indicators of treatment improvement., Methods: This single-center retrospective pediatric cohort included all consecutive patients admitted to our hospital over the period from 2003 to 2017 because of a steroid-refractory acute CNS event presumed to be inflammatory who required TPE. Functional status assessment to identify improvement included the following performance category scales: visual outcome, bladder control, gait, and Expanded Disability Status Scale (EDSS). These assessments were performed before and after TPE in every patient., Results: Sixty-five children requiring TPE to treat 78 CNS attacks were included for analysis. Median age at TPE was 10.5 years (1.9-18 years); 45% were girls. Seropositivity (aquaporin-4 water channel-immunoglobulin G [IgG] or myelin oligodendrocyte glycoprotein-IgG) was found in 20 of 42 (48%) patients. Attack phenotypes leading to TPE were optic neuritis (ON) in 42%, longitudinally extensive transverse myelitis (LETM) in 31%, ON + LETM in 15%, and other combined syndromes in 11%. Overall, moderate to marked neurologic improvement was observed in 72% of children at the end of TPE and in 88.5% at 6 months of follow-up. Lower baseline scores on the EDSS, visual outcome, and gait scales were found to be independent prognostic indicators of treatment benefit. Sex, age at onset and at TPE, attack phenotype, disease duration, and time from attack onset to TPE initiation were not significantly associated with treatment outcome. Adverse events were observed in 31 of 524 (5.9%) procedures, being severe in 4., Conclusions: TPE was an effective rescue therapy associated with functional improvement. No therapeutic window for TPE initiation was identified in this pediatric cohort. Overall frequency of adverse events was low; however, serious events should be anticipated and avoided., Classification of Evidence: This study provides Class IV evidence that for children with acute inflammatory demyelinating CNS syndromes, TPE leads to functional improvement., (© 2019 American Academy of Neurology.)

Background: Up to 30-40% of Ewing sarcoma (EwS) patients with non-metastatic disease develop local or metastatic relapse within a time span of 2-10 years. This is in part caused by the absence of prognostic biomarkers that can identify high-risk patients and thus assign them to risk-adapted monitoring and treatment regimens. Since cancer stemness has been associated with tumour relapse and poor patient outcomes, we investigated in the current study the prognostic potential SOX2 (sex determining region Y box 2) - a major transcription factor involved in development and stemness - which was previously described to contribute to the undifferentiated phenotype of EwS., Methods: Two independent patient cohorts, one consisting of 189 retrospectively collected EwS tumours with corresponding mRNA expression data (test-cohort) and the other consisting of 141 prospectively collected formalin-fixed and paraffin-embedded resected tumours (validation and cohort), were employed to analyse SOX2 expression levels through DNA microarrays or immunohistochemistry, respectively, and to compare them with clinical parameters and patient outcomes. Two methods were employed to test the validity of the results at both the mRNA and protein levels., Findings: Both cohorts showed that only a subset of EwS patients (16-20%) expressed high SOX2 mRNA or protein levels, which significantly correlated with poor overall survival. Multivariate analyses of our validation-cohort revealed that high SOX2 expression represents a major risk-factor for poor survival (HR = 3·19; 95%CI 1·74-5·84; p < 0·01) that is independent from metastasis and other known clinical risk-factors at the time of diagnosis. Univariate analyses demonstrated that SOX2-high expression was correlated with tumour relapse (p = 0·002). The median first relapse was at 14·7 months (range: 3·5-180·7)., Interpretation: High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcomes. This may help to identify patients with localised disease who are at high risk for tumour relapse within the first two years after diagnosis., Funding: The laboratory of T. G. P. Grünewald is supported by grants from the 'Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)', by LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the 'Mehr LEBEN für krebskranke Kinder - Bettina-Bräu-Stiftung', the Walter Schulz Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Friedrich-Baur foundation, the Matthias-Lackas foundation, the Barbara & Hubertus Trettner foundation, the Dr. Leopold & Carmen Ellinger foundation, the Gert & Susanna Mayer foundation, the Deutsche Forschungsgemeinschaft (DFG 391665916), and by the German Cancer Aid (DKH-111886 and DKH-70112257). J. Li was supported by a scholarship of the China Scholarship Council (CSC), J. Musa was supported by a scholarship of the Kind-Philipp foundation, and T. L. B. Hölting by a scholarship of the German Cancer Aid. M. F. Orth and M. M. L. Knott were supported by scholarships of the German National Academic Foundation. G. Sannino was supported by a scholarship from the Fritz-Thyssen Foundation (FTF-40.15.0.030MN). The work of U. Dirksen is supported by grants from the German Cancer Aid (DKH-108128, DKH-70112018, and DKH-70113419), the ERA-Net-TRANSCAN consortium (project number 01KT1310), and Euro Ewing Consortium (EEC, project number EU-FP7 602,856), both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/), the Barbara & Hubertus Trettner foundation, and the Gert & Susanna Mayer foundation. G. Hardiman was supported by grants from the National Science Foundation (SC EPSCoR) and National Institutes of Health (U01-DA045300). The laboratory of J. Alonso was supported by Instituto de Salud Carlos III (PI12/00816; PI16CIII/00026); Asociación Pablo Ugarte (TPY-M 1149/13; TRPV 205/18), ASION (TVP 141/17), Fundación Sonrisa de Alex & Todos somos Iván (TVP 1324/15)., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Among the different procedures that model gambling behavior in non-human animals, the "suboptimal choice procedure" has been extensively employed for analyzing the impact of environmental cues on choice behavior. It has been repeatedly demonstrated that pigeons prefer an alternative that infrequently presents a stimulus that signals a larger amount of reinforcement, than another alternative that always presents a stimulus associated with a smaller amount of reinforcement, even though the net rate of reinforcement is lower in the former. In the present study, we tested rats in the magnitude version of the suboptimal choice procedure. Eight rats were given a choice between two alternatives: a) one in which a stimulus predicting the delivery of ten pellets was presented with probability (p) = 0.2 and a stimulus predicting zero pellets was presented with p = 0.8, and b) one in which either of two stimuli predicted the delivery of three pellets with p = 1.0. Contrary to the consistent and robust suboptimal behavior of pigeons, rats preferred the optimal alternative. This effect occurred despite the high index of discrimination of the stimuli associated with the different outcomes shown by the rats. The relevance of this result to the development of animal models of gambling behavior is discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Soft-tissue sarcomas are rare, heterogeneous, and often aggressive mesenchymal cancers. Many of them are associated with poor outcome, partially because biomarkers that can identify high-risk patients are lacking. Studies on sarcomas are often limited by small sample-sizes rendering the identification of biomarkers difficult when focusing on individual cohorts. However, the increasing number of publicly available 'omics' data opens inroads to overcome this obstacle. Here, we combine transcriptome analyses, immunohistochemistry, and functional assays to show that high adenosine monophosphate deaminase 2 (AMPD2) is a robust prognostic biomarker for worse outcome in undifferentiated pleomorphic sarcoma (UPS). Gene expression and survival data for UPS from two independent studies were subjected to survival association-testing. Genes, whose high expression was significantly correlated with worse outcome in both cohorts, were considered as biomarker candidates. The best candidate, AMPD2, was validated in a tissue microarray. Analysis of DNA copy-number data and matched transcriptomes indicated that high AMPD2 expression is significantly correlated with gains at the AMPD2 locus. Gene set enrichment analyses of AMPD2 co-expressed genes in both transcriptome datasets suggested that AMPD2-high UPS are enriched in tumorigenic signatures. Consistently, knockdown of AMPD2 by RNA interference in an UPS cell line inhibited proliferation in vitro and tumorigenicity in vivo. Collectively, we provide evidence that AMPD2 may serve as a biomarker for outcome prediction in UPS. Our study exemplifies how the integration of 'omics' data, immunohistochemistry, and functional experiments can identify novel biomarkers even in a rare sarcoma, which may serve as a blueprint for biomarker identification for other rare cancers., (© 2018 UICC.)

Ewing sarcoma (EwS) is an aggressive cancer characterized by chromosomal translocations generating fusions of the EWSR1 gene with ETS transcription factors (in 85% FLI1). EWSR1-FLI1 induces gene expression via binding to enhancer-like GGAA-microsatellites, whose activity correlates with the number of consecutive GGAA-repeats. Herein we investigate the role of the secretory neuropeptide CALCB (calcitonin-related polypeptide β) in EwS, which signals via the CGRP (calcitonin gene-related peptide) receptor complex, containing RAMP1 (receptor activity modifying protein 1) as crucial part for receptor specificity. Analysis of 2678 gene expression microarrays comprising 50 tumor entities and 71 normal tissue types revealed that CALCB is specifically and highly overexpressed in EwS. Time-course knockdown experiments showed that CALCB expression is tightly linked to that of EWSR1-FLI1. Consistently, gene set enrichment analyses of genes whose expression in primary EwS is correlated to that of CALCB indicated that it is co-expressed with other EWSR1-FLI1 target genes and associated with signatures involved in stemness and proliferation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data for FLI1 and histone marks from EwS cell lines demonstrated that EWSR1-FLI1 binds to a GGAA-microsatellite close to CALCB, which exhibits characteristics of an active enhancer. Reporter assays confirmed the strong EWSR1-FLI1- and length-dependent enhancer activity of this GGAA-microsatellite. Mass spectrometric analyses of EwS cell culture supernatants demonstrated that CALCB is secreted by EwS cells. While short-term RNA interference-mediated CALCB knockdown had no effect on proliferation and clonogenic growth of EwS cells in vitro, its long-term knockdown decreased EwS growth in vitro and in vivo. Similarly, knockdown of RAMP1 reduced clonogenic/spheroidal growth and tumorigenicity, and small-molecule inhibitors directed against the RAMP1-comprising CGRP receptor reduced growth of EwS. Collectively, our findings suggest that CALCB is a direct EWSR1-FLI1 target and that targeting the CALCB/RAMP1 axis may offer a new therapeutic strategy for inhibition of EwS growth.

Previous research has shown that pigeons and other birds display a strong and consistent preference for an alternative of reinforcement that presents stimuli that allow to discriminate whether a reinforcer will be delivered or not, even when its probability of reinforcement is lower than that of another alternative without those stimuli. In contrast, most of the studies performed with rats report that they show the opposite preference, choosing the alternative with higher probability of reinforcement. To explain these opposite preferences, it has been proposed that rats and pigeons have a differential sensitivity to the conditioned inhibition that emerges from the stimulus that predicts non-reinforcement: While it does not have an impact in pigeons, it strongly influences rats´ preferences. Alternatively, it was recently proposed that there is not a fundamental difference in the behavior of rats and pigeons, but that the procedure employed to evaluate each of these species has generated the difference; in particular, it was proposed that both species prefer the discriminative alternative when the discriminative stimuli have incentive salience. Two recent studies provide support for each of these hypotheses, so that the available evidence does not allow to distinguish between them. In the present report, we present three studies that systematically explore the influence of the procedural differences between the studies with discrepant results. The obtained results provide support for the following ideas: a) there is a fundamental difference between pigeons and rats in their choice behavior in the "suboptimal choice procedure", b) considering the incentive salience of the discriminative stimuli does not resolve it, and c) rats' optimality is a consistent phenomenon, which resists manipulations in reinforcement probabilities and the absence of conditioned inhibitors in the discriminative alternative., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Previous research has shown great variation in the extent to which individual rats attribute incentive salience to stimuli that are predictors of reinforcement. When using the Pavlovian Conditioned Approach procedure, in which a discrete stimulus is presented contingently before the delivery of reinforcement, the attribution of incentive salience is demonstrated by sign-tracking behavior (responses directed toward the stimulus predictor of reinforcement), while an absence of this attribution is reflected by goal-tracking behavior (responses directed toward the source of reinforcement). It has been reported that sign-tracking subjects have a higher tendency to perform some maladaptive behaviors than goal-tracking subjects, and that in non-classified rats, increasing the incentive salience of the stimuli promotes suboptimal choice in the "suboptimal choice procedure". In this task, subjects are presented with two alternatives, one of them better in terms of the information provided by the discriminative stimuli, but worse in terms of probability of reinforcement (suboptimal alternative). Integrating these ideas, we hypothesized that sign-trackers would behave suboptimally, in contrast to goal-trackers. In the present study, 45 rats were classified according to their performance in the Pavlovian Conditioned Approach procedure and subjects with extreme values (sign-trackers, and goal-trackers) were evaluated in the suboptimal choice procedure. Both groups were found to behave optimally, with no differences between them. The difference between groups in capacity of attribution of incentive salience was preserved during the entire experiment, suggesting that this variable is not related to choice performance in the suboptimal choice procedure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main large vessel vasculitides. They share some similarities regarding their clinical, radiological and histological presentations but some pathogenic processes in GCA and TAK are activated differently, thus explaining their different sensitivity to biological therapies. The treatment of GCA and TAK essentially relies on glucocorticoids. However, thanks to major progress in our understanding of their pathogenesis, the role of biological therapies in the treatment of these two vasculitides is expanding, especially in relapsing or refractory diseases. In this review, the efficacy, the safety and the limits of the main biological therapies ever tested in GCA and TAK are discussed. Briefly, anti TNF-α agents appear to be effective in treating TAK but not GCA. Recent randomized placebo-controlled trials have reported on the efficacy and safety of abatacept and mostly tocilizumab in inducing and maintaining remission of GCA. Abatacept was not effective in TAK and robust data are still lacking to draw any conclusions concerning the use of tocilizumab in TAK. Furthermore, ustekinumab appears promising in relapsing/refractory GCA whereas rituximab has been reported to be effective in only a few cases of refractory TAK patients. If a biological therapy is indicated, and in light of the data discussed in this review, the first choice would be tocilizumab in GCA and anti-TNF-α agents (mainly infliximab) in TAK., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

This work is a review on the basic aspects of the treatment of Helicobacter pylori, highlighting the causes of treatment failure and strategies exist to optimize the treatment according to the best evidence posted. Stands out the antimicrobial resistance as the main cause of treatment failure, as well as the different compartments where the microorganism is hosted. Shows major schemes currently available and how to choose therapies first, second, third line and rescue therapies.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disease in which diverse autoantibodies have been described but systematic screening has never been performed. Detection of CIDP-specific antibodies may be clinically useful. We developed a screening protocol to uncover novel reactivities in CIDP. Sixty-five CIDP patients and 28 controls were included in our study. Three patients (4.6%) had antibodies against neurofascin 155, four (6.2%) against contactin-1 and one (1.5%) against the contactin-1/contactin-associated protein-1 complex. Eleven (18.6%) patients showed anti-ganglioside antibodies, and one (1.6%) antibodies against peripheral myelin protein 2. No antibodies against myelin protein zero, contactin-2/contactin-associated protein-2 complex, neuronal cell adhesion molecule, gliomedin or the voltage-gated sodium channel were detected. In IgG experiments, three patients (5.3%) showed a weak reactivity against motor neurons; 14 (24.6%) reacted against DRG neurons, four of them strongly (7.0%), and seven (12.3%) reacted against Schwann cells, three of them strongly (5.3%). In IgM experiments, six patients (10.7%) reacted against DRG neurons, while three (5.4%) reacted against Schwann cells. However, results were not statistically significant when compared to controls. Immunoprecipitation experiments identified CD9 and L1CAM as potential antigens, but reactivity could not be confirmed with cell-based assays. In summary, we describe a diverse autoantibody repertoire in CIDP patients, reinforcing the hypothesis of CIDP's pathophysiological heterogeneity.

Previous research has identified clear differences between pigeons and rats in the suboptimal choice procedure. Pigeons behave suboptimally, preferring an alternative with discriminative stimuli and a smaller probability of reinforcement, over another with a higher probability of reinforcement, but without discriminative stimuli. In contrast, rats behave optimally showing the opposite preference. It has been proposed that these dissimilarities are consequence of a higher sensitivity to conditioned inhibition in rats than in pigeons. Alternatively, recent research suggests that differences in optimality can be accounted for by a differential incentive salience of the stimuli employed as discriminative stimuli, and that both species are suboptimal when such stimuli have high incentive salience; specifically, rats were found to be suboptimal when levers were used as discriminative stimuli. However, in the evaluation of this hypothesis, a conditioned inhibitor was not employed. In the present report, eight rats were exposed to a choice procedure that integrated both variables discussed above: a conditioned inhibitor was associated with the discriminative alternative and the stimuli had high incentive salience. A clear preference for the optimal alternative was found, suggesting that the conditioned inhibitor had a considerable impact on rats' preference, and that species-differences remain even in procedures in which the discriminative stimuli have incentive salience., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: To study the early postoperative intensive care unit (ICU) management and complications in the first 2 wk of patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: Our study is a retrospective, observational study performed at Icahn School of Medicine at Mount Sinai, quaternary care hospital in New York City. All adult patients who underwent CRS and HIPEC between January 1, 2007 and December 31, 2012 and admitted to ICU postoperatively were studied. Fifty-one patients came to the ICU postoperatively out of 170 who underwent CRS and HIPEC therapy during the study period. Data analysis was performed using descriptive statistics., Results: Of the 170 patients who underwent CRS and HIPEC therapy, 51 (30%) came to the ICU postoperatively. Mean ICU length of stay was 4 d (range 1-60 d) and mean APACHE II score was 15 (range 7-23). Thirty-one/fifty-one (62%) patients developed postoperative complications. Aggressive intraoperative and postoperative fluid resuscitation is required in most patients. Hypovolemia was seen in all patients and median amount of fluids required in the first 48 h was 6 L (range 1-14 L). Thirteen patients (25%) developed postoperative hypotension with seven requiring vasopressor support. The major cause of sepsis was intraabdominal, with 8 (15%) developing anastomotic leaks and 5 (10%) developing intraabdominal abscess. The median survival was 14 mo with 30 d mortality of 4% (2/51) and 90 d mortality of 16% (8/51). One year survival was 56.4% (28/51). Preoperative medical co morbidities, extent of surgical debulking, intraoperative blood losses, amount of intra op blood products required and total operative time are the factors to be considered while deciding ICU vs non ICU admission., Conclusion: Overall, ICU outcomes of this study population are excellent. Triage of these patients should consider preoperative and intraoperative factors. Intensivists should be vigilant to aggressive postop fluid resuscitation, pain control and early detection and management of surgical complications., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose.

Background : Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A*02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8 + ) T cells against ES. Patients and Methods : Three refractory HLA-A2 + ES patients were treated with HLA-A*02:01/peptide-specific allorepertoire-derived (i.e., allorestricted) CD8 + T cells. Patient #1 received up to 4.8 × 10 5 /kg body weight HLA-A*02:01 - allorestricted donor-derived wild-type CD8 + T cells. Patient #2 received up to 8.2 × 10 6 /kg HLA-A*02:01 - donor-derived and patient #3 up to 6 × 10 6 /kg autologous allorestricted TCR transgenic CD8 + T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1 319 ). Results : HLA-A*02:01/CHM1 319 -specific allorestricted CD8 + T cells showed specific in vitro lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1 319 TCR transgenic T cells could be tracked in his BM for weeks. Conclusions : CHM1 319 -TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A*02:01/antigen-specific allorestricted T cells proliferate in vivo without causing GvHD.

Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin-like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e., IGF binding proteins (IGFBPs), thereby setting free IGFs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA is associated with various cancers. It is overexpressed and required for proliferation in ES. PAPPA also stimulates normal bone growth. We isolated HLA-A*02:01 + /peptide-restricted T cells from A*02:01 - healthy donors directed against PAPPA, generated by priming with A*02:01 + PAPPA peptide loaded dendritic cells. After TCR identification, retrovirally TCR transduced CD8 + T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2 -/- γc -/- mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity toward HLA-A*02:01 + /PAPPA + ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2 -/- γc -/- mice and in vivo engraftment in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells in contrast to controls. Tumors of treated mice revealed tumor-infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a first-rate target for TCR-based immunotherapy of ES.

Introduction: The increasing prevalence of obesity or overweight at all ages, their associated morbidity and mortality associated, and the increased perception of the problem by the society have generated several hypotheses in response to the scientific and the international community., Objective: Investigate the preventive interventions in childhood obesity so far., Methods: Integrative review during the study period from April 2013 to November 2014. The MEDLINE international database was used, including PubMed, the Cochrane Library (Issue 4 2002), the national database Isooc (CSIC) national database, as well as the Internet. The review included health articles published in Spanish and English between 1990 and 2014 that focused on or included education, prevention, diagnostic, and treatment of obesity interventions., Results: Of the 726 articles identified, 34 of most relevant (peer reviewed) were selected. It was noted that there is limited generisable evidence on interventions that could be implemented in Primary Care or referral services available, although numerous studies suggest that improvements in the overweight are possible., Conclusions: Despite the abundant literature and that many institutions place childhood obesity as one of the priorities of Public Health, we face the paradox that the evidence on cost-effectiveness of prevention interventions is sparse. Knowing these gaps in knowledge should lead to filling them with rigorous and well-designed studies., (Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Recent studies have generated interest in the function of human adenovirus serotype 5 (HAdV-5) hexon:  factor X (FX) binding and subsequent hepatocyte transduction and interaction with the immune system. Here, we retargeted adenovirus serotype 5 vectors, ablated for FX interaction, by replacing amino acids in hexon HVR7 with RGD-4C or inserting the peptide into the fibre HI loop. These genetic modifications in the capsid were compatible with virus assembly, and could efficiently retarget transduction of the vector via the αvβ3/5 integrin-mediated pathway, but did not alter immune recognition by pre-existing human neutralizing anti-HAdV-5 antibodies or by natural antibodies in mouse serum. Thus, FX-binding-ablated HAdV-5 can be retargeted but remain sensitive to immune-mediated attack. These findings further refine HAdV-5-based vectors for human gene therapy and inform future vector development.

Unlabelled: Adenovirus is one of the most complex icosahedral, nonenveloped viruses. Even after its structure was solved at near-atomic resolution by both cryo-electron microscopy and X-ray crystallography, the location of minor coat proteins is still a subject of debate. The elaborated capsid architecture is the product of a correspondingly complex assembly process, about which many aspects remain unknown. Genome encapsidation involves the concerted action of five virus proteins, and proteolytic processing by the virus protease is needed to prime the virion for sequential uncoating. Protein L1 52/55k is required for packaging, and multiple cleavages by the maturation protease facilitate its release from the nascent virion. Light-density particles are routinely produced in adenovirus infections and are thought to represent assembly intermediates. Here, we present the molecular and structural characterization of two different types of human adenovirus light particles produced by a mutant with delayed packaging. We show that these particles lack core polypeptide V but do not lack the density corresponding to this protein in the X-ray structure, thereby adding support to the adenovirus cryo-electron microscopy model. The two types of light particles present different degrees of proteolytic processing. Their structures provide the first glimpse of the organization of L1 52/55k protein inside the capsid shell and of how this organization changes upon partial maturation. Immature, full-length L1 52/55k is poised beneath the vertices to engage the virus genome. Upon proteolytic processing, L1 52/55k disengages from the capsid shell, facilitating genome release during uncoating., Importance: Adenoviruses have been extensively characterized as experimental systems in molecular biology, as human pathogens, and as therapeutic vectors. However, a clear picture of many aspects of their basic biology is still lacking. Two of these aspects are the location of minor coat proteins in the capsid and the molecular details of capsid assembly. Here, we provide evidence supporting one of the two current models for capsid architecture. We also show for the first time the location of the packaging protein L1 52/55k in particles lacking the virus genome and how this location changes during maturation. Our results contribute to clarifying standing questions in adenovirus capsid architecture and provide new details on the role of L1 52/55k protein in assembly., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Chikungunya infection is a febrile illness, which currently is afflicting the Caribbean islands including the Dominican Republic. We would like to report our experience with Chikungunya-related musculoskeletal manifestations in our arthritis clinics in the Dominican Republic. A total of 514 patients presented for the first time to our arthritis clinic exhibiting musculoskeletal manifestations, 473/514 (92%) exhibiting symmetric polyarthralgias, 344/514 (67%) arthritis, and 385 (75%) skin rash. The great majority 457.46 (89%) exhibited very good clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs), 370 (72%) require low-dose steroids, and only 5 patients (0.97%) required methotrexate therapy. In addition, of a total of 328 patients with rheumatoid arthritis on biological treatment, 53 exhibited Chikungunya-related musculoskeletal manifestations; 51/53 (96.2%) exhibited symmetric polyarthralgias, 25/53 (47.1%) arthritis, and 13/53 (24.5%) tendinopathy. Of most patients, 51/53 responded to NSAIDs, of which, 23 patients only responded partially, and in total 25 (47.1%) required low-dose steroids. Disease-modifying antirheumatic drug (DMARD) therapy including biologics remained unchanged in this population.

Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.

Aims: This study aims to describe the information needs of urological and breast cancer patients and factors related to use of the Internet as a source of health information., Methodology: A cross-sectional descriptive study was carried out, using individual questionnaire-based interviews held during the oncology appointments of 169 patients with urological cancer and 100 with breast cancer at the Virgen de las Nieves University Hospital in Granada, Spain. The variables studied were use of the Internet as a source of health information, health status, patient's role in the decision-making process, information sources, satisfaction with the health-care system, type of information received, and Internet use. A multivariate logistic regression analysis was carried out., Results: Breast cancer patients are more concerned with long-term results and the effects on their family and personal life. They are also interested in the experiences of other patients and support groups or staff who could help them to cope with their illness. The information needs of patients with urological cancer are linked to short-term alternative treatments, their sex life, keeping healthy, and exercise. More clinical aspects, such as tests and experiments linked to their treatment, are not a frequent information need. The factors linked to use of the Internet as a source of health information are younger age, high level of education, the patient's active role in the decision-making process, and undergoing more aggressive treatment. There is no link between using the Internet as a source of health information and level of satisfaction with the health-care system, or with Internet use in general., Conclusion: Patients need additional information about their illness on top of that given to them by health-care staff, and they often use the Internet to find it. The greatest information need is related to the effects of their illness on their day-to-day life. Health-care staff should provide patients with advice about reliable websites and how to search the Internet.

Adenoviral vectors hold immense potential for a wide variety of gene therapy based applications; however, their efficacy and toxicity is dictated by "off target" interactions that preclude cell specific targeting to sites of disease. A number of "off target" interactions have been described in the literature that occur between the three major capsid proteins (hexon, penton, and fiber) and components of the circulatory system, including cells such as erythrocytes, white blood cells, and platelets, as well as circulatory proteins including complement proteins, coagulation factors, von Willebrand Factor, p-selectin as well as neutralizing antibodies. Thus, to improve efficacious targeting to sites of disease and limit nonspecific uptake of virus to non-target tissues, specifically the liver and the spleen, it is necessary to develop suitable strategies for genetically modifying the capsid proteins to preclude these interactions. To this end we have developed versatile systems based on homologous recombination for modification of each of the major capsid proteins, which are described herein.

Two studies summarize the development and initial validation of the Multicultural Personality Inventory (MPI). In Study 1, the 115-item prototype MPI was administered to 415 university students where exploratory factor analysis resulted in a 70-item, 7-factor model. In Study 2, the 70-item MPI and theoretically related companion instruments were administered to a multisite sample of 576 university students. Confirmatory factory analysis found the 7-factor structure to be a relatively good fit to the data (Comparative Fit Index =.954; root mean square error of approximation =.057), and MPI factors predicted variance in criterion variables above and beyond the variance accounted for by broad personality traits (i.e., Big Five). Study limitations and directions for further validation research are specified.

We investigate the difference that immigrant enclaves make for the residential contexts of Latino families in the U.S. We argue that enclaves may no longer function simply as temporary way stations, the classic depiction of them, because of the compromised legal status of many Latinos. We examine this role with an innovative method that uses publicly available census tabulations (from the 2000 Census in our case) to develop HLM models, in which race/ethnicity and income are controlled at the family level, along with neighbourhood context and metropolitan characteristics. Comparing Latino residential patterns to those of whites and blacks reveals the large neighbourhood disadvantages of Latinos, which except for greater exposure to whites are on the order of those suffered by African Americans. We find that Hispanic families improve their residential situations as their incomes go up and usually also when they live in suburbs. But residence outside of immigrant enclaves produces the largest positive changes. The enclaves are a fundamentally different kind of residential space, in which the potential for neighbourhood improvement is modest.

Background: People who use the Internet to research health topics do not usually find all the information they need and do not trust what they read. This study was designed to assess the reliability, accessibility, readability, and popularity of cancer Web sites in Spanish and to analyze the suitability of Web site content in accordance with the specific information needs of cancer patients., Materials and Methods: This was a two-phase, cross-sectional, descriptive study. The first phase involved data gathering through online searches and direct observation. The second phase involved individual structured interviews with 169 patients with breast, prostate, bladder, and kidney cancer. Spearman rank correlations were calculated between variables., Results: Most sites belonged to nonprofit organizations, followed by universities or medical centers (14%). Thirty-one percent of the Web sites had quality seals, 59% provided details of authorship, 62% provided references to bibliographic sources, 38% identified their funding sources, and 54% showed the date of their last update. Twenty-one percent of the Web sites did not meet the minimum accessibility criteria. With regard to readability, 24% of the texts were considered to be "quite difficult." Patients' information needs vary depending on the type of cancer they have, although all patients want to know about the likelihood of a cure, survival rates, the side effects, and risks of treatment., Conclusions: The health information on cancer available on the Internet in Spanish is not very reliable, accessible, or readable and is not necessarily the information that breast, kidney, prostate, and bladder cancer patients require. The content of cancer Web sites needs to be assessed according to the information needs of patients.

Background: It is during embryogenesis that the plant body plan is established and the meristems responsible for all post-embryonic growth are specified. The molecular mechanisms governing conifer embryogenesis are still largely unknown. Their elucidation may contribute valuable information to clarify if the distinct features of embryo development in angiosperms and gymnosperms result from differential gene regulation. To address this issue, we have performed the first transcriptomic analysis of zygotic embryo development in a conifer species (Pinus pinaster) focusing our study in particular on regulatory genes playing important roles during plant embryo development, namely epigenetic regulators and transcription factors., Results: Microarray analysis of P. pinaster zygotic embryogenesis was performed at five periods of embryo development from early developing to mature embryos. Our results show that most changes in transcript levels occurred in the first and the last embryo stage-to-stage transitions, namely early to pre-cotyledonary embryo and cotyledonary to mature embryo. An analysis of functional categories for genes that were differentially expressed through embryogenesis highlighted several epigenetic regulation mechanisms. While putative orthologs of transcripts associated with mechanisms that target transposable elements and repetitive sequences were strongly expressed in early embryogenesis, PRC2-mediated repression of genes seemed more relevant during late embryogenesis. On the other hand, functions related to sRNA pathways appeared differentially regulated across all stages of embryo development with a prevalence of miRNA functions in mid to late embryogenesis. Identification of putative transcription factor genes differentially regulated between consecutive embryo stages was strongly suggestive of the relevance of auxin responses and regulation of auxin carriers during early embryogenesis. Such responses could be involved in establishing embryo patterning. Later in development, transcripts with homology to genes acting on modulation of auxin flow and determination of adaxial-abaxial polarity were up-regulated, as were putative orthologs of genes required for meristem formation and function as well as establishment of organ boundaries. Comparative analysis with A. thaliana embryogenesis also highlighted genes involved in auxin-mediated responses, as well as epigenetic regulation, indicating highly correlated transcript profiles between the two species., Conclusions: This is the first report of a time-course transcriptomic analysis of zygotic embryogenesis in a conifer. Taken together our results show that epigenetic regulation and transcriptional control related to auxin transport and response are critical during early to mid stages of pine embryogenesis and that important events during embryogenesis seem to be coordinated by putative orthologs of major developmental regulators in angiosperms.

Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression., Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3)., Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies., Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.

This exploratory study has two aims: (1) to find out if and how social media (SM) applications are used by hospitals in Spain and (2) to assess hospital managers' perception of these applications in terms of their evaluation of them, reasons for use, success factors, and difficulties encountered during their implementation. A cross-sectional survey has been carried out using Spanish hospitals as the unit of analysis. Geographical differences in the use of SM were found. Social networks are used most often by larger hospitals (30% by medium-size, 28% by large-size). They are also more frequently used by public hospitals (19%, p<0.01) than by private ones. Respondents with a negative perception of SM felt that there is a chance they may be abused by healthcare professionals, whereas those with a positive perception believed that they can be used to improve communication both within and outside the hospital. Reasons for the use of SM include the idea of maximizing exposure of the hospital. The results show that Spanish hospitals are only just beginning to use SM applications and that hospital type can influence their use. The perceptions, reasons for use, success factors, and difficulties encountered during the implementation of SM mean that it is very important for healthcare professionals to use SM correctly and adequately.

The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the capsid hexon protein and blood coagulation factor X (FX), whilst penton-α(v)integrin interactions are thought to contribute to the induction of anti-Ad5 inflammatory and innate immune responses. To overcome these limitations, we sought to develop and characterise for the first time novel Ad5 vectors possessing mutations ablating both hexon:FX and penton:integrin interactions. As expected, intravascular administration of the FX binding-ablated Ad5HVR5*HVR7*E451Q vector (AdT*) resulted in significantly reduced liver transduction in vivo compared to Ad5. In macrophage-depleted mice, increased spleen uptake of AdT* was accompanied by an elevation in the levels of several inflammatory mediators. However ablation of the penton RGD motif in the AdT* vector background (AdT*RGE) resulted in a significant 5-fold reduction in spleen uptake and attenuated the antiviral inflammatory response. A reduction in spleen uptake and inflammatory activation was also observed in animals after intravascular administration of Ad5RGE compared to the parental Ad5 vector, with reduced co-localisation of the viral beta-galactosidase transgene with MAdCAM-1+ sinus-lining endothelial cells. Our detailed assessment of these novel adenoviruses indicates that penton base RGE mutation in combination with FX binding-ablation may be a viable strategy to attenuate the undesired liver uptake and pro-inflammatory responses to Ad5 vectors after intravascular delivery., (Copyright © 2012 Elsevier B.V. All rights reserved.)