Disease Severity Research Articles

The effect of gene dosage and age at the disease onset on the severity of familial Mediterranean fever

ABSTRACT Objective To compare the demographic and clinical characteristics of familial Mediterranean fever (FMF) patients according to age at disease onset and evaluate the dose effect of the number of pathogenic or likely pathogenic exon 10 mutations of the MEFV gene on disease severity. Methods This medical record review study was performed on 485 pediatric FMF patients with uni- or bialelic exon 10 mutations of the MEFV gene (M694V, M694I, M680I, V726A, R761H, T267I). Patients were grouped according to age at disease onset (Group 1:<6 years; Group 2:6–11 years; and Group 3:>11 years). Disease severity was assessed by the international severity scoring system for FMF (ISSF). Results Of the patients, 294 (60.6%) were classified in Group 1, 152 (31.4%) in Group 2 and 39 (8%) in Group 3. The mean elapsed time to diagnosis was 26.7 ± 27.4 months in Group 1 and was higher than the other groups (p < 0.001). During the attack, fever was higher in Group 1, arthritis in Group 2, and chest pain in Group 3 (p < 0.001). The median ISSF score was similar in patients with uni- or bialelic mutations in Group 1 and 3 (p = 0.086, p = 0.35, respectively) but lower in heterozygous patients in Group 2 (p < 0.001). In Groups 1 and 2, mild disease severity was higher in heterozygotes, while moderate disease severity was higher in homozygotes (p = 0.034, p = 0.001, respectively). Conclusion The presence of pathogenic or likely pathogenic homozygous or compound heterozygous mutations in exon 10 of the MEFV gene in patients with early-onset disease is associated with a more severe disease course compared to patients with heterozygous mutations. The gene dose effect of the number of mutations on disease severity is more common in children aged 6-11 years.

Familial hypercholesterolemia: Current limitations and future breakthroughs

Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels due to genetic mutations, presenting with xanthomas, corneal arch, and severe cardiovascular diseases. Early identification, diagnosis, and treatment are crucial to prevent severe complications like acute myocardial infarction. Statins are the primary treatment, supplemented by Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, though their effectiveness can be limited in severe cases. Over 90% of FH cases remain undiagnosed, and current treatments are often inadequate, underscoring the need for improved diagnostic and management systems. Future strategies include advancements in gene testing, precision medicine, and novel drugs, along with gene therapy approaches like AAV-mediated gene therapy and clustered regularly interspaced short palindromic repeats. Lifestyle modifications, including health education, dietary control, and regular exercise, are essential for managing FH and preventing related diseases. Research into FH-related gene mutations, especially LDLR , is critical for accurate diagnosis and effective treatment.

Divers treated in Townsville, Australia: worse symptoms lead to poorer outcomes.

Hyperbaric oxygen treatment (HBOT) is considered definitive treatment for decompression illness. Delay to HBOT may be due to dive site remoteness and limited facility availability. Review of cases may help identify factors contributing to clinical outcomes. Injured divers treated in Townsville from November 2003 through December 2018 were identified. Information on demographics, initial disease severity, time to symptom onset post-dive, time to pre-HBOT oxygen therapy (in-water recompression or normobaric), time to HBOT, and clinical outcome was reviewed. Data were reported as median (interquartile range [IQR]) with Kruskal-Wallis and chi-square tests used to evaluate group differences. Significance was accepted at P < 0.05. A total of 306 divers (184 males, 122 females) were included with a median age of 29 (IQR 24, 35) years. Most divers had mild initial disease severity (n = 216, 70%). Time to symptom onset was 60 (10, 360) min, time to pre-HBOT oxygen therapy was 4:00 (00:30, 24:27) h:min, and time to start of HBOT was 38:51 (22:11, 69:15) h:min. Most divers (93%) had a good (no residual or minor residual symptoms) outcome and no treated diver died. Higher initial disease severity was significantly associated with shorter times to symptom onset, oxygen therapy, and HBOT, and with worse outcomes. The paucity of cases receiving HBOT with minimal delay precluded meaningful evaluation of the effect of delay to HBOT. Most divers had mild initial disease severity and a good outcome. Higher initial disease severity accelerated the speed of care obtained and was the only factor associated with poorer outcome.

Predicting severe multivessel coronary artery disease to guide access strategy in patients undergoing invasive coronary angiography.

Given radial artery conduits are increasingly utilized for coronary artery bypass grafting (CABG), avoiding transradial access (TRA) for invasive coronary angiography (ICA) may benefit patients who ultimately undergo CABG. We sought to predict the likelihood of severe multivessel disease (MVD) before ICA to guide this decision. This was a single-center study of 1485 patients with stable symptoms who underwent ICA. A model to predict severe MVD was developed. Relative importance analyses were performed to identify clinical characteristics most associated with the presence or absence of severe MVD. When predicting severe MVD, the model had a sensitivity of 70.3% and specificity of 71.8% (area under the curve = 0.7105). With a prevalence of 12.5% in our cohort, the model had a strong negative predictive value of 94.4%. Relative importance analyses showed factors most associated with the presence of severe MVD were a history of abnormal noninvasive tests, typical chest pain, aspirin use, insulin-dependent diabetes, increasing age, and a family history of coronary artery disease. Conversely, the absence of severe MVD was most associated with female sex, undergoing ICA as workup for either noncardiac or valve surgery, lung disease, atypical chest pain, and increased BMI. Clinical information available before ICA can risk stratify the likelihood of severe MVD and therefore aid in identifying patients that may need CABG and could stand to benefit from TRA avoidance. The potential benefits of maximizing radial artery conduit availability by avoiding TRA must be balanced against the risks of alternative access on an individual patient basis.

Symptoms, Quality of Life, and Executive Function in Children Who Snore.

Mild sleep-disordered breathing (mSDB) in children is associated with both neurobehavioral morbidity and reduced quality of life (QOL). However, the association between symptom burden and QOL with executive function is not well understood, and it is not known whether QOL and symptom burden may help identify children with neurocognitive dysfunction. To assess associations among executive function, QOL, and symptom burden in children with mSDB. This cross-sectional study was a secondary analysis of the multicenter Pediatric Adenotonsillectomy Trial for Snoring, which included children aged 3 to 12 years randomized to watchful waiting or adenotonsillectomy for mSDB (snoring and an obstructive apnea-hypopnea index <3) between June 29, 2016, and February 1, 2021. The data for this report were analyzed between December 22, 2020, and October 3, 2024. Pediatric mSDB. Quality of life was assessed using the Obstructive Sleep Apnea-18 (OSA-18), and symptom burden was assessed using the Pediatric Sleep Questionnaire-Sleep-Related Breathing Disorder Scale (PSQ-SRBD). Executive function, including self-control and working memory, was measured using the Behavior Rating Inventory of Executive Function Global Executive Composite (BRIEF GEC), and inhibitory control and sustained attention were measured by the GoNoGo vigilance test. Partial Pearson correlations and multiple linear regression models were used to assess the associations among QOL, symptoms, and executive function. The sample included 459 children (mean [SD] age, 6.1 [2.3] years; 230 female [50.1%]). Moderate correlations were found between the BRIEF GEC and the PSQ-SRBD and OSA-18 (r = 0.58 [95% CI, 0.51-0.64] and 0.59 [95% CI, 0.52-0.64], respectively). After adjusting for age, sex, race and ethnicity, body mass index percentile, household income, maternal education, attention-deficit/hyperactivity disorder, test characteristics, and disease severity, both OSA-18 and PSQ-SRBD scores were associated with the BRIEF GEC (β = 0.41 [95% CI, 0.36-0.47] and 3.66 [95% CI, 3.17-4.15], respectively). In the fully adjusted model, PSQ-SRBD was also associated with GoNoGo inhibitory control (β = -0.04 [95% CI, -0.08 to -0.01]) and sustained attention (β = -0.05 [95% CI, -0.10 to -0.01]). In this study, disease-specific QOL and symptom burden were associated with executive function in children with mSDB. These findings may be useful in identifying those children who are at risk for neurocognitive dysfunction.

Assessing the effectiveness of measurement scales in evaluating the health-related quality of life in rare disease patients after treatment: a systematic review

BackgroundRare diseases often entail significant challenges in clinical management and health-related quality of life (HRQoL) assessment. HRQoL assessment tools for rare diseases show substantial variability in outcomes, influenced by disease heterogeneity, intervention types, and scale characteristics. The variability in reported quality of life (QoL) improvements following interventions reflects a need to evaluate the effectiveness of HRQoL assessment tools and understand their suitability across diverse contexts.ObjectiveThis systematic review aims to analyse the effectiveness of various assessment scales in evaluating QoL and explores the general trends observed in the studies using the same and different assessment scales on rare diseases.MethodsA comprehensive literature search was conducted across various databases to identify studies that reported QoL outcomes related to interventions for rare diseases. Search terms included various synonyms, and both the generic and specific terms related to rare diseases and QoL. Key variables, including intervention types, patient demographics, study design, and geographical factors, were analysed to determine their role in influencing the reported HRQoL outcomes. The findings were then compared with existing literature to identify consistent patterns and discrepancies.ResultsA total of 39 studies were included, comprising randomised controlled trials, observational studies, and cohort studies, with 4737 participants. Significant variations were observed in QoL improvements across studies, even when using the same assessment scales. These differences were primarily attributed to the heterogeneity in disease severity, intervention types, and patient characteristics. Studies employing disease-specific scales reported more nuanced outcomes than generic ones. Additionally, methodological differences, including study design and intervention type, contributed to variations in results and geographical factors influencing patients’ perceptions of health and well-being.ConclusionThe reported differences in QoL outcomes across studies can be explained by a combination of factors, including disease heterogeneity, treatment modalities, patient demographics, and assessment scale characteristics. These findings underscore the importance of selecting appropriate HRQoL assessment tools based on the research context and patient population. For more accurate comparisons across studies, it is crucial to consider these factors alongside consistent methodology and cultural adaptability of scales. Future research should focus on developing standardised guidelines for QoL assessments that accommodate the diverse needs of patients with rare diseases.

Clinical significance of lactate-to-albumin ratio in patients with influenza A virus-induced acute respiratory distress syndrome: a single-center retrospective study

BackgroundThe lactate-to-albumin ratio (LAR) is predictive of disease prognosis in some cases. However, the clinical significance of LAR in patients with influenza A virus-induced acute respiratory distress syndrome (ARDS) has yet to be explored. This study aims to investigate whether LAR can be used as a predictor of influenza A virus-induced ARDS.MethodsIn this single-center retrospective study, we enrolled 105 patients with influenza A virus pneumonia into the study and divided the patients into an ARDS group (74 patients) and a non-ARDS group (31 patients) during hospitalization. Clinical characteristics and laboratory data were collected within 24 h after admission. We explored the risk factors for ARDS using logistic regression analysis. The predictive performance of potential risk factors for ARDS and ARDS-associated complications were evaluated by receiver operating characteristic (ROC) curves, and Pearson’s correlation analysis was used to evaluate the correlations between risk factors and clinical and laboratory variables.ResultsLAR was an independent predictor for the development of ARDS in patients with influenza A virus pneumonia and was significantly predictive for ARDS. LAR’s area under the curve (AUC) was higher than that of lactate and albumin alone; its AUC was 0.878, with a sensitivity of 71.6% and a specificity of 96.8%. The optimal ROC threshold for distinguishing ARDS from non-ARDS cases was 44.81 × 10− 3. Correlation analysis indicated that LAR was positively associated with duration of invasive ventilation, and APACHE II and SOFA scores in ARDS patients but was negatively associated with PaO2/FiO2 (p < 0.001). Subsequent ROC curve analysis determined that LAR was a robust predictor for the 14-day invasive ventilation (AUC = 0.924), septic shock (AUC = 0.860), and hepatic injury (AUC = 0.905) in hospitalized ARDS patients. It also showed a promising predictive value for 28-day mortality (AUC = 0.881).ConclusionLAR strongly predicted ARDS development in patients with influenza A virus pneumonia. It showed a significant correlation with disease severity and provided promising predictive efficiency for extrapulmonary complications and 28-day mortality in patients with influenza A virus-induced ARDS.

Zhishi Xiebai Guizhi Decoction modulates hypoxia and lipid toxicity to alleviate pulmonary vascular remodeling of pulmonary hypertension in rats

BackgroundPulmonary hypertension (PH) is a severe cardio-pulmonary vascular disease, involves complex molecular mechanism especially during the pathological process of pulmonary vascular remodeling, brings a significant challenge to clinical treatment and thus resulting in high mortality rates. Classic Traditional Chinese medicine formula, Zhishi Xiebai Guizhi Decoction (ZXGD), holds therapeutic potential for PH. In present study, we sought to explore therapeutic potential of ZXGD against PH in rats.MethodsWe employed a combination methods of chemical profiling, echocardiographic, morphologic measurements, molecular biology, rats models and cultured pulmonary artery smooth muscle cells (PASMCs) to achieve this.ResultsEighteen compounds were precisely identified in ZXGD using UHPLC-QTOF-MS/MS. Our data demonstrated ZXGD could alleviate PH by reducing pulmonary artery pressure and alleviating pulmonary vascular remodeling in rats. Specifically, ZXGD was found to intervene in abnormal expansion of PASMCs, thereby attenuating pulmonary vascular remodeling. ZXGD was also observed to modulate expressions of HIF-1α, ROS, and Nrf2 to alleviate hypoxia and oxidative stress. Additionally, ZXGD significantly regulated disorders in pro-inflammatory cytokines, thus mitigating inflammation. Furthermore, ZXGD decreased levels of decadienyl-l-carnitine and LDL-C, while elevating HDL-C and lipid droplet counts, thereby reducing cholesterol and lipid toxicity and preserving mitochondrial function. Importantly, inhibition of HIF-1α reversed expression of key pathological triggers for pulmonary vascular remodeling. Neohesperidin and naringin in ZXGD extract were identified as the primary contributors to its pharmacological effects against PH.ConclusionAltogether, our study empirically explored therapeutic potential and pharmacological mechanisms of ZXGD in treating PH, offering a groundwork for the development of novel anti-PH drugs.Graphical

Severe congenital liver disease caused by FOCAD gene compound heterozygous variation in a child

Severe congenital liver disease caused by FOCAD gene compound heterozygous variation in a child

Updated genetic background of generalized pustular psoriasis as an autoinflammatory keratinization disease.

Generalized pustular psoriasis (GPP) is a severe autoinflammatory keratinization disease (AiKD) characterized by acute flares of widespread sterile pustules and high fever. GPP is potentially life-threatening. Recently clarified genetic predisposing factors for GPP suggest that the excessive activation of innate immune pathways in the skin, including of interleukin (IL)-1 and IL-36 signaling, plays a significant role in the GPP pathogenesis. IL36RN, CARD14, AP1S3, MPO, SERPINA3, BTN3A3, and MEFV have been identified as GPP-related genes. The pathogenesis of GPP provoked by variants in these seven genes is tightly associated with the excessive activation of innate immune pathways and the resulting autoinflammation in the skin. Various biologics, including inhibitors for the tumor necrosis factor, IL-17, and IL-23 pathways, are used as treatments for GPP. The new understanding of the genetic background of GPP, mentioned above, indicates that the genetic predisposing factors are predominantly related to the excessive activation of innate immunity and autoinflammation. In this context, inhibitors of inflammatory signaling, including of the IL-1 and IL-36 pathways, have been used in clinical practice and investigated as potential future therapies.

Familial Hyperkalemic Hypertension.

The rare disease Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in the genes encoding Cullin 3 (CUL3), Kelch-Like 3 (KLHL3), and two members of the With-No-Lysine [K] (WNK) kinase family, WNK1 and WNK4. In the kidney, these mutations ultimately cause hyperactivation of NCC along the renal distal convoluted tubule. Hypertension results from increased NaCl retention, and hyperkalemia by impaired K + secretion by downstream nephron segments. CUL3 and KLHL3 are now known to form a ubiquitin ligase complex that promotes proteasomal degradation of WNK kinases, which activate downstream kinases that phosphorylate and thus activate NCC. For CUL3, potent effects on the vasculature that contribute to the more severe hypertensive phenotype have also been identified. Here we outline the in vitro and in vivo studies that led to the discovery of the molecular pathways regulating NCC and vascular tone, and how FHHt-causing mutations disrupt these pathways. Potential mechanisms for variability in disease severity related to differential effects of each mutation on the kidney and vasculature are described, and other possible effects of the mutant proteins beyond the kidney and vasculature are explored. © 2024 American Physiological Society. Compr Physiol 14:5839-5874, 2024.

Role of STING Deficiency in Amelioration of Mouse Models of Lupus and Atherosclerosis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome characterized by autoreactive responses to nucleic acids, dysregulation of the type I interferon (IFN-I) pathway, and accelerated atherosclerosis. The stimulator of IFN genes (STING), a cytosolic DNA sensor, has pathogenic implications in various inflammatory diseases. However, its specific role in SLE pathogenesis, particularly in tissue damage, remains unclear. This study aimed to elucidate the role of STING in murine models of Toll-like receptor 7 (TLR7)-driven lupus and atherosclerosis. A TLR7-driven lupus model was induced using imiquimod (IMQ) in wild-type (WT) and STING knockout (Sting1-/-) mice on a B6 background. Mice were assessed for organ involvement, serum autoantibodies, and innate and adaptive immune responses. Additionally, Sting1-/- mice were backcrossed to apolipoprotein E knockout (Apoe-/-) mice, and both Apoe-/- and Apoe-/-Sting1-/- mice were fed a high-fat chow diet to induce atherosclerosis. Phenotypic assessments were conducted. Compared with IMQ-treated WT mice, Sting1-/- mice exhibited reduced disease severity in the lupus-like phenotype, characterized by decreased splenomegaly, lower renal immune complex deposition and renal damage, diminished expansion of myeloid cells, and reduced activation of T and B lymphocytes. IMQ-induced DNA release associated with IFN-β production and subsequent IFN-induced responses were attenuated in Sting1-/- mice. DNase I treatment mitigated IMQ-induced proinflammatory responses in WT mice but had no effect in Sting1-/- mice. Furthermore, STING deficiency conferred protection against vascular damage and reduced atherosclerosis burden, accompanied by decreased IFN-I production. Human monocyte-derived macrophages treated with IFN-I significantly internalized more acetylated low-density lipoprotein when compared with untreated cells, whereas an association between oxidized nucleic acids and disease activity and vascular damage was found in human SLE. These findings highlight a pathogenic role of STING and downstream IFN responses in TLR7-driven autoimmunity, vascular damage and atherosclerosis, supporting a therapeutic potential for STING inhibition in SLE treatment. Further research is warranted to elucidate the mechanisms underlying STING's involvement in these processes and to explore the feasibility of targeting STING as a therapeutic strategy in SLE and related autoimmune disorders.

European S2k guidelines for hidradenitis suppurativa/acne inversa part 2: Treatment.

This second part of the S2k guidelines is an update of the 2015 S1 European guidelines. These guidelines aim to provide an accepted decision aid for the selection, implementation and assessment of appropriate and sufficient therapy for patients with hidradenitis suppurativa/acne inversa (HS). The chapters have been selected after a Delphi procedure among the experts/authors. Certain passages have been adopted without changes from the previous version. Potential treatment complications are not included, being beyond the scope of these guidelines. Since the S1 guidelines publication, validation of new therapeutic approaches has almost completely overhauled the knowledge in the field of HS treatment. Inflammatory nodules/abscesses/draining tunnels are the primary lesions, which enable the classification of the disease severity by new validated tools. In relation to the degree of detectable inflammation, HS is classified into the inflammatory and the predominantly non-inflammatory forms. While the intensity of the inflammatory form can be subdivided by the IHS4 classification in mild, moderate and severe HS and is treated by medication accordingly, the decision on surgical treatment of the predominantly non-inflammatory form is based on the Hurley stage of the affected localization. The effectiveness of oral tetracyclines as an alternative to the oral combination of clindamycin/rifampicin should be noted. The duration of systemic antibiotic therapy can be shortened by a 5-day intravenous clindamycin treatment. Adalimumab, secukinumab and bimekizumab subcutaneous administration has been approved by the EMA for the treatment of moderate-to-severe HS. Various surgical procedures are available for the predominantly non-inflammatory form of the disease. The combination of a medical therapy to reduce inflammation with a surgical procedure to remove irreversible tissue damage is currently considered a holistic therapeutic approach. Suitable therapeutic options while considering HS severity in the therapeutic algorithm according to standardized criteria are aimed at ensuring a proper therapy.

Communicating on Vaccine Benefit-Risk Ratios: A Discrete-Choice Experiment among Health Care Professionals and the General Population in France.

We explored preferences around the benefit-risk ratio (BRR) of vaccination among the general adult population and health care sector workers (HCSWs). We estimated preference weights and expected vaccine uptake for different BRR levels for a vaccine recommended during an infectious disease emergence. In addition, we explored how far qualitative information about disease severity, epidemiological context, and indirect protection interacts with these preferences. This was a cross-sectional study, using a self-administered online questionnaire containing a single-profile discrete choice experiment among HCSWs and the general population in France (quasi-representative sample). The questionnaire was available from January 12 to April 27, 2023, for HCSWs and from April 17 to May 3, 2023, for the general population. BRR is represented as the number of vaccine-prevented disease events for 1 event related to a vaccine side effect. Results are reported in 4 groups: general population sample, non-HCSWs, non-university-degree HCSWs, and university-degree HCSWs. Among the 1,869 participants, 1,038 (55.5%) varied their vaccine decision among the different vaccine scenarios. Hypothetical vaccine acceptance among university-degree HCSWs increased when the vaccination BRR was 100:1, while non-university-degree HCSWs and non-HCSWs were more sensitive to qualitative information about the vaccine BRR than quantitative indicators. Among participants in the general population sample with varied decisions, expected acceptance increased by 40% sample if disease risk was high. Among serial vaccine nondemanders, high disease risk decreased their certitude to refuse hypothetical vaccination. Our results suggest that only university-degree HCSWs are sensitive to the notion of BRR, but not the general public. Given that previous research found speaking about BRR might reduce vaccine acceptance, this notion should be avoided in vaccine promotion. The notion of benefit-risk ratio (BRR) of vaccination appears to be taken into account in vaccine decisions by university-degree HCSWs, but not by the general public. Mentioning a favorable BRR could imply that the vaccine is not safe and reduce vaccine motivation.Mentioning qualitative attributes of BRR surrounding disease frequency and severity, and indirect protection effects, strongly affected theoretical vaccine decisions in all participants, irrespective of professional categories.Expected vaccine acceptance increased by 40% among the general population sample if disease risk was presented as high, and expected vaccine coverage exceeded 50% in scenarios with high disease risk.Among those refusing vaccination in all vaccine scenarios, only a high risk of developing the disease decreased their certitude to refuse vaccination. This further underlines the importance of disease risk perception on vaccine decision making, including among persons who a priori are unlikely to accept vaccination.

Computational deconvolution of cell type-specific gene expression in COPD and IPF lungs reveals disease severity associations

BackgroundChronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity.ResultsWe analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n = 465; IPF, n = 213; control, n = 348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner.ConclusionsUtilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.

Effects of acute-phase COVID-19-related indicators on pulmonary fibrosis and follow-up evaluation

BackgroundPost-COVID-19 pulmonary fibrosis is a significant long-term respiratory morbidity affecting patients’ respiratory health. This exploratory study aims to investigate the incidence, clinical characteristics, and acute-phase risk factors for pulmonary fibrosis in COVID-19 patients. Additionally, it evaluates pulmonary function and chest CT outcomes to provide clinical evidence for the early identification of high-risk patients and the prevention of post-COVID-19 pulmonary fibrosis.MethodsWe retrospectively analyzed 595 patients hospitalized for COVID-19 from January 2022 to July 2023. Patients were divided into fibrosis and nonfibrosis groups on the basis of imaging changes. Baseline data, including demographics, disease severity, laboratory indicators, and chest imaging characteristics, were collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for pulmonary fibrosis. Pulmonary function and chest CT follow-ups were conducted for the fibrosis group. The data were processed via SPSS 26.0, with P < 0.05 considered statistically significant.ResultsThe incidence of pulmonary fibrosis was 4.37%, with 2.08% in moderate cases and 8.22% in severe cases. Significant differences were found between the fibrosis and nonfibrosis groups in sex; disease severity; NLR; ALB and LDH levels; and percentages of lung reticular lesions, consolidations, and GGOs (P < 0.05). Multivariate analysis revealed LDH (OR = 1.004, 95% CI 1.000–1.007, P = 0.035), ALB (OR = 0.871, 95% CI 0.778–0.974, P = 0.015), lung reticular lesion volume (OR = 1.116, 95% CI 1.040–1.199, P = 0.002), and lung consolidation volume (OR = 1.131, 95% CI 1.012–1.264, P = 0.030) as independent risk factors. The follow-up results revealed significant improvements in pulmonary function, specifically in the FVC%, FEV1%, and DLCO%, but not in the FEV1/FVC. Quantitative chest CT analysis revealed significant differences in lung reticular lesions, consolidation, and GGO volumes but no significant difference in honeycomb volume.ConclusionsThe incidence of pulmonary fibrosis post-COVID-19 increases with disease severity. LDH, ALB, lung reticular lesions, and consolidation volume are independent risk factors for patients with fibrosis.

How low can you go? Antibiotic use in Swedish dogs with gastroenteritis

BackgroundCanine gastroenteritis (CGE) is a common cause for seeking veterinary care in companion animal medicine and an area where antibiotics have been reported to be widely used. Therefore, creating relevant benchmarks for antibiotic use in CGE is important when implementing and analyzing antibiotic stewardship interventions. The aim of this paper was to describe the level and temporal trend of systemic antibiotic use for CGE in Sweden between 2020 and 2023.Materials and methodsThis was an observational multicenter cohort study. Retrospective data from 93,641 CGE consultations was extracted from the electronic health record and analyzed. All CGE consultations were included irrespective of age, breed, severity of disease and level of care. To evaluate the data, 100 medical records of CGE consultations were also manually reviewed using a predefined study protocol.ResultsThe overall level of systemic antibiotic use in Swedish dogs diagnosed with gastroenteritis was 5.7% during the study period, with aminopenicillins being the most abundantly used antibiotics (60.2%). The yearly level of antibiotic use in CGE declined from 8.1% in 2020 to 3.9% in 2023, with a statistically significant annual percentage change (APC) of −21.3% (95% CI, −22.8 to −19.7). Concurrently, the annual all-cause mortality decreased for all CGE consultations. Higher levels of antibiotic use were seen in hospitalized CGE (21.7% compared to 2.1% for non-hospitalized CGE, OR 13.1, 95% CI: 12.3–14.0, p &amp;lt; 0.001) and hemorrhagic diarrhetic CGE (21.0% compared to 5.5% for non-hemorrhagic diarrhetic CGE, OR 4.6, 95% CI: 4.2–4.9, p &amp;lt; 0.001).ConclusionThis study revealed a low level and a significantly declining trend of antibiotic use in canine gastroenteritis in Sweden, implicating a high level of awareness and compliance to antibiotic guidelines among Swedish veterinarians. During the same period, the all-cause mortality rates decreased significantly for all CGE consultations, implicating that this level of antibiotic use do not compromise patient safety. Benefiting from automatic surveillance, we hereby provide important benchmarks which should encourage more prudent use of antibiotics in CGE internationally.

The serum biomarkers NSE and S100B predict intracranial complications and in-hospital survival in patients undergoing veno-venous ECMO

Neurological complications in patients undergoing veno-venous extracorporeal membrane oxygenation (V-V ECMO) are challenging, with new intracranial pathologies posing a grave risk. We aimed to evaluate the utility of neuron-specific enolase (NSE) and S100B biomarkers for predicting outcomes in new-onset intracranial pathology during V-V ECMO. A retrospective analysis spanning 2013–2021 at a German university hospital was conducted. Cases with electronically available data on NSE and S100B serum levels, new intracranial pathologies (intracerebral hemorrhage [ICH], subarachnoid hemorrhage [SAH], cerebral ischemia, hypoxic-ischemic encephalopathy [HIE]), and survival during or after V-V ECMO were screened. The primary objective was to assess the prognostic value of NSE and S100B for in-hospital survival during V-V ECMO. Secondary objectives included analyzing clinical characteristics, outcome parameters, and biomarker distribution in V-V ECMO patients. Additionally, the prognostic value of NSE and S100B for in-hospital death and occurrence of intracranial pathology was calculated. Among 744 ECMO recipients, 426 underwent V-V ECMO. No significant differences in disease severity or organ failure scores were observed between groups, except for SAPS at discharge, which was higher in patients with new intracranial pathologies. Patients with new intracranial pathologies had lower median survival and higher in-hospital mortality. Weaning success from ECMO was also significantly reduced in these patients. Cut-off values of 58.4 µg/lfor NSE and 1.52 µg/l for S100B were associated with detrimental outcomes, characterized by significantly reduced median survival. A significant difference in maximum serum NSE concentration was found between patients with and without new intracranial pathology. All screened cases with new intracranial pathology had an unfavorable neurological outcome (modified Rankin Score [mRS] > 3) at discharge, with a higher proportion having an mRS of 6 in the high NSE group. The emergence of intracranial pathology during V-V ECMO significantly increases the risk of death. Changes in NSE and S100B levels serve as valuable follow-up parameters for predicting new intracranial pathology and survival during V-V ECMO therapy.

MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment.

The Impact of Vaccination on COVID-19 Outcomes in Vietnam

We assessed the effectiveness of the COVID-19 vaccine in this observational study involving 3102 confirmed COVID-19 patients from Vietnam. Participants were classified into unvaccinated, partially vaccinated (one dose) (PV), fully vaccinated (two doses) (FV), and boosted (three doses) groups. We used a regression model to assess the relationship between vaccine status and disease outcome, including mortality, persistent symptoms after treatment, and hospital duration. The proportions of unvaccinated, PV, FV, and boosted groups were 43.39%, 4.63%, 43.93%, and 8.05%, respectively, and 48% of the participants had at least one of comorbidity. The proportion of severe clinical disease was significantly higher in the unvaccinated compared with the vaccinated. Biomarkers of cellular injury and organ failure, e.g., aspartate aminotransferase (AST), ferritin, troponin T, proBNP, D-dimer, and urea plasma concentration were significantly higher in unvaccinated and PV patients compared with FV and boosted patients. Age was the most crucial predictor of critical illness, followed by vaccine status, hypertension, diabetes, heart disease, and chronic kidney disease. The unvaccinated group had the highest proportion of deaths (5.2% vs. 1.4% and 0.3% in FV and boosted groups, respectively). Vaccination reduced mortality, and both hospitalization length and disease severity in COVID-19 survivors, especially the elderly and patients with chronic comorbidities.