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Staphylococcus aureus is a prevalent pathogen in pneumonia and harbors glycolipids, which may serve as molecular patterns in Mincle (macrophage-inducible C-type lectin)-dependent pathogen recognition. We examined the role of Mincle in lung defense against S aureus in wild-type (WT), Mincle knockout (KO), and Mincle transgenic (tg) mice. Two glycolipids, glucosyl-diacylglycerol (Glc-DAG) and diglucosyl-diacylglycerol (Glc2-DAG), were purified, of which only Glc-DAG triggered Mincle reporter cell activation and professional phagocyte responses. Proteomic profiling revealed that Glc2-DAG blocked Glc-DAG-induced cytokine responses, thereby acting as inhibitor of Glc-DAG/Mincle signaling. WT mice responded to S aureus with a similar lung pathology as Mincle KO mice, most likely due to Glc2-DAG-dependent inhibition of Glc-DAG/Mincle signaling. In contrast, ectopic Mincle expression caused severe lung pathology in S aureus-infected mice, characterized by bacterial outgrowth and fatal pneumonia. Collectively, Glc2-DAG inhibits Glc-DAG/Mincle-dependent responses in WT mice, whereas sustained Mincle expression overrides Glc2-DAG-mediated inhibitory effects, conferring increased host susceptibility to S aureus.
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Lectinas Tipo C , Proteínas de Membrana , Camundongos Knockout , Pneumonia Estafilocócica , Staphylococcus aureus , Animais , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/imunologia , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Suscetibilidade a Doenças , Citocinas/metabolismoRESUMO
Assessment of lung function is an important clinical tool for the diagnosis and monitoring of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In mice, lung function maneuvers use algorithm-based ventilation strategies including forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure-volume (PV) maneuvers via the FlexiVent system. This lung function test (LFT) is usually performed as end-point measurement only, requiring several mice for each time point to be analyzed. Repetitive lung function maneuvers would allow monitoring of a disease process within the same individual while reducing the numbers of laboratory animals. However, its feasibility in mice and impact on developing lung fibrosis has not been studied so far. Using orotracheal cannulation without surgical exposure of the trachea, we examined the tolerability to repetitive lung function maneuvers (up to four times) in one and the same mouse, both under healthy conditions and in a model of AdTGF-ß1 induced lung fibrosis. In essence, we found that repetitive invasive lung function maneuvers were well tolerated and did not accentuate experimental lung fibrosis in mice. This study contributes to the 3R principle aiming to reduce the numbers of experimental animals used in biomedical research.
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Modelos Animais de Doenças , Testes de Função Respiratória , Animais , Camundongos , Pulmão/fisiopatologia , Pulmão/patologia , Fibrose Pulmonar/fisiopatologia , Fibrose Pulmonar/patologia , Camundongos Endogâmicos C57BL , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Fibrose Pulmonar Idiopática/fisiopatologia , Fibrose Pulmonar Idiopática/patologiaRESUMO
OBJECTIVES: Neutrophil extracellular trap formation and cell-free DNA (cfDNA) contribute to the inflammation in rheumatoid arthritis (RA), but it is unknown if mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) is more abundant in the circulation. It is unclear if DNA concentration measurements may assist in clinical decision-making. METHODS: This single-center prospective observational study collected plasma from consecutive RA patients and healthy blood donors. Platelets were removed, and mtDNA and nDNA copy numbers were quantified by polymerase chain reaction (PCR). RESULTS: One hundred six RA patients and 85 healthy controls (HC) were recruited. Circulating median mtDNA copy numbers were increased 19.4-fold in the plasma of patients with RA (median 1.1 x108 copies/mL) compared to HC (median 5.4 x106 copies/mL, p<0.0001). Receiver operating characteristics (ROC) curve analysis of mtDNA copy numbers identified RA patients with high sensitivity (92.5%) and specificity (89.4%) with an area under the curve (AUC) of 0.97, p <0.0001 and a positive likelihood ratio of 8.7. Demographic, serological (rheumatoid factor (RF) positivity, anti-citrullinated protein antibodies (ACPA) positivity) and treatment factors were not associated with DNA concentrations. mtDNA plasma concentrations, however, correlated significantly with disease activity score-28- erythrocyte sedimentation rate (DAS28-ESR) and increased numerically with increasing DAS28-ESR and clinical disease activity index (CDAI) activity. MtDNA copy numbers also discriminated RA in remission (DAS28 <2.6) from HC (p<0.0001). Also, a correlation was observed between mtDNA and the ESR (p = 0.006, R= 0.29). Similar analyses showed no significance for nDNA. CONCLUSION: In contrast to nDNA, mtDNA is significantly elevated in the plasma of RA patients compared with HC. Regardless of RA activity, the abundance of circulating mtDNA is a sensitive discriminator between RA patients and HC. Further validation of the diagnostic value of mtDNA testing is required.
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Artrite Reumatoide , Biomarcadores , DNA Mitocondrial , Inflamação , Humanos , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , DNA Mitocondrial/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Idoso , Estudos Prospectivos , Adulto , Inflamação/sangue , Inflamação/diagnósticoRESUMO
OBJECTIVE: Automated machine learning (autoML) platforms allow health care professionals to play an active role in the development of machine learning (ML) algorithms according to scientific or clinical needs. The aim of this study was to develop and evaluate such a model for automated detection and grading of distal hand osteoarthritis (OA). METHODS: A total of 13,690 hand radiographs from 2,863 patients within the Swiss Cohort of Quality Management (SCQM) and an external control data set of 346 non-SCQM patients were collected and scored for distal interphalangeal OA (DIP-OA) using the modified Kellgren/Lawrence (K/L) score. Giotto (Learn to Forecast [L2F]) was used as an autoML platform for training two convolutional neural networks for DIP joint extraction and subsequent classification according to the K/L scores. A total of 48,892 DIP joints were extracted and then used to train the classification model. Heatmaps were generated independently of the platform. User experience of a web application as a provisional user interface was investigated by rheumatologists and radiologists. RESULTS: The sensitivity and specificity of this model for detecting DIP-OA were 79% and 86%, respectively. The accuracy for grading the correct K/L score was 75%, with a κ score of 0.76. The accuracy per DIP-OA class differed, with 86% for no OA (defined as K/L scores 0 and 1), 71% for a K/L score of 2, 46% for a K/L score of 3, and 67% for a K/L score of 4. Similar values were obtained in an independent external test set. Qualitative and quantitative user experience testing of the web application revealed a moderate to high demand for automated DIP-OA scoring among rheumatologists. Conversely, radiologists expressed a low demand, except for the use of heatmaps. CONCLUSION: AutoML platforms are an opportunity to develop clinical end-to-end ML algorithms. Here, automated radiographic DIP-OA detection is both feasible and usable, whereas grading among individual K/L scores (eg, for clinical trials) remains challenging.
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Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-ß1 (AdTGF-ß1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH2O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH2O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-ß1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5-8 cmH2O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-ß1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH2O. A further decrease in Pao down to 2 cmH2O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2-5 cmH2O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-ß1 exposed mice is high. H is optimized at PEEP 5-8 cmH2O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-ß1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH2O argues for the use of PEEP = 8 cmH2O for lung protective mechanical ventilation in this animal model.
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Atelectasia Pulmonar , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Respiração com Pressão Positiva/métodos , Pulmão , Alvéolos Pulmonares/fisiologiaRESUMO
For five years now, Merck KGaA, Darmstadt, Germany has hosted The Compound Challenge-a global retrosynthesis competition. When the event kicked off in 2018 on the occasion of the 350th anniversary of the company, no one could have predicted the path it would take-from a novel competition to a pivotal event within the synthetic chemistry community. But what makes the Compound Challenge tick and what drives its popularity? And, more importantly, what lessons can be taken from the Compound Challenge and applied to other challenges in scientific education and outreach? In this Viewpoint Article we will tell the story of the Compound Challenge, from its inception to its current status. Through examining feedback following each of its iterations, we begin to define what makes an open innovation challenge so compelling. It is our hope that educators, leaders, and innovators will be able to learn from our successes as well as our mistakes and apply these lessons to their future outreach activities.
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Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.
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Heterozigoto , Hidropisia Fetal , Mutação de Sentido Incorreto , Humanos , Feminino , Mutação de Sentido Incorreto/genética , Hidropisia Fetal/genética , Hidropisia Fetal/patologia , Gravidez , Derrame Pleural/genética , Derrame Pleural/patologia , Caderinas/genética , Sequenciamento do Exoma , Polaridade Celular/genéticaRESUMO
The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50â years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.
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Deficiência Intelectual , Microcefalia , Transtornos dos Movimentos , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Animais , Feminino , Humanos , Masculino , Transportadores de Cassetes de Ligação de ATP , Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Malformações do Sistema Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Tremor , Peixe-Zebra , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-IdadeRESUMO
In this review, the advantages of the robotic platform in rTAPP are presented and discussed. Against the background of the unchanged results of conventional TAPP for decades (approx. 10% chronic pain and approx. 3.5% recurrence), a new anatomy-guided concept for endoscopic inguinal hernia repair with the robot is presented. The focus is on the identification of Hesselbach's ligament. The current results give hope that the results of TAPP can be improved by rTAPP and that rTAPP is not just a more expensive version of conventional TAPP. To support the rationale presented here, we analyzed 132 video recordings of rTAPP's for the anatomical structures depicted therein. The main finding is, that in all cases (132/132 or 100%) Hesselbach's ligament was present and following its lateral continuity with the ileopubic tract offered a safe framework to develop all the critical anatomical structures for clearing the myopectineal orifice, repair the posterior wall of the groin and perform a flawless mesh fixation. Future studies are needed to integrate all the resources of the robotic platform into an rTAPP concept that will lead out of the stalemate of the indisputably high rate of chronic pain and recurrences.
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Dor Crônica , Hérnia Inguinal , Laparoscopia , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Hérnia Inguinal/cirurgia , Virilha/cirurgia , Dor Crônica/cirurgia , Herniorrafia/métodos , Laparoscopia/métodosRESUMO
An innovative strategy to address recent challenges in the oral administration of poorly soluble drugs is the formulation of amorphous solid dispersions (ASDs), where the drug is dissolved in a highly soluble carrier polymer. Therefore, special knowledge of the drug-polymer phase behavior is essential for an effective product and process design, accelerating the introduction of novel efficacious ASD products. Flory-Huggins theory can be applied to model solubility temperatures of crystalline drugs in carrier polymers over the drug fraction. However, predicted solubility temperatures lack accuracy in cases of strong drug/polymer interactions that are not represented in the Flory-Huggins lattice model. Within this study, a modeling strategy is proposed to improve the predictive power through an extension of the Flory-Huggins interaction parameter by a correlation with the drug fraction. Therefore, the composition dependency of the Flory-Huggins interaction parameter was evaluated experimentally for various drug-polymer formulations that cover a wide variety of drug and polymer characteristics regarding molecular weights, glass transition temperatures and melting temperatures, as well as drug-polymer interactions of different strengths and effects. The extended model was successfully approved for nine exemplary ASD formulations containing the drugs acetaminophen, itraconazole, and griseofulvine, as well as the following polymers: basic butylated methacrylate copolymer, Soluplus®, and vinylpyrrolidone/vinyl acetate copolymer. A high correlation between the predicted solubility temperatures and experimental and literature data was found, particularly at low drug fractions, since the model accounts for composition dependent drug-polymer interactions.
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BACKGROUND: Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS: 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS: Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.
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Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Pulmão , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/induzido quimicamente , Imunossupressores/uso terapêutico , Inflamação/induzido quimicamenteRESUMO
BACKGROUND: Mesenchymal stromal cells (MSCs) are excessively investigated in the context of inflammation-driven diseases, but the clinical results are often moderate. MSCs are naturally activated by inflammatory signals, which lead to the secretion of immune inhibitory factors in inflamed tissues. Many work groups try to improve the therapeutic outcome of MSCs by genetic modification and the constitutive overexpression of immune modulatory transgenes. However, the ectopic secretion of immune inhibitory transgenes increases the chances of infections, and constitutive transgene expression is not necessary for chronic diseases undergoing different inflammatory stages. METHODS: We designed and tested inflammation-induced promoters to control transgene expression from integrating lentiviral vectors in human umbilical cord MSCs. Therefore, we investigated different combinations of general transcription factor elements to achieve a minimal promoter with low basal activity. The best candidates were combined with interferon-induced GAS or ISRE DNA motifs. The constructs with the highest transgene expression upon addition of pro-inflammatory cytokines were compared to vectorized promoters from inflammation-induced genes (CD317, CXCL9, CXCL10, CXCL11 and IDO1). Finally, we investigated IL10 as a potential immune inhibitory transgene by transcriptome analyses, ELISA and in an acute lung injury mouse model. RESULTS: The synthetic promoters achieved a high and specific transgene expression upon IFN-γ addition. However, the CXCL11 promoter showed synergistic activity upon IFN-γ, TNF-α and IL1-ß treatment and surpassed the transgene expression height of all tested promoters in the study. We observed in transcriptome analyses that IL10 has no effect on MSCs and in ELISA that IL10 is only secreted by our genetically modified and activated CXCL11-IL10-MSCs. Finally, transplanted CXCL11-IL10-MSCs increased CD19+ and CD4+ lymphoid cells, and decreased CD11b+ Ly6g myeloid cells in an ALI mouse model. CONCLUSION: These results provide new insights into MSC inflammatory activation and the subsequent translation into a tool for a tailored expression of transgenes in inflammatory microenvironments. The newly developed promoter elements are potentially interesting for other inflamed tissues, and can be combined with other elements or used in other cell types.
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Interleucina-10 , Células-Tronco Mesenquimais , Humanos , Animais , Camundongos , Interleucina-10/genética , Transgenes , Fatores Imunológicos , Ensaio de Imunoadsorção EnzimáticaRESUMO
Background: Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking. Aims: To describe the systemic sclerosis-primary biliary cholangitis phenotype, including baseline characteristics and outcomes. Methods: We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis-specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit. Results: A total of 261 patients were enrolled (115 primary biliary cholangitis-systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis-primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies (p = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis-systemic sclerosis patients (p = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension (p < 0.001) and of conduction blocks (p = 0.0256) was observed in systemic sclerosis patients without primary biliary cholangitis. Patients with primary biliary cholangitis had higher levels of liver enzymes at baseline than systemic sclerosis patients; a significant decrease in liver enzymes was observed at follow-up. Out of 18 patients with cholangitis, one received a liver transplant at follow-up. Conclusion: Our data show that systemic sclerosis-primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable.
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S100A8/A9 has important immunomodulatory roles in antibacterial defense, but its relevance in focal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) is understudied. We show that S100A9 was significantly increased in BAL fluids of patients with bacterial but not viral pneumonia and correlated with procalcitonin and sequential organ failure assessment scores. Mice deficient in S100A9 exhibited drastically elevated Zn2+ levels in lungs, which led to bacterial outgrowth and significantly reduced survival. In addition, reduced survival of S100A9 KO mice was characterized by excessive release of neutrophil elastase, which resulted in degradation of opsonophagocytically important collectins surfactant proteins A and D. All of these features were attenuated in S. pneumoniae-challenged chimeric WTâS100A9 KO mice. Similarly, therapy of S. pneumoniae-infected S100A9 KO mice with a mutant S100A8/A9 protein showing increased half-life significantly decreased lung bacterial loads and lung injury. Collectively, S100A9 controls central antibacterial immune mechanisms of the lung with essential relevance to survival of pneumococcal pneumonia. Moreover, S100A9 appears to be a promising biomarker to distinguish patients with bacterial from those with viral pneumonia. Trial registration: Clinical Trials register (DRKS00000620).
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Pneumonia Pneumocócica , Camundongos , Animais , Calgranulina B/genética , Calgranulina B/metabolismo , Pulmão , Streptococcus pneumoniae/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Bactérias/metabolismo , Camundongos KnockoutRESUMO
Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins. Here, we present a brief progress update on Target 2035 and highlight some of industry's contributions.
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BACKGROUND: The Chronic Care Model (CCM) is a longstanding and widely adopted model guiding chronic illness management. Little is known about how CCM elements are implemented in rare disease care or how patients' care experiences relate to health-related quality of life (HRQoL). We engaged patients living with systemic sclerosis (SSc) to assess current care according to the CCM from the patient perspective and their HRQoL. METHODS: We employed an explanatory sequential mixed methods design. First, we conducted a cross-sectional quantitative survey (n = 101) using the Patient Assessment of Chronic Illness Care (PACIC) and Systemic Sclerosis Quality of Life (SScQoL) questionnaires. Next, we used data from individual patient interviews (n = 4) and one patient focus group (n = 4) to further explore care experiences of people living with SSc with a focus on the PACIC dimensions. RESULTS: The mean overall PACIC score was 3.0/5.0 (95% CI 2.8-3.2, n = 100), indicating care was 'never' to 'generally not' aligned with the CCM. Lowest PACIC subscale scores related to 'goal setting/tailoring' (mean = 2.5, 95% CI 2.2-2.7) and 'problem solving/contextual counselling' (mean = 2.9, 95% CI 2.7-3.2). No significant correlations were identified between the mean PACIC and SScQoL scores. Interviews revealed patients frequently encounter major shortcomings in care including 'experiencing organized care with limited participation', 'not knowing which strategies are effective or harmful' and 'feeling left alone with disease and psychosocial consequences'. Patients often responded to challenges by 'dealing with the illness in tailored measure', 'taking over complex coordination of care' and 'relying on an accessible and trustworthy team'. CONCLUSIONS: The low PACIC mean overall score is comparable to findings in patients with common chronic diseases. Key elements of the CCM have yet to be systematically implemented in Swiss SSc management. Identified gaps in care related to lack of shared decision-making, goal-setting and individual counselling-aspects that are essential for supporting patient self-management skills. Furthermore, there appears to be a lack of complex care coordination tailored to individual patient needs.