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Introdução: O diagnóstico de tuberculose (TB) na infância fundamenta-se na aplicação de escore clínico. Febre é o sintoma mais frequente tanto na forma de TB pulmonar quanto extrapulmonar (TBE). A disseminação da TB associa-se ao comprometimento imunológico por doenças subjacentes ou ausência de vacinação levando a formas graves de TB/TBE. Este caso se inicia como febre de origem indeterminada (FOI) levando 17 meses para diagnosticar TB em aparelho auditivo (TBA) em criança, sexo, feminino, de 10 anos. Objetivo: Apresentar manifestações clínicas, diagnóstico e evolução de um caso raro de TBA. Método: Relato de caso baseado em dados clínicos e laboratoriais de prontuário. Resultados: Queixa inicial otalgia em orelha esquerda (OE) e febre tratada como otite média aguda em abril/2022 com amoxicilina com melhora. Recidiva otalgia, odinofagia e febre acima de 38°C intermitentes por 4 meses.Em junho/2022 inicia tosse produtiva, radiografia de tórax normal, tratada como IVAS. É internada por FOI, apresentou derrame pericárdico suspeito de endocardite, realizada punção de Marfan, culturas negativas, biópsia inconclusiva, investigação reumatológica suspeita de lúpus eritematoso sistêmico ou síndrome genética. Recebeu pulso terapia com corticoide que resolveu a febre, iniciou 1mg/kg/dia de prednisona uso contínuo. Evolui com hematúria, hipertensão arterial, apatia e fácies cushingoide. Março/2023 piora a otalgia, zumbido, hipoacusia e secreção purulenta em OE. Novamente internada, na tomografia de mastoide apresentou pólipo em orelha média esquerda, com bióspia excesional em julho/23: processo inflamatório granulomatoso com reação gigantocelular de tipo Langhans, necrotizante, com granulomas confluentes, pesquisa histoquímica para BAAR positiva. Manteve tosse produtiva, baciloscopia no escarro positiva. Foi iniciado rifampicina (R), isoniazida (H), pirazinamida, etambutol na fase de ataque, segue em fase de manutenção com RH. Realizado desmame de corticoide e hipotensores com remissão total da febre, dos sintomas otológicos, urinários, vasculares e psíquicos em 90 dias. No quarto mês houve drenagem de secreção purulenta pela cicatriz da punção de Marfan, sem fístula, com resolução em 40 dias, derrame pericárdico residual em ecocardiograma preservada função cardiológica. Segue em tratamento, mantendo ferida operatória retroauricular OE em cicatrização por segunda intenção. Conclusão: TBA foi a principal manifestação de TB disseminada isso mostra a importância de insistir na busca por TB/TBE na presença de FOI no Brasil.

Introdução: Tuberculose ocular (TO) é uma forma rara de tuberculose extrapulmonar (TE), tem apresentação clínica variável, apresenta poucos dados na literatura e o diagnóstico é realizado de forma presumida. Neste estudo levantamos dados de casos do Programa de Controle de Tuberculose (TB) de São Bernardo do Campo, SP. Objetivo: Análise do perfil epidemiológico dos casos de TO de um serviço de referência terciária para TB. Método: Foram analisados retrospectivamente casos diagnosticados e tratados no período de 01/01/2018 a 31/12/2023, através da plataforma TBWEB e prontuário. O diagnóstico de TO foi realizado segundo 3 critérios, dois obrigatórios para o início do tratamento: a) apresentação clínica oftalmológica, b) teste tuberculínico maior de 10mm (ou IGRA reagente); e o terceiro critério avaliado após 6 meses: c) resposta terapêutica. Os dados foram comparados com dados de literatura publicada. Resultados: Avaliou-se 35 casos de TO, correspondendo a 2,1% do total os casos de TB (1652) e 11,1% dos casos de TE (314), dados de literatura relatam 2% de TO em relação à frequência de TE. A faixa etária adulta entre 18 e 60 anos abrangeu 97,1%(34) dos casos. Quanto ao sexo 71,4%(25) femininos e 28,6%(10) masculinos. A forma clínica predominante 31,4%(11) foi uveíte unilateral, 20%(7) uveíte bilateral, 17,1%(6) esclerite unilateral e 8,6%(3) coriorretinites, outras apresentações somaram 22,9%(8) dos casos. Dos sintomas: 49%(17) relataram perda parcial da visão, 23%(8) turvação visual, 23%(8) hiperemia e 11%(4) dor ocular. Quanto à exposição 62,8%(22) eram não expostos para TB, 28,6%(10) eram contato de TB confirmado, 8,6%(3) trataram TB pulmonar. Das comorbidades:14,3%(5) diabetes. Diagnóstico diferencial: 48%(17) excluíram outras doenças infecciosas (HIV, CMV, sífilis e toxoplasmose) e 17,1%(6) excluíram doenças reumatológicas. O tratamento em 100%(35) dos casos foi: rifampicina, isoniazida, pirazinamida e etambutol, via oral; variando entre: 6 meses 40%(14) dos casos, 7 meses 8,6%(3), 9 meses 25,7%(9) e 12 meses 17,1%(6). Desfecho: 40%(14) apresentaram recuperação total, 28,6%(10) apresentaram melhora parcial dos sintomas, 20%(7) não melhoraram, 2,9%(1) mudaram o diagnóstico, 2,9%(1) perderam segmento por transferência, 5,7%(2) não houve registro no prontuário. Conclusão: TO apresentou frequência 5,5 vezes maior em relação aos dados de literatura, talvez por ser um serviço de referência regional. A resolutividade (total + parcial) de 68,6%(24) sugere a necessidade de investimentos em diagnóstico diferencial.

Abstract In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of several cancer hallmark pathways such as MAPK, mTOR and integrin/ILK/actin, affecting epithelial and stromal colonic cells. Importantly, an independent analysis of protein arrays of human colon tumors colonized with SGG showed up-regulation of PI3K/Akt/mTOR and MAPK pathways, providing clinical relevance to our findings. To test SGG’s capacity to induce pre-cancerous transformation of the murine colonic epithelium, we grew ex vivo organoids which revealed unusual structures with compact morphology. Taken together, our results demonstrate the oncogenic role of SGG UCN34 in a murine model of CRC associated with activation of multiple cancer-related signaling pathways.

Wildfires have short- and long-term impacts on the geoenvironment, including the changes to biogeochemical and mechanical properties of soils, landfill stability, surface- and groundwater, air pollution, and vegetation. Climate change has increased the extent and severity of wildfires across the world. Simultaneously, anthropogenic activities—through the expansion of urban areas into wildlands, abandonment of rural practices, and accidental or intentional fire-inception activities—are also responsible for a majority of fires. This paper provides an overall review and critical appraisal of existing knowledge about processes induced by wildfires and their impact on the geoenvironment. Burning of vegetation leads to loss of root reinforcement and changes in soil hydromechanical properties. Also, depending on the fire temperature, soil can be rendered hydrophobic or hydrophilic and compromise soil nutrition levels, hinder revegetation, and, in turn, increase post-fire erosion and the debris flow susceptibility of hillslopes. In addition to direct hazards, wildfires pollute air and soil with smoke and fire suppression agents releasing toxic, persistent, and relatively mobile contaminants into the geoenvironment. Nevertheless, the mitigation of wildfires’ geoenvironmental impacts does not fit within the scope of this paper. In the end, and in no exhaustive way, some of the areas requiring future research are highlighted.

Abstract Background The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients’ data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients’ data and an effective tool for data sharing; it facilitates specialists’ consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. Results Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion—amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. Conclusions In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a “map” of neuromuscular patients across Europe that might be improved by a wider use of CPMS.

ABSTRACTQuickly understanding the genomic changes that lead to pathogen emergence is necessary to launch mitigation efforts and reduce harm. In this study, we tracked in real time a 2022 bacterial plant disease outbreak in U.S. geraniums (Pelargonium × hortorum) caused by Xhp2022, a novel lineage of Xanthomonas hortorum. Genomes from 31 Xhp2022 isolates from seven states showed limited chromosomal variation and all contained a single plasmid (p93). Time tree and single nucleotide polymorphism whole-genome analysis estimated that Xhp2022 emerged within the last decade. The phylogenomic analysis determined that p93 resulted from the cointegration of three plasmids (p31, p45, and p66) found sporadically across isolates from previous outbreaks. Although p93 had a 49 kb nucleotide reduction, it retained putative fitness genes, which became predominant in the 2022 outbreak. Overall, we demonstrated, through rapid whole-genome sequencing and analysis, a recent, traceable event of genome reduction for niche adaptation typically observed over millennia in obligate and fastidious pathogens.IMPORTANCEThe geranium industry, valued at $4 million annually, faces an ongoing Xanthomonas hortorum pv. pelargonii (Xhp) pathogen outbreak. To track and describe the outbreak, we compared the genome structure across historical and globally distributed isolates. Our research revealed Xhp population has not had chromosome rearrangements since 1974 and has three distinct plasmids. In 2012, we found all three plasmids in individual Xhp isolates. However, in 2022, the three plasmids co-integrated into one plasmid named p93. p93 retained putative fitness genes but lost extraneous genomic material. Our findings show that the 2022 strain group of the bacterial plant pathogen Xanthomonas hortorum underwent a plasmid reduction. We also observed several Xanthomonas species from different years, hosts, and continents have similar plasmids to p93, possibly due to shared agricultural settings. We noticed parallels between genome efficiency and reduction that we see across millennia with obligate parasites with increased niche specificity.

Background: Dupilumab has been shown to be a safe and effective drug for the treatment of atopic dermatitis (AD) in children from 6 months to 11 years in randomized clinical trials. Aim: The aim of this real-life study was to determine the effectiveness in disease control and safety of dupilumab at W52 in moderate-to-severe AD children aged 6-11 years. Methods: All data were collected from 36 Italian dermatological or paediatric referral centres. Dupilumab was administered at label dosage with an induction dose of 300 mg on day 1 (D1), followed by 300 mg on D15 and 300 mg every 4 weeks (Q4W). Treatment effect was determined as overall disease severity, using EASI, P-NRS, S-NRS and c-DLQI at baseline, W16, W24, and W52. Ninety-six AD children diagnosed with moderate-to-severe AD and treated with dupilumab were enrolled. Results: Ninety-one (94.8%) patients completed the 52-week treatment period and were included in the study. A significant improvement in EASI score, P-NRS, S-NRS and c-DLQI was observed from baseline to weeks 16, 24 and 52. Conclusions: Our real-life data seem to confirm dupilumab effectiveness and safety in paediatric patients. Moreover, our experience highlighted that patients achieving clinical improvement at W16 preserved this condition over time.

Cytomegalovirus (CMV) is a highly prevalent pathogen that remains dormant in majority of the cases. Severe CMV infection is generally limited to immunocompromised hosts. While occasional cases of CMV hepatitis are observed in healthy immunocompetent hosts, it is very rare to find this associated with focal liver lesions mimicking malignancy. Cases of non-immunosuppressed CMV reactivation, CMV-associated liver lesions, and CMV-associated portal vein thrombosis have all been reported individually, we present a single case of CMV with all of these rare manifestations.

This study presents a novel framework in which numerical modelling contributes to the performance of district-scale, subsidence-induced damage assessment in cities where ground settlements affect entire quarters. Therein, the implementation of expeditious procedures offers geotechnical engineers the possibility of contributing beyond the typical site scale. For this purpose, several 'typified' hydro-geomechanical-loading (HGL) models, which represent (simplified) scenarios of masonry buildings undergoing settlements, were set up to account for different predisposing or triggering factors (i.e., soil heterogeneity, loading conditions, and groundwater variations) of settlement occurrence in built-up areas. These models exploit multi-source, wide-area input datasets encompassing the hydro-mechanical properties of geomaterials, in situ investigations and measurements (e.g., groundwater levels in wells), and innovative remote sensing data (i.e., DInSAR techniques). With reference to a district in Rotterdam City (the Netherlands), which was built on 'soft soils', the numerical simulations of different scenarios (i) provide an overview of the comparative role of predisposing or triggering factors on settlement occurrence and (ii) allow assessments of the expected induced damage to masonry buildings over 30 years with the exploitation of fragility curves. Considering the widespread diffusion of such geohazards, the proposed approach could help prioritise (rather expensive) maintenance work to the built heritage within sustainable strategies for subsidence risk mitigation. Key words: settlement modelling, building damage assessment, soil variability, groundwater lowering, soft soils. Le but de la presente publication est de presenter un nouveau cadre au sein duquel la modelisation numerique contribue a la performance de l'evaluation des dommages induits par les affaissements a l'echelle du quartier dans les villes ou les tassements du sol affectent des quartiers entiers. La mise en oeuvre de procedures rapides offre ainsi aux ingenieurs geotechniques la possibilite de contribuer a une evaluation au-dela de l'echelle typique du site. Dans ce but, differentsmodeles hydro-geomecaniques de chargement (HGL) << types >>, permettant de representer des scenarios (simplifies) de batiments en maconnerie subissant des tassements, ont ete mis en place pour tenir compte des differents facteurs predisposants ou declencheurs (c'est-a-dire l'heterogeneite du sol, les conditions de chargement et les variations des eaux souterraines) de l'apparition des tassements dans les zones baties. Ce sont principalement les proprietes hydro-mecaniques des geomateriaux, les enquetes et les mesures in situ (par exemple, le niveau des eaux souterraines dans les puits) et les donnees de teledetection innovantes (par exemple, les techniques DInSAR) qui sont exploitees dans ces modeles. Les simulations numeriques de differents scenarios, en se referant a un quartier de la ville de Rotterdam (Pays-Bas), construit sur des << sols mous >>, (i) fournissent une vue d'ensemble du role comparatif des facteurs predisposants ou declencheurs sur l'apparition des tassements et (ii) permettent d'evaluer les dommages induits attendus sur les batiments en maconnerie sur 30 ans grace a l'exploitation des courbes de fragilite. Dans le cadre d'une strategie durable d'attenuation des risques d'affaissement, la demarche suggeree permet de hierarchiser les travaux d'entretien (plutot couteux) du patrimoine bati, compte tenu de la diffusion generalisee de ces georisques. [Traduit par la Redaction] Mots-cles : modelisation du tassement, evaluation des dommages aux batiments, variabilite du sol, abaissement de la nappe phreatique, sols mous., 1. Introduction Many urbanised areas worldwide have subsided due to the presence of highly compressible soils (namely 'soft soils'; Erkens et al. 2015; Herrera-Garcia et al. 2021). The occurrence, magnitude, [...]

Abstract The monitoring and prediction of the groundwater level (GWL) significantly influence the landslide kinematics. Based on the long-term fluctuation characteristics of the GWL and the time lag of triggering factors, a dynamic prediction model of the GWL based on the Maximum information coefficient (MIC) algorithm and the long-term short-term memory (LSTM) model was proposed. The Sifangbei landslide in the Three Gorges Reservoir area (TGRA) in China, wherein eight GWL monitoring sensors were installed in different locations, was taken as a case study. The monitoring data represented that the fluctuation of the GWL has a specific time lag concerning the accumulated rainfall (AR) and the reservoir water level (RWL). In addition, there were spatial differences in the fluctuation of the GWL, which was controlled by the elevation and the micro landform. From January 19, 2015, to March 6, 2017, the measured data were used to set up the predicted models. The MIC algorithm was adopted to calculate the lag time of the GWL, the RWL, and the AR. The LSTM model is a time series prediction algorithm that can transmit historical information. The Gray wolf optimization (GWO) algorithm was used to seek the most suitable hyperparameter of the LSTM model under the specific prediction conditions. The single-factor GWO-LSTM model without considering triggering factors and the support vector machine regression (SVR) model were considered to compare the prediction results. The results indicate that the MIC-GWO-LSTM model reached the highest accuracy and improved the prediction accuracy by considering the factor selection process with the learner training process. The proposed MIC-GWO-LSTM model combines the advantages of each algorithm and effectively constructs the response relationship between the GWL fluctuation and triggering factors; it also provides a new exploration for the GWL prediction, monitoring, and early warning system in the TGRA.

Haploinsufficiency of FOXP1 gene is responsible for a neurodevelopmental disorder presenting with intellectual disability (ID), autism spectrum disorder (ASD), hypotonia, mild dysmorphic features, and multiple congenital anomalies. Joint contractures are not listed as a major feature of FOXP1‐related disorder. We report five unrelated individuals, each harboring likely gene disruptive de novo FOXP1 variants or whole gene microdeletion, who showed multiple joint contractures affecting at least two proximal and/or distal joints. Consistent with the phenotype of FOXP1‐related disorder, all five patients showed developmental delay with moderate‐to‐severe speech delay, ID, ASD, and facial dysmorphic features. FOXP1 is implicated in neuronal differentiation and in organizing motor axon projections, thus providing a potential developmental basis for the joint contractures. The combination of joint contractures and neurodevelopmental disorders supports the clinical suspicion of FOXP1‐related phenotype. [ABSTRACT FROM AUTHOR]

Abstract This paper proposes a three-phase method that combines multi-source (i.e. topographic, thematic, monitoring) input data in a GIS environment to rank—at small (1:250,000) scale—administrative units (e.g. municipalities) based on their exposure to slow-moving landslide risk within a selected area (e.g. a region) and, accordingly, detect those primarily requiring mitigation measures. The method is applied in the Calabria region (southern Italy) where several municipalities are widely affected by slow-moving landslides that systematically cause damage to buildings and infrastructure networks resulting in significant economic losses. The results obtained are validated based on the information gathered from previous studies carried out at large (municipal) scale. The work undertaken represents a first, fundamental step of a wider circular approach that can profitably facilitate the decision makers in addressing the issue of the slow-moving landslide risk mitigation in a sustainable way.

Summary: Predicting the pathogenicity of acceptor splice-site variants outside the essential AG is challenging, due to high sequence diversity of the extended splice-site region. Critical analysis of 24,445 intronic extended acceptor splice-site variants reported in ClinVar and the Leiden Open Variation Database (LOVD) demonstrates 41.9% of pathogenic variants create an AG dinucleotide between the predicted branchpoint and acceptor (AG-creating variants in the AG exclusion zone), 28.4% result in loss of a pyrimidine at the −3 position, and 15.1% result in loss of one or more pyrimidines in the polypyrimidine tract. Pathogenicity of AG-creating variants was highly influenced by their position. We define a high-risk zone for pathogenicity: > 6 nucleotides downstream of the predicted branchpoint and >5 nucleotides upstream from the acceptor, where 93.1% of pathogenic AG-creating variants arise and where naturally occurring AG dinucleotides are concordantly depleted (5.8% of natural AGs). SpliceAI effectively predicts pathogenicity of AG-creating variants, achieving 95% sensitivity and 69% specificity. We highlight clinical examples showing contrasting mechanisms for mis-splicing arising from AG variants: (1) cryptic acceptor created; (2) splicing silencer created: an introduced AG silences the acceptor, resulting in exon skipping, intron retention, and/or use of an alternative existing cryptic acceptor; and (3) splicing silencer disrupted: loss of a deep intronic AG activates inclusion of a pseudo-exon. In conclusion, we establish AG-creating variants as a common class of pathogenic extended acceptor variant and outline factors conferring critical risk for mis-splicing for AG-creating variants in the AG exclusion zone, between the branchpoint and acceptor.

Ilena Pochiero,1 Fabrizio Calisti,1 Alessandro Comandini,1 Alessandra Del Vecchio,1 Isabella Costamagna,1 Maria Teresa Rosignoli,1 Agnese Cattaneo,1 Sasikiran Nunna,2 Ilaria Peduto,3 Franca Heiman,3 Hsiu-Ching Chang,2 Chi-Chang Chen,2 Christoph Correll4– 6 1Angelini Regulatory, Research & Development, Angelini Pharma S.p.A., Rome, Italy; 2IQVIA, Plymouth Meeting, PA, USA; 3IQVIA Solutions Italy S.r.l., RWS, Milan, Italy; 4Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany; 5Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 6Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USACorrespondence: Ilena PochieroAngelini Pharma S.p.A., Viale Amelia 70, Rome, ItalyEmail ilena.pochiero@angelinipharma.comPurpose: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥ 7%) weight changes.Patients and Methods: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019.Results: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥ 7% weight loss was significantly greater with lurasidone versus all antipsychotics (p< 0.05), except ziprasidone.Conclusion: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.Keywords: retrospective studies, weight gain, real world clinical trials