Search

Abstract Socio‐ecological resilience is the capacity of a system to adapt to changing ecological and social disturbances. Its assessment is extremely important to integrate long‐term management of ecological and social features of natural ecosystems. This is especially true for Sacred Natural Sites, such as sacred forests and groves, where it can reveal the influence of social processes in ecosystem recovery or degradation. Using tree ages determined through dendrochronology and tree population size‐class distributions collected in five sacred forests in Epirus (NW Greece), we explore spatial and temporal dynamics of resilience in a socio‐ecological system, identifying which cultural and social elements characterize resilience in space and time. Our main results show that over past centuries sacred forests in Epirus underwent periods of varying tree establishment rate, depending on the intensity of human activities and historical disturbance events. We also identified strong evidence of the role of the social component (i.e. the church and associated cultural praxis) in determining the spatial extent of the forests' current recovery phase, and thus the overall resilience of the system. Policy implications. Appreciation of the ways sacred forests' ecological resilience is linked to changing socio‐cultural praxis over both temporal and spatial scales is crucial for guiding conservation and restoration strategies. We argue that greater attention should be paid to the role of the social component of socio‐ecological systems and specifically for sacred natural sites that provide both a nucleus of established forest habitat and the conditions necessary for forest recovery and restoration. Read the free Plain Language Summary for this article on the Journal blog.

Introduction: Pilomatricoma is a benign adnexal dermal or subcutaneous tumor derived from immature hair matrix cells. Objectives: The aim of our study is to evaluate clinical and dermoscopic features of pilomatricomas, with a specific focus on pediatric lesions, and to provide a concise review of the existing literature. Methods: A single-center retrospective study was undertaken on 55 patients with a histopathological diagnosis of pilomatricoma referred to the Dermatology Unit, University of Bologna, Bologna, Italy, between 2005 and 2023. Pilomatricomas were retrospectively evaluated relying on clinical and dermoscopic images. A PubMed search was conducted. All the relevant research up to July 31, 2023, was reviewed. We classified the cases as “typical” or “atypical” based on whether they were suspected of being pilomatricomas or not. Results: A total of 55 children with pilomatricomas.were observed and studied. Two patients presented with 2 pilomatricomas, leading to the identification of 58 pilomatricomas. Typical’ pilomatricomas were observed in 79% of cases as nodular and pigmented lesions with one or more colors, ranging from blue-gray to red to yellow/white, evident on clinical examination and even better on dermoscopy. In 21% of cases, pilomatricomas presented in an ‘atypical’ form, which did not allow for a well-founded suspicion, placing them in differential diagnosis with other lesions and therefore requiring histological examination. Conclusions: According to our case series and systematic review of the literature, clinical appearance and dermoscopy may be sufficient to diagnose or suspect pilomatricoma in around 80% of cases, while histological examination is necessary to confirm the diagnosis in the remaining 20% of cases.

In the face of global climate change, the built environment is experiencing an increasing demand for energy to maintain indoor comfort conditions. Inspired by systemic thinking and biomimicry, adaptive architecture can give rise to complex building organisms that dynamically respond to environmental stimuli by modulating the physicality of their envelope, thereby reducing energy consumption for climate control. Illustrating a representative framework of projects and research highlights the role of modularity in adaptive architecture in terms of operational principles, control modes, response mechanisms, functional complexity, and structural complexity. This contribution underscores the centrality of modularity as a strategy to address the multidimensional complexity of technological systems for adaptive envelopes. Article info Received: 08/09/2023; Revised: 14/10/2023; Accepted: 26/10/2023

Chromosomal instability leads to aneuploidy, a state of karyotype imbalance. By inducing controlled chromosome mis-segregation, Santaguida and colleagues show that aneuploidy can also instigate chromosomal instability.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator.

Multiple eruptive cutaneous non-melanoma skin cancers(NMSCs) have been reported to arise at the sites of skin surgery, including the area affected by the primary tumour and split thickness skin graft(STSG) donor and recipient sites. The aim of this study is to make a critical revision of the literature, analysing the clinical, histological features and outcomes of eruptive NMSCs after cutaneous surgery. Up to August 2021, according to our systematic review of the literature, we have collected 18 published articles and a total of 33 patients, including our two cases. The results of this review highlight five red flags that clinicians should consider: (i) lower and upper limbs represent the cutaneous site with the highest risk, representing 82.35% of the cases in the literature; (ii) the median time to onset of eruptive NMSCs that is approximately 6 weeks; (iii) primary NMSCs were completely excised with free margins on histologic examination in all cases of the literature, and therefore the eruptive NMSCs reported could not be considered recurrences; (iv) any surgical technique involves a risk to promote eruptive NMSCs; (v) treatment of eruptive NMSCs includes surgery or combined surgical and medical treatment. However, eruptive NMSCs recurrences are a real medical challenge and have always been treated combining surgical and medical treatment, with complete resolution in about one third of patients. In conclusion, even though the pathogenesis remains unclear, this review highlights 5 red flags which could support clinicians in the diagnosis and management of eruptive of NMSCs after skin surgery.

In 2050, about 80% of the European building stock will consist of buildings currently in use. In Italy, a significant share of such stock was built during post-war reconstruction through the Ina Casa social housing programme, which solved such problems as unemployment and housing demand. The rationale behind the building focussed on tradition and saving and drove the implementation of architectural solutions which do not meet the current European Green Deal requirements. Due to the energy crisis, such architectural solutions are also expensive to manage. The wish to rehabilitate the above-mentioned stock stimulates the adoption of new instruments, such as energy communities and participatory energy management models. These instruments achieve a sustainable energy set-up and drive both social and economic development.

Abstract Background This study’s main purpose was to examine the psychometric properties of FoMOs’ adaptation among the Indonesian adolescents’ population. The second aim was to investigate the concurrent validity of the Indonesian version to provide evidence for the validity. Also, FoMOs’ difference level between demographic variance analyses was performed. Method The study involved a cross-sectional online survey design with 638 Indonesian adolescents aged 16–24 (M = 19.08, SD = 14.70). FoMO was measured by a 16-item that has been modified from the original 10-item. Exploratory and confirmatory factor analyses were carried out to study its scores’ evidence of structural validity. Besides, to study its scores’ evidence of convergent, discriminant, and predictive validity concerning other variables such as stress, anxiety, and depression (Depression and Anxiety Stress Scale-21), and general health condition (General Health Questionnaire Scale-12), correlation analyses were conducted. To study the sensitivity, we assessed the effect of sociodemographic and social media use on the scale’s ability to identify the population’s risk to the FoMO by conducting analyses of variance. The Cronbach alpha values (α = .93) indicated that internal consistency of the scale was at an adequate level. Results Exploratory factorial analyses revealed adequate adjustment for the new version of the scale showing the three factorial structures. Confirmatory factor analyses showed that the 12-item of Indonesian FoMO had a good fit (χ2/df = 289.324/51; goodness-of-fit index (GFI) = 0.928; RMSEA = 0.086; comparative fit index (CFI) = 0.915; normed fit index (NFI) = 0.899; parsimony normed fit index (PNFI) = .695; Tucker–Lewis index (TLI) = 0.890). Conclusion This study has shown that the modified 12-item Fear of Missing Out Scale is a valid and reliable instrument for Indonesian adolescents. It showed that the Indonesian version of Fear of Missing Out Scale has adequate psychometric properties to measure Indonesian adolescents’ online behavior.

Abstract Parkinson's disease (PD) is characterized by motor impairment, affecting quality of life and increasing fall risk, due to ineffective postural control. To this day, the diagnosis remains based on clinical approach. Similarly, motor evaluation is based on heterogeneous, operator-dependent observational criteria. A synthetic, replicable index to quantify motor impairment is still lacking. Hence, we have designed a new measure of postural stability which assesses the trunk displacement in relation to the center of mass, that we named trunk displacement index (TDI). Twenty-three PD patients and twenty-three healthy controls underwent motor examination through a stereophotogrammetric system. A correlation analysis was performed to assess the relationship of TDI with gait parameters and clinical motor scale (UPDRS-III). The TDI sensitivity was estimated, comparing pre- and post- L-DOPA subclinical dose intake. The TDI showed significant correlations with many gait parameters and with the UPDRS-III. Furthermore, the TDI resulted capable in discriminating between off and on state in PD, whereas gait parameters failed two show any difference between those two conditions. Our results suggest that the TDI may be considered a highly sensitive biomechanical index, reflecting the overall motor condition in PD, and provided of clinical relevance due to the correlation with the clinical evaluation.

The synthetic indices are widely used to describe balance and stability during gait. Some of these are employed to describe the gait features in Parkinson's disease (PD). However, the results are sometimes inconsistent, and the same indices are rarely used to compare the individuals affected by PD before and after levodopa intake (OFF and ON condition, respectively). Our aim was to investigate which synthetic measure among Harmonic Ratio, Jerk Ratio, Golden Ratio and Trunk Displacement Index is representative of gait stability and harmony, and which of these are more sensitive to the variations between OFF and ON condition. We found that all indices, except the Jerk Ratio, significantly improve after levodopa. Only the improvement of the Trunk Displacement Index showed a direct correlation with the motor improvement measured through the clinical scale UPDRS-III (Unified Parkinson's Disease Rating Scale-part III). In conclusion, we suggest that the synthetic indices can be useful to detect motor changes induced by, but not all of them clearly correlate with the clinical changes achieved with the levodopa administration. In our analysis, only the Trunk Displacement Index was able to show a clear relationship with the PD clinical motor improvement.

The development of societies, including spiritual development, is closely connected to forests. The larger interrelations among changing societies, transforming forest landscapes, and evolving spiritual values related to forests have yet to be extensively considered. Addressing this research gap is important to avoid the neglect of spiritual values in forest policy and management. Our exploratory study investigates spiritual values of forests from European and Asian perspectives, assessing 13 countries. Based on expert knowledge from 18 interdisciplinary experts, we first define forest spiritual values (forest spirituality). We then elaborate on the idea that forest spirituality evolves as societies and landscapes change, and propose a transition hypothesis for forest spirituality. We identify indicators and drivers and portray four stages of such a transition using country-specific examples. We find that during a first stage (“nature is powerful”), forest spirituality is omnipresent through the abundance of sacred natural sites and practices of people who often directly depend on forests for their livelihoods. An alternative form of spirituality is observed in the second stage (“taming of nature”). Connected to increasing transformation of forest landscapes and intensifying land-use practices, “modern” religions guide human–nature interrelations. In a third stage (“rational management of nature”), forest spirituality is overshadowed by planned rational forest management transforming forests into commodities for the economy, often focusing on provisioning ecosystem services. During a fourth stage (“reconnecting with nature”), a revival of forest spirituality (re-spiritualization) can be observed due to factors such as urbanization and individualizing spirituality. Our core contribution is in showing the connections among changing forest perceptions, changing land-use governance and practices, and changing forest spirituality. Increasing the understanding of this relationship holds promise for supporting forest policy-making and management in addressing trade-offs between spiritual values and other aspects of forests.

We describe a case of acute relapse in a woman with Multiple Sclerosis (MS) shortly after the mRNA COVID-19 vaccination. The patient received a diagnosis of MS in November 2016 at the MS Centre of the A. Cardarelli Hospital (South of Italy). Since that moment, her clinical conditions and pharmacological therapies have been managed at this MS centre where, according to national recommendations, in April 2021, the patient received the BNT162b2 vaccine. Almost 48 h after receiving the vaccine, the patient developed paraesthesia and weakness in her left arm and limbs. The neurological examination revealed walking difficulties while the MRI showed three new voluminous enhancing lesions. After having received methylprednisolone iv for 5 days, the patient's neurological symptoms fully recovered. Along with the implementation of COVID-19 vaccination programmes among vulnerable population, further studies are needed in order to improve our knowledge on the benefit/risk ratio of COVID-19 vaccines.

The aim of this study is to assess the potential of Earth Observation and climate data for the forestry sector focusing on the Copernicus Climate Change Service (C3S). Although forestry researchers recognize the importance of Earth Observation and climate data, forestry practitioners currently work mainly with land cover information, largely neglecting climate data. Understanding its potential for the forestry sector becomes thus important, as to align the vast offer of climate services in Europe to different forestry users and stakeholders’ necessities. Interviews, surveys, and dedicated workshops were used to collect a series of forestry end-users’ needs and requirements regarding climate data. End-user’s requirements were categorized through a SWOT analysis, which allowed to identify perceived internal strengths and weaknesses, external opportunities and threats to the increased use of the C3S. Results indicate that improved climate services for the forestry sector based on C3S data would benefit from enhanced training on the use of climate data, improved provision of services integrating climate with non-climate data, the provision of new variables and indicators, and the integration of machine learning techniques for developing data and information in support of the deployment of climate services. These findings are relevant to close the gap between demand and supply of climate services for the forestry sector and provide a basis for further exploring the value of climate data in serving a wide array of forestry stakeholders. Going forward, increased knowledge on user requirements from both forest practitioners and policy-makers can be beneficial to develop accessible tailored services.

Applying systemic thinking to the resolution of complexity in biomimetic design allows technological integration between biological and man-made systems, thereby creating an autopoietic building organism. Emulating Nature in projects requires know-how cross-fertilization and hybridization. Mechanical solutions and those associated with the properties of materials are by no means the only options adaptive architecture can resort to in reproducing natural processes. This paper illustrates experiences that adopt adaptive autopoietic strategies at both urban and architectural product level. These strategies are typical of the natural world and involve the integration of technology and biology. The described experiences aim at highlighting the link between biomimetic design and the heteronomy of disciplines.

Future scenarios foresee a city as a fragmented and uneven system in relation to rapidly evolving environmental, economic and social phenomena. The traditional urban planning tools, based on a theoretical-predictive approach, adapt poorly. We need to rethink how to govern the transformations of a city, which can be described by models of urban metabolism. City Sensing has changed the way a city is explored and used. With the transition from digitisation to datafication, through a computational approach, one can process georeferenced datasets within algorithms in order to achieve a higher quality of the project. This process exploits data provided by public administrations, companies and citizens taking part in inclusive and adaptive urban planning.

We present an overview of the concentrations and distributions of water-soluble ion species and elemental components in ambient particulate matter for five measurement sites in southern Italy with the aim of investigating the influence of the different site characteristics on PM levels. The sites encompass different characteristics, ranging from urban to coastal and high-altitude remote areas. PM10 and PM2.5 fractions were collected simultaneously using dual channel samplers during the winter period from November 2015 to January 2016 and analyzed for water-soluble ion species, using ion chromatography, and elemental composition, using inductively coupled plasma mass spectrometry (ICP-MS). In all sites, PM2.5 represented the higher contribution to particulate mass, usually more than two times that of the coarse fraction (PM2.5−10). At the coastal site in Capo Granitola (Western Sicily), sea salts constituted about 30% of total PM10 mass. On average, ion species accounted for 30% to 60% of total PM10 mass and 15% to 50% of PM2.5 mass. We found that secondary ion species, i.e., SO42−, NO3− and NH4+ dominated the identifiable components within both PM2.5 and PM10 fractions. The chlorine–sodium ratio was usually lower than that expected from the natural level in sea salt, evidencing aged air masses. At the monitoring site in Naples, a highly urbanized area affected by high levels of anthropogenic source emissions, an increased contribution of ammonium was found, which was imputed to the increased ammonia emissions from industrial combustion sources and road traffic. The concentrations of the investigated elements showed noteworthy differences from one site to another. The PM10 fraction was highly enriched by sources of anthropogenic origin in the samples from the most urbanized areas. In general, the enrichment factors of the elements were similar between the PM10 and PM2.5 fractions, confirming common sources for all elements.

Background. The so-called “vaccine hesitancy” still represents a common phenomenon that undermines the effectiveness of vaccination campaigns. In 2020, the Italian Medicines Agency recommended to bring forward the flu vaccination campaign, whose importance was also emphasized for patients with Multiple Sclerosis (MS). We aimed to assess vaccination behavior in patients with MS to prepare for the upcoming SARS-CoV-2 vaccination challenge. Methods. This is an observational study carried out in one MS clinical Centre that enrolled all MS patients who were eligible for any of the flu vaccines recommended by the Italian medicines Agency. Results. 194 patients were enrolled. Patients’ mean age was 43.9 years and 66% were female. Comorbidities, mainly represented by non-autoimmune diseases, were identified in 52% of patients. Almost all patients were receiving a DMT during the study period, mainly dimethyl fumarate, natalizumab, teriflunomide, and interferon. Out of 194 patients, 58.2% accepted to be vaccinated. No statistically significant differences were found, except for the use of natalizumab, which was higher among vaccinated patients. Conclusion. The results of our study emphasize the importance of education and communication campaigns addressed both to healthcare providers and patients with MS, especially considering that MS patients are currently receiving COVID-19 vaccinations.

Executive projects must guarantee that technical specifications are properly interpreted, so that construction work can be adequately implemented. In view of the upcoming automation of building sites arising from the cyber-physical system-based Industry 4.0 framework, the detailed design “grammar rules” are bound to change, too. The reported discussions focus on information integration between on-site and off-site production, as well as among humans, machines and sensors. This study surveys and updates the state of the art in the research of the building process automation. Based on that, it defines an information management model for integrated processes which encompasses the entire construction process (Integrated Design Process, Construction Management and Facility Management) and it is ready to be shared on the cloud.

Der Artikel stellt die Ergebnisse einer Vorstudie zur endgültigen Erschließung der Exilbibliothek von Charlotte und Karl Bühler vor. Bei einer Nachlassbibliothek wie der Exilbibliothek von Charlotte und Karl Bühler machen vor allem die Benutzungs- und Lesespuren den einmaligen Wert des Bestands aus. Demgemäß ging es in erster Linie darum, diese Exemplarspezifika zu sichern, zu erfassen und zugänglich zu machen. Da es derzeit allerdings (noch) keine einheitliche Vorgehensweise innerhalb des Österreichischen Bibliothekenverbunds bezüglich der elektronischen Verzeichnung von exemplarspezifischen Benutzungsspuren gibt, bestand die Kernaufgabe des Projekts darin, eine auf die Bedürfnisse der Bühlerschen Exilbibliothek zugeschnittene Lösung zu entwickeln.

There is general agreement that the neuropathological processes leading to Alzheimer’s disease (AD) begin decades before the clinical onset. In order to detect early topological changes, we applied functional connectivity and network analysis to magnetoencephalographic (MEG) data obtained from 16 patients with amnestic Mild Cognitive Impairment (aMCI), a prodromal stage of AD, and 16 matched healthy control (HCs). Significant differences between the two groups were found in the theta band, which is associated with memory processes, in both temporal poles (TPs). In aMCI, the degree and betweenness centrality (BC) were lower in the left superior TP, whereas in the right middle TP the BC was higher. A statistically significant negative linear correlation was found between the BC of the left superior TP and a delayed recall score, a sensitive marker of the “hippocampal memory” deficit in early AD. Our results suggest that the TPs, which are involved early in AD pathology and belong to the memory circuitry, have an altered role in the functional network in aMCI.

The knirps (kni) locus encodes transcription factors required for induction of the L2 wing vein in Drosophila. Here, we employ diverse CRISPR/Cas9 genome editing tools to generate a series of targeted lesions within the endogenous cis-regulatory module (CRM) required for kni expression in the L2 vein primordium. Phenotypic analysis of these ‘in locus’ mutations based on both expression of Kni protein and adult wing phenotypes, reveals novel unexpected features of L2-CRM function including evidence for a chromosome pairing-dependent process that promotes transcription. We also demonstrate that self-propagating active genetic elements (CopyCat elements) can efficiently delete and replace the L2-CRM with orthologous sequences from other divergent fly species. Wing vein phenotypes resulting from these trans-species enhancer replacements parallel features of the respective donor fly species. This highly sensitive phenotypic readout of enhancer function in a native genomic context reveals novel features of CRM function undetected by traditional reporter gene analysis.

This work provides the first continuous measurements of carbonaceous aerosol at the Global Atmosphere Watch (GAW) Monte Curcio regional station, within the southern Mediterranean basin. We specifically analyzed elemental carbon (EC) and organic carbon (OC) concentrations in particulate matter (PM) samples, collected from April to December during the two years of 2016 and 2017. The purpose of the study is to understand the behavior of both PM and carbonaceous species, in their fine and coarse size fraction, along with their seasonal variability. Based on 18 months of observations, we obtained a dataset that resulted in a vast range of variability. We found the maximum values in summer, mainly related to the enhanced formation of secondary pollutants owing to intense solar radiation, also due to the high frequency of wildfires in the surrounding areas, as well as to the reduced precipitation and aerosol-wet removal. We otherwise observed the lowest levels during fall, coinciding with well-ventilated conditions, low photochemical activity, higher precipitation amounts, and less frequency of Saharan dust episodes. We employed the HYSPLIT model to identify long-range transport from Saharan desert. We found that the Saharan dust events caused higher concentrations of PM and OC in the coarser size fraction whereas the wildfire events likely influenced the highest PM, OC, and EC concentrations we recorded for the finer fraction.

We present Lipschitz continuity estimates for a class of convex functions with respect to Hörmander vector fields. These results have been recently obtained in collaboration with M. Scienza, [22].

Introdução: Neste estudo, descreve-se o perfil clínico das pacientes e as características histopatológicas dos carcinomas de endométrio tratados no setor de Oncologia Genital do Hospital de Clínicas de Porto Alegre (HCPA), assim como as formas de tratamento, fatores prognósticos e sobrevida. Métodos: Estudo de coorte histórica incluindo todas as pacientes submetidas a tratamento cirúrgico primário entre 1996 a 2012. Após revisão de prontuários médicos, foram analisadas as variáveis idade, status hormonal, tipo histológico e grau tumoral, invasão miometrial, estadiamento cirúrgico, cirurgia realizada, tratamento complementar e sobrevida. Resultados: Cento e sessenta e quatro pacientes foram incluídas no estudo, com idade média de 64,2 anos (31-95 anos), sendo quase 90% delas pós-menopáusicas. O tempo de seguimento variou de 4 dias a 14,6 anos. O tipo histológico endometrioide foi o mais encontrado (78% dos casos). A histerectomia com salpingo-ooforectomia bilateral com linfadenectomia pélvica foi a cirurgia mais realizada (77,5%). Tratamento complementar foi realizado em 57,9% das pacientes, sendo a radioterapia o tratamento de escolha em 87,4% deles. Ocorreram 36 óbitos (22%) durante o seguimento, com uma sobrevida média global de 125 meses. Em análise bivariada, idade ≥ 65 anos, tipo histológico não endometrioide, tumores pouco diferenciados (G3), invasão miometrial ≥ 50% e metástase linfonodal relacionaram-se significativamente a um menor tempo de sobrevida. Em análise multivariada, a histologia não endometrioide estádio III e IV, e a presença de comprometimento linfonodal foram significativamente associados ao óbito. Conclusão: Os resultados encontrados são compatíveis com a literatura existente e vêm em acréscimo à escassa estatística nacional.

The article shows the results of a research that has been conducted within the project: “Energyskin: active building façades”. The project has been financed by the Piedmont Region and ESF (European Social Fund), among different industrial and academic partners with the aim to develop, monitor and optimize an adaptive dynamic innovative envelope component, that integrates the heat pump and the solar thermal system technology, by using the envelope as source/well for collecting heat. The research starts with the idea to integrate academic expertise with industrial realities, in order to start together the process that leads to the innovation and overcome the barriers of individual specializations. Those competences, under current practice, characterize both the functional specific models of companies on the one hand and the academic areas of expertise on the other hand.

The Veterans Health Administration (VHA) runs the largest integrated healthcare system in the nation. Formulary management within VHA primarily involves 3 national groups: the Medical Advisory Panel, the Veterans Integrated Service Network Formulary Leaders, and the Pharmacy Benefits Management Strategic Healthcare Group. Together, these groups manage the VHA national drug formulary with a goal of providing a comprehensive, safe, and cost-effective pharmacy benefit for veterans. Traditionally, VHA has relied on cost-minimization analyses in formulary decisions. More recently, VHA has emphasized the use of cost-effectiveness data, especially for newer, costly drugs. In addition to including this data in drug monographs, the VHA has begun requiring formal cost-effectiveness analysis from manufacturers of selected pharmaceuticals. VHA has also requested that clinically relevant information such as quality of life plus mortality benefit be made available from industry so that internal cost analyses can be performed. It is hoped that by setting the expectation that cost-effectiveness will be formally considered in all VHA formulary decisions, the pharmaceutical industry and others will be stimulated to collect and report data that enables these analyses. We believe that if other organizations also place an emphasis on economic evaluations, industry and the public will be more accepting of decisions that incorporate cost considerations. [ABSTRACT FROM AUTHOR]

Shiga toxin-producing Escherichia coli (STEC) are a heterogeneous group of foodborne pathogens causing a broad spectrum of human disease, from uncomplicated diarrhea to hemolytic uremic syndrome (HUS). In this study, we report an HUS case associated with an O59:NM[H19] strain, harboring stx 2a , iha, lpfA O26 , lpfA O113 genes associated with STEC, and aatA, aap, pic, sigA, agg4A genes associated with enteroaggregative E. coli (EAEC), named Stx-EAEC. The strain showed low toxicity on Vero cells, and was resistant to streptomycin and trimethoprim/sulfonamides. The child carried the bacteria for more than 100 days. Since the large outbreak associated with Stx-EAEC O104:H4, many strains with similar profiles have been described. In Germany, an O59:NM[H19] strain, with comparable characteristics to the Argentine strain, was isolated from a bloody diarrhea case. In Argentina, this is the first report of an HUS case associated with a Stx-EAEC infection, and represents a new challenge for the surveillance system., (Copyright © 2019. Publicado por Elsevier España, S.L.U.)

In the setting of flecainide toxicity, supraventricular tachycardia can manifest as a bizarre right or left bundle branch block, sometimes with a northwest axis, and can easily be mistaken for ventricular tachycardia leading to inappropriate therapy. We conducted a comprehensive literature review for cases of flecainide toxicity. We found 21 articles of flecainide toxicity in adult patients in which 22 ECG tracings were published. In patients with flecainide toxicity and QRS duration ≤ 200 ms, the ECGs were more likely to show RBBB, visible P waves (p = 0.03), and shorter QT (p = 0.02) and QTc intervals (p = 0.004). With QRS duration > 200 ms, the ECGs were more likely to show LBBB, loss of P waves, a northwest axis (p = 0.01), and longer QT and QTc intervals. Deaths were reported only in patients with QRS duration >200 ms, and the outcome of death or requirement for mechanical circulatory support was more prevalent in patients with a QRS duration > 200 ms [2/13 (15.4 %) vs. 6/10 (60 %), p = 0.04]. In patients with access to the medication, flecainide toxicity should be suspected with: (1) broad QRS, (2) RBBB morphology with QRS ≤ 200 ms; RBBB or LBBB morphology with QRS ≥ 200 ms (3) HR out of proportion to the degree of hemodynamic instability. The duration of the QRS interval is prognostic, with mortality and the requirement for mechanical circulatory support being more common in patients with a QRS > 200 ms.

Over the past decade, the Department of Veterans Affairs (VA) Pharmacy Benefits Management Services (PBM) has enhanced its formulary management activities and added programs to ensure that the national drug plan continues to meet the pharmacy needs of veterans and to promote safe and appropriate drug therapy in the face of rising medication expenditures. This article describes the broad range of services provided by the VA PBM that work in partnership to deliver a high-quality and sustainable pharmacy benefit for veterans. In support of formulary management, VA PBM pharmacists prepare extensive clinical guidance documents (e.g., drug monographs and criteria for use) that are used by physicians and pharmacists with operational and clinical oversight of the VA national formulary. The VA PBM has utilized various contracting techniques and continually evaluates drug utilization data to identify opportunities for potential savings. Remarkably, since before 2004, the average acquisition cost for a 1-month supply of medication has remained fairly stable at approximately $13-$15. Two new VA PBM programs are the VA Center for Medication Safety (VA MedSAFE) and the Clinical Pharmacy Practice Office (CPPO). VA MedSAFE is a comprehensive pharmacovigilance program focused on the detection, assessment, and prevention of adverse drug events, and CPPO is dedicated to improving safe and appropriate medication use by supporting and expanding clinical pharmacy practice. Moving forward, the VA PBM will consider new initiatives to stay at the forefront of providing quality care while maintaining economic viability., Disclosures: No outside funding supported this research. This work was supported by VA Pharmacy Benefits Management Services (VA PBM), Hines, Illinois, and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. Glassman is co-director of the VA Center for Medication Safety, which is part of the VA PBM. He is also part of the Medical Advisory Panel for the VA PMB. All other authors are employed by the VA PBM. The views expressed in this article are those of the authors, and no official endorsement by the U.S. Department of Veteran Affairs or the U.S. government is intended or should be inferred. Study concept and design were contributed by Valentino, Cunningham, Good, Aspinall, and Sales. Calabrese and Ourth took the lead in data collection, along with Good, Cunningham, Aspinall, Sales, Burk, Moore, Neuhauser, and Golterman. Data interpretation was performed by Burk, Newhauser, and Golterman, along with Glassman, Calabrese, Moore, and Ourth. The manuscript was written by Aspinall and Sales, along with Burk, Newhauser, Golterman, Ourth, and Cunningham. Good, Glassman, and Moore revised the manuscript, along with Calabrese, Valentino, and Aspinall.

Context: There exists a disparity between the views of physicians and the views of their patients on end-of-life decisions. However, the timing of when the end-of-life preferences of physicians and non-medically-trained individuals diverge is currently unknown. The objective of this paper is to characterise how preferences for medical interventions change throughout medical education and residency or fellowship training when confronted with scenarios of critical or terminal illness., Methods: This is a single-centre cross-sectional study that enrolled medical students at Sidney Kimmel Medical College and residents and fellows at Thomas Jefferson University Hospital. Through an online survey we determined the preferences of medical trainees for specific interventions throughout medical training when presented with different clinical scenarios. Interventions were organised into three categories: standard, intermediate and aggressive. We analysed responses to questions regarding different scenarios in separate repeated measures logistic regression models. The probability of declining medical interventions was modelled, and significant predictors of refusal of interventions were identified., Results: Years of training was a significant predictor of declining interventions for several scenarios. When faced with permanent physical disability, increased years of training led to a higher rate of refusal of intermediate (OR = 1.14 [1.02-1.28], p = 0.02) and aggressive interventions (OR = 1.15 [1.03-1.28], p = 0.01). For the scenario of terminal illness with associated physical disability, years of training significantly influenced refusal of intermediate (OR = 1.14 [1.04-1.26], p = 0.006) and aggressive (OR = 1.20 [1.08-1.34], p = 0.001) interventions. For the scenario of permanent cognitive impairment, increased years of training led to a higher rate of refusal of standard (OR = 1.14 [1.01-1.29], p = 0.03), intermediate (OR = 1.30 [1.13-1.50], p < 0.001) and aggressive (OR = 1.38 [1.14-1.66], p = 0.001) interventions., Conclusion: Changes in end-of-life preferences occur throughout medical training. Years of training influenced the likelihood of declining medical interventions when faced with scenarios of terminal illness and physical or cognitive disability., (© 2016 John Wiley & Sons Ltd.)

Obesity is a world-wide pandemic and its incidence is on the rise along with associated comorbidities. Currently, there are few effective therapies to combat obesity. The use of lifestyle modification therapy, namely, improvements in diet and exercise, is preferable over bariatric surgery or pharmacotherapy due to surgical risks and issues with drug efficacy and safety. Although they are initially successful in producing weight loss, such lifestyle intervention strategies are generally unsuccessful in achieving long-term weight maintenance, with the vast majority of obese patients regaining their lost weight during followup. Recently, various compensatory mechanisms have been elucidated by which the body may oppose new weight loss, and this compensation may result in weight regain back to the obese baseline. The present review summarizes the available evidence on these compensatory mechanisms, with a focus on weight loss-induced changes in energy expenditure, neuroendocrine pathways, nutrient metabolism, and gut physiology. These findings have added a major focus to the field of antiobesity research. In addition to investigating pathways that induce weight loss, the present work also focuses on pathways that may instead prevent weight regain. Such strategies will be necessary for improving long-term weight loss maintenance and outcomes for patients who struggle with obesity.

The increase in obesity in the Unites States and around the world in the last decade is overwhelming. The number of overweight adults in the world surpassed 1 billion in 2008. Health hazards associated with obesity are serious and include heart disease, sleep apnea, diabetes, and cancer. Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone. Thus, the development of anti-obesity therapeutics represents a major unmet medical need. Historically, anti-obesity pharmacotherapies have been unsafe and minimally efficacious. A better understanding of the biology of appetite and metabolism provides an opportunity to develop drugs that may offer safer and more effective alternatives for weight management. This review discusses drugs that are currently on the market and in development as anti-obesity therapeutics based on their target and mechanism of action. It should serve as a roadmap to establish expectations for the near future for anti-obesity drug development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c(-/-)) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c(-/-) mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.

Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.

Obesity has escalated into a pandemic over the past few decades. In turn, research efforts have sought to elucidate the molecular mechanisms underlying the regulation of energy balance. A host of endogenous mediators regulate appetite and metabolism, and thereby control both short- and long-term energy balance. These mediators, which include gut, pancreatic and adipose neuropeptides, have been targeted in the development of anti-obesity pharmacotherapy, with the goal of amplifying anorexigenic and lipolytic signaling or blocking orexigenic and lipogenic signaling. This article presents the efficacy and safety of these anti-obesity drugs.

Killer Immunoglobulin-like Receptor (KIR) genes may affect both resistance and susceptibility to autoimmune disorders, but their role in the pathogenesis of Multiple Sclerosis (MS) is still unclear. To evaluate the involvement of KIRs and their HLA ligands in the development of MS we performed genotyping of HLA -A, -B, -Cw, -DRB1 and KIRs loci in 121 RRMS patients and 103 healthy controls (HC). Results evidenced a possible protective role of the activating KIR2DS1 gene (p(y)=0.001; OR:0.38), enhanced in the presence of its ligand group HLA-C2 (p(y)=0.0001; OR:0.23). Our data suggest that the presence of functional compounds of activating KIR receptors together with their HLA ligands, allowing the immunomodulatory function of NK cells, may have a protective role against the disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)

With the eruption of the obesity pandemic over the past few decades, much research has been devoted to understanding the molecular mechanisms by which the human body regulates energy balance. These studies have revealed several mediators, including gut/pancreatic/adipose hormones and neuropeptides that control both short- and long-term energy balance by regulating appetite and/or metabolism. These endogenous mediators of energy balance have been the focus of many anti-obesity drug-development programs aimed at either amplifying endogenous anorexigenic/lipolytic signaling or blocking endogenous orexigenic/lipogenic signaling. Here, we discuss the efficacy and safety of targeting these pathways for the pharmacologic treatment of obesity.

Obesity has emerged as one of the principal worldwide health concerns of the modern era, and there exists a tremendous unmet clinical need for safe and effective therapies to combat this global pandemic. The prevalence of obesity and its associated comorbidities, including cardiovascular and metabolic diseases, has focused the attention of those in drug discovery and development on generating effective modalities for the treatment and prevention of obesity. Early efforts in the field of obesity pharmacotherapy centered on the development of agents with indeterminate mechanisms of action. This led to treatment paradigms characterized by significant off-target effects. In the past two decades, new insights have been made into the physiologic regulation of energy balance and the subordinate central and peripheral circuits coordinating appetite, metabolism, and lipogenesis. These studies have revealed previously unrecognized molecular targets for controlling appetite and managing weight from which has emerged a new wave of targeted pharmacotherapies to prevent and control obesity.

Guanylyl cyclase C (GCC) is the receptor expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin that coordinate mucosal homeostasis and its silencing contributes to intestinal transformation. It orchestrates proliferative and metabolic circuits by limiting the cell cycle and programming metabolic transitions central to regeneration along the crypt-villus axis. Mice deficient in GCC are more susceptible to colon cancer induced by germline mutations or carcinogens. Moreover, guanylin and uroguanylin are the most commonly lost gene products in colon cancer. The role of GCC as a tumor suppressor and the universal loss of its hormones in transformation suggest a paradigm in which colorectal cancer is a disease of paracrine hormone insufficiency. Indeed, GCC signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. These data suggest a pathophysiological hypothesis in which GCC is a tumor suppressor coordinating proliferative homeostasis whose silencing through hormone loss initiates transformation. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy employing GCC ligands., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)