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The Central Volcanic Zone of the Andes (CVZA) extends from southern Peru, through the Altiplano of Bolivia, to the Puna of northern Chile and Argentina, between latitudes 14–28° S of the Andean cordillera, with altitudes rising up to more than 4000 m above sea level. Given the large number of active volcanoes in this area, which are often located close to both urban areas and critical infrastructure, prioritization of volcanic risk reduction strategies is crucial. The identification of hazardous active volcanoes is challenging due to the limited accessibility, the scarce historical record, and the difficulty in identifying relative or absolute ages due to the extreme arid climate. Here, we identify the highest-risk volcanoes combining complementary strategies: (i) a regional mapping based on volcanic hazard parameters and surrounding density of elements at risk and (ii) the application of the recently developed volcanic risk ranking (VRR) methodology that integrates hazard, exposure, and vulnerability as factors that increase risk and resilience as a factor that reduces risk. We identified 59 active and potentially active volcanoes that not only include the volcanic centres with the most intense and frequent volcanic eruptions (e.g. the El Misti and Ubinas volcanoes, Peru) but also the highest density of exposed elements (e.g. the cities of Arequipa and Moquegua, Peru). VRR was carried out for 19 out of the 59 volcanoes, active within the last 1000 years or with unrest signs, highlighting those with the highest potential impact (i.e. Cerro Blanco in Argentina and Yucamane, Huaynaputina, Tutupaca, and Ticsani in Peru) and requiring risk mitigation actions to improve the capacity to face or overcome a disaster (e.g. volcanic hazard and risk/impact assessments, monitoring systems, educational activities, and implementation of early warning systems).

Abstract Background Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1–40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance. Methods We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation, and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5 to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000 Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR. Results UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity, and precision (0.977 ± 0.018; 1.000 ± 0.0005; 0.993 ± 0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R 2 = 0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40 quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and explored KIV-2 SNP haplotype patterns across five ancestries. Conclusions UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale.

Abstract Glycan-mediated interactions play a crucial role in biology and medicine, influencing signalling, immune responses, and disease pathogenesis. However, the use of glycans in biosensing and diagnostics is limited by cross-reactivity, as certain glycan motifs can be recognised by multiple biologically distinct protein receptors. To address this specificity challenge, we report the enzymatic synthesis of a 150-member library of site-specifically fluorinated Lewisx analogues (‘glycofluoroforms’) using naturally occurring enzymes and fluorinated monosaccharides. Subsequent incorporation of a subset of these glycans into nanoparticles or a microarray revealed a striking spectrum of distinct binding intensities across different proteins that recognise Lewisx. Notably, we show that for two proteins with unique binding sites for Lewisx, glycofluoroforms exhibited enhanced binding to one protein, whilst reduced binding to the other, with selectivity governed by fluorination patterns. We finally showcase the potential diagnostic utility of this approach in glycofluoroform-mediated bacterial toxin detection by lateral flow.

Abstract Compared to other malignancies, few studies have investigated the role of family history of cancer (FHC) in patients with lung cancer, yielding largely heterogeneous results. We performed a systematic literature review in accordance with PRISMA guidelines, searching the PubMed and Scopus databases from their inception to November 25, 2023, to identify studies reporting on the role of FHC in patients with lung cancer. A total of 53 articles were included, most with a retrospective design and encompassing a variety of geographical areas and ethnicities. Thirty studies (56.6%) assessed patients with non-small cell lung cancer (NSCLC), while 17 studies (32.1%) assessed patients with mixed histologies. Overall, the rates of FHC ranged from 8.3 to 68.9%, and the rates of family history of lung cancer ranged from 2 to 46.8%. Twenty-seven studies investigated FHC as a potential risk factor for lung cancer, with more than half reporting an increased risk for subjects with FHC. Five studies reported on the potential role of FHC in determining clinical outcomes, and twelve studies examined the relationship between FHC and germline mutations. Notably, only one study reported a significantly increased rate of germline mutations, including ATM, BRCA2, and TP53, for patients with a family history of lung cancer compared to those without, but both groups had a low prevalence of mutations (

Abstract Frailty is a common age-related clinical syndrome characterized by a decline in the function of multiple organ systems, increased vulnerability to stressors, and a huge socio-economic burden. Despite recent research efforts, the physiopathological mechanisms underlying frailty remain elusive and biomarkers able to predate its occurrence in the early stages are still lacking. Beyond its physical component, cognitive decline represents a critical domain of frailty associated with higher risk of adverse health outcomes. We measured by High-Performance Liquid Chromatography (HPLC) a pool of serum amino acids including L-glutamate, L-aspartate, glycine, and D-serine, as well as their precursors L-glutamine, L-asparagine, and L-serine in a cohort of elderly subjects encompassing the entire continuum from fitness to frailty. These amino acids are known to orchestrate excitatory and inhibitory neurotransmission, and in turn, to play a key role as intermediates of energy homeostasis and in liver, kidney, muscle, and immune system metabolism. To comprehensively assess frailty, we employed both the Edmonton Frail Scale (EFS), as a practical tool to capture the multidimensionality of frailty, and the frailty phenotype, as a measure of physical function. We found that D-serine and D-/Total serine ratio were independent predictors of EFS but not of physical frailty. Furthermore, higher levels of glycine, glycine/L-serine and D-/Total serine were associated with worse cognition and depressive symptoms in the frail group. These findings suggest that changes in peripheral glycine and serine enantiomers homeostasis may represent a novel biochemical correlate of frailty.

Abstract Plastic foams, near-ubiquitous in everyday life and industry, show properties that depend primarily on density. Density measurement, although straightforward in principle, is not always easy. As such, while several methods are available, plastic foam industry is not yet supported with a standard technique that effectively enables to control density maps. To overcome this issue, this paper proposes Terahertz (THz) time-of-flight imaging using normal reflection measurements as a fast, relatively cheap, contactless, non-destructive and non-dangerous way to map plastic foam density, based on the expected relationship between density and refractive index. The approach is demonstrated in the case of polypropylene foams. First, the relationship between the estimated effective refractive index and the polypropylene foam density is derived by characterizing a set of carefully crafted samples having uniform density in the range 70–900 kg/m3. The obtained calibration curve subtends a linear relationship between the density and the refractive index in the range of interest. This relationship is validated against a set of test samples, whose estimated average densities are consistent with the nominal ones, with an absolute error lower than 10 kg/m3 and a percentage error on the estimate of 5%. Exploiting the calibration curve, it is possible to build quantitative images depicting the spatial distribution of the sample density. THz images are able to reveal the non-uniform density distribution of some samples, which cannot be appreciated from visual inspection. Finally, the complex spatial density pattern of a graded foam sample is characterized and quantitatively compared with the density map obtained via X-ray microscopy. The comparison confirms that the proposed THz approach successfully determines the density pattern with an accuracy and a spatial scale variability compliant with those commonly required for plastic foam density estimate.

Background: Patients with head and neck cancer (HNC) bear a significant load, due to both disease-related symptoms and to toxicities associated with treatments. Evaluating quality of life (QoL) is crucial to gauge the physical and psychological impact on these patients. Our primary aim was to assess whether QoL has been incorporated as an endpoint in phase II and III clinical trials for HNC patients in the last 15 years. Material and methods: We investigated publications from 11 major journals to identify randomized and non-randomized phase II and phase III clinical trials assessing locoregional and systemic treatments as either single or multimodal strategies, published from 2008 to March 2023 in patients with HNC. Results: We screened 2045 studies and we selected 158 articles that met the eligibility criteria including a total of 31.734 patients. Globally, QoL was the primary end point in 2 publications (1 %), secondary in 38 (24 %), and exploratory in 7 (4 %). The quota of primary publications with QoL among endpoints increased over time: 14 (17 %) publications between 2008 and 2015 and 33 (42 %) between 2016 and 2023. Notably, in phase III trials, QoL was included among endpoints in 30 (49 %) publications, whereas in phase II studies, QoL was present in 17 (17 %). Conclusions: In HNC, the assessment of QoL as an endpoint in clinical trials is still missing, even in phase III trials. Efforts should be focused on the adoption of Patient-Reported Outcomes (PROs) in trials to improve the definition of treatment value in this vulnerable population.

Background: Inclusion of patient-reported outcomes (PROs) in oncology clinical trials is strongly recommended. However, selecting the most appropriate patient-reported outcome measures (PROMs) is not easy. This study aimed to develop a breast cancer (BC) specific comprehensive archive of PROMs. Methods: As part of the PRO4All project, we identified available PROMs in oncology by searching facit.org, eortc.org, eprovide.mapi-trust.org, PubMed, ema.europa.eu (European Public Assessment Reports) and published reviews. For this analysis, only BC tools were extracted. We described information about PROM name, type of questionnaire, questionnaire variant(s), recall period, number of items, and presence of minimum clinically important difference (MCID) reference in literature. Then, we assigned each item to a specific domain according to a predefined taxonomy of 38 items for outcome classification. Results: We identified and analyzed 383 PROMs. Of these, 29 were BC specific, but 2 were excluded because the questionnaires description was not available. 6 (22.2 %) were variants of another questionnaire. All questionnaires were self-reported. In 6 cases (22.2 %) the recall period to consider was the “last week”. The mean number of items per questionnaire was 25.81 (range 6–71). 602 items were assigned to an outcome domain: emotional functioning/wellbeing in 26.6 % of cases, physical functioning in 14.1 %, delivery of care in 10.8 %, and general outcomes in 10.5 %. MCID reference was found only in 4 (14.8 %) cases. Conclusions: The newly developed archive represents a useful tool to optimize the use of PROMs in the evaluation of treatments in BC patients, promoting a patient-centered approach both in clinical research and practice.

An emergence of multidrug-resistant (MDR) Staphylococcus haemolyticus has been observed in the neonatal intensive care unit (NICU) of Nîmes University Hospital in southern France. A case–control analysis was conducted on 96 neonates, to identify risk factors associated with S. haemolyticus infection, focusing on clinical outcomes. Forty-eight MDR S. haemolyticus strains, isolated from neonates between October 2019 and July 2022, were investigated using routine in vitro procedures and whole-genome sequencing. Additionally, five S. haemolyticus isolates from adult patients were sequenced to identify clusters circulating within the hospital environment. The incidence of neonatal S. haemolyticus was significantly associated with low birth weight, lower gestational age, and central catheter use (p

Introdução A busca de referências sobre divulgação/disseminação de ATS para profissionais de saúde e para docentes de faculdades da área de saúde, revela uma lacuna na produção do conhecimento sobre o acesso desse público a essa temática. Destacamos que esses profissionais e docentes são responsáveis pelo diagnóstico, solicitação de exames, prescrições; ensino e preceptoria para adoção de tecnologias eficazes, efetivas e eficientes e contribuem para a evolução do conhecimento científico. Objetivo Identificar a usabilidade e o interesse de profissionais e docentes, em relação a um informe com a divulgação da incorporação e desincorporação de tecnologias no SUS em um hospital universitário na cidade do Rio de Janeiro em 2022. Métodos Estudo transversal quantitativo, com amostra não probabilística de profissionais e docentes de um hospital universitário, utilizando um questionário autoaplicável no forms para identificar a usabilidade dos dados de um informe que divulga internamente desde 2015, resultados de ATS pela CONITEC e o interesse no recebimento desse tipo de material. Resultados Responderam ao forms 153 (n para 90% de confiança =113) representantes da comunidade hospitalar, sendo 50,3% profissionais de saúde, 30,5% docentes e 19% técnicos administrativos. Em relação ao recebimento do informe do Núcleo de Avaliação de tecnologias em Saúde (NATS) do hospital no período 2015 a 2021, 52,3% responderam sim, 31,4% não lembravam e 16,3% declararam nunca ter recebido. Declararam abrir e ler o informe 72 respondentes (90%) dos que receberam e destes 95% consideram as informações relevantes ou muito relevantes. Dentre os respondentes que receberam os informes, abriram e leram, 31,2% declararam já ter utilizado as informações na docência, 45% na pratica clínica, 57,5% no processo de trabalho e 37,5% em outras situações. Dentre os 153 respondentes, 74,5% declararam ter interesse em participar de conversa remota sobre ATS, 13,1% não ter interesse e 12,4% não souberam responder. Em relação a continuar recebendo o informe NATS 83,7% disseram que sim, 7,8% não e 8,5% disseram não saber. Discussão e conclusões Com vistas a equidade na disseminação/divulgação de informações sobre ATS, o acesso por profissionais de saúde e docentes é importante já que esse público é estratégico para a institucionalização das decisões da CONITEC em prol de um SUS de qualidade.

Background Whether the presence of right ventricular (RV) dysfunction may influence the clinical outcome of patients with low‐flow, low‐gradient aortic stenosis (LFLG‐AS) undergoing transcatheter aortic valve replacement (TAVR) has not yet been established. Methods and Results This study included consecutive patients with LFLG‐AS undergoing TAVR at 2 high‐volume Italian centers. RV dysfunction before TAVR procedure was defined as tricuspid annular plane systolic excursion assessed by transthoracic echocardiography lower than

Summary: Background: We studied the poorly-known dynamics of circulating DNA (cir-nDNA), as monitored prospectively over an extended post-surgery period, in patients with cancer. Methods: On patients with stage III colon cancer (N = 120), using personalised molecular tags we carried out the prospective, multicenter, blinded cohort study of the post-surgery serial analysis of cir-nDNA concentration. 74 patients were included and 357 plasma samples tested. Findings: During post-operative follow-up, the patients’ median cir-nDNA concentration was greater (P 18 months post-surgery, the data suggest that the persistence of NETs formation is not due to the adjuvant CT. Interpretation: (1), Given the inter-patient heterogeneity, the post-surgery cir-nDNA level cannot be considered a reliable value, and caution must be exercised when determining mutation allele frequency or the mutation status; and (2), specific studies must be undertaken to investigate the possible clinical impact of the persistent, low-grade inflammation resulting from elevated NETs levels, such as observed in these post-surgery patients, given that such levels are known to potentially induce adverse cardiovascular or thrombotic events. Funding: This work was supported by the H2020 European ERA-NET grant on Translational Cancer Research (TRANSCAN-2).

Abstract Background Variable number tandem repeats (VNTRs) are highly polymorphic DNA regions harboring many potentially disease-causing variants. However, VNTRs often appear unresolved (“dark”) in variation databases due to their repetitive nature. One particularly complex and medically relevant VNTR is the KIV-2 VNTR located in the cardiovascular disease gene LPA which encompasses up to 70% of the coding sequence. Results Using the highly complex LPA gene as a model, we develop a computational approach to resolve intra-repeat variation in VNTRs from largely available short-read sequencing data. We apply the approach to six protein-coding VNTRs in 2504 samples from the 1000 Genomes Project and developed an optimized method for the LPA KIV-2 VNTR that discriminates the confounding KIV-2 subtypes upfront. This results in an F1-score improvement of up to 2.1-fold compared to previously published strategies. Finally, we analyze the LPA VNTR in > 199,000 UK Biobank samples, detecting > 700 KIV-2 mutations. This approach successfully reveals new strong Lp(a)-lowering effects for KIV-2 variants, with protective effect against coronary artery disease, and also validated previous findings based on tagging SNPs. Conclusions Our approach paves the way for reliable variant detection in VNTRs at scale and we show that it is transferable to other dark regions, which will help unlock medical information hidden in VNTRs.

Cyber-Physical Energy Systems (CPESs) integrate cyber and hardware components to ensure a reliable and safe physical power production and supply. Renewable Energy Sources (RESs) add uncertainty to energy demand that can be dealt with flexible operation (e.g., load-following) of CPES; at the same time, scenarios that could result in severe consequences due to both component stochastic failures and aging of the cyber system of CPES (commonly overlooked) must be accounted for Operation & Maintenance (O&M) planning. In this paper, we make use of Deep Reinforcement Learning (DRL) to search for the optimal O&M strategy that, not only considers the actual system hardware components health conditions and their Remaining Useful Life (RUL), but also the possible accident scenarios caused by the failures and the aging of the hardware and the cyber components, respectively. The novelty of the work lies in embedding the cyber aging model into the CPES model of production planning and failure process; this model is used to help the RL agent, trained with Proximal Policy Optimization (PPO) and Imitation Learning (IL), finding the proper rejuvenation timing for the cyber system accounting for the uncertainty of the cyber system aging process. An application is provided, with regards to the Advanced Lead-cooled Fast Reactor European Demonstrator (ALFRED).

Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca2+ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson's disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca2+/CaM, thus impeding the formation of the CaMKIIα:Ca2+/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca2+/CaM interaction. We observed CaMKIIα:Ca2+/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson's disease (PD) patients' specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca2+/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O2●-) and hydrogen peroxide (H2O2) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca2+/CaM complex disruption associated to a stable Ca2+CAM-independent CaMKIIα kinase activity and intracellular Ca2+ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.

The ketogenic diet (KD) is marked by a substantial decrease in carbohydrate intake and an elevated consumption of fats and proteins, leading to a metabolic state referred to as “ketosis,” where fats become the primary source of energy. Recent research has underscored the potential advantages of the KD in mitigating the risk of various illnesses, including type 2 diabetes, hyperlipidemia, heart disease, and cancer. The macronutrient distribution in the KD typically entails high lipid intake, moderate protein consumption, and low carbohydrate intake. Restricting carbohydrates to below 50 g/day induces a catabolic state, prompting metabolic alterations such as gluconeogenesis and ketogenesis. Ketogenesis diminishes fat and glucose accumulation as energy reserves, stimulating the production of fatty acids. Neurodegenerative diseases, encompassing Alzheimer’s disease, Parkinson’s disease are hallmarked by persistent neuroinflammation. Evolving evidence indicates that immune activation and neuroinflammation play a significant role in the pathogenesis of these diseases. The protective effects of the KD are linked to the generation of ketone bodies (KB), which play a pivotal role in this dietary protocol. Considering these findings, this narrative review seeks to delve into the potential effects of the KD in neuroinflammation by modulating the immune response. Grasping the immunomodulatory effects of the KD on the central nervous system could offer valuable insights into innovative therapeutic approaches for these incapacitating conditions.

The number of primary total hip arthroplasties (THAs) and revisions is expected to steadily grow in the future. The femoral revision surgery can be technically demanding whether severe bone defects need to be addressed. The femoral revision aims to obtain a proper primary stability of the stem with a more proximal fixation as possible. Several authors previously proposed classification systems to describe the morphology of the bony femoral defect and to drive accordingly the surgeon in the revision procedure. The previous classifications mainly considered cortical and medullary bone at the level of the defect of poor quality by definition. Therefore, the surgical strategies aimed to achieve a distal fixation bypassing the defect or to fill the defect with bone impaction grafting or structured bone grafts up to the replacement of the proximal femur with megaprosthesis. The consensus on a comprehensive and reliable classification system and management algorithm is still lacking. A new classification system should be developed taking into account the bone quality. The rationale of a new classification is that ‘functional’ residual bone stock could be present at the level of the defect. Therefore, it can be used to achieve a primary (mechanical) and secondary (biological) stability of the implants with a femoral fixation more proximal as possible.