Disease Severity Research Articles

The clinical significance of resolvin D1 in patients with systemic lupus erythematosus treated with Belimumab

Objectives: To explore the changes and significance of resolvin D1 (RvD1) in the treatment of systemic lupus erythematosus (SLE) with Belimumab. Methods: The clinical data from patients with moderate to severe disease activity SLE who received oral stable doses of glucocorticoids (≤10 mg/d) and/or immunosuppressants for more than 3 months at the outpatient or inpatient department of the First Affiliated Hospital of Soochow University from January 2022 to November, 2023 were retrospectively collected. All patients were treated with 10 mg/kg intravenous infusion of Belimumab. The medication was administered once on the 1st, 15th, and 29th days, and then every 4 weeks for a total of 24 weeks and 8 doses. Peripheral blood plasma before and after treatment were collected, and RvD1 levels before and after treatment were detected using enzyme-linked immunosorbent assay (ELISA). According to the guidelines, SLE patients were divided into kidney involvement group and kidney non-involvement group; the patients were further divided into a blood system involvement group and a blood system non-involvement group; according to the SLE Disease Activity Index (SLEDAI), the patients were divided into moderate activity group and severe activity group. After 24 weeks of treatment, the patients were divided into complete remission group, low disease activity group, and no remission group according the treatment effects. The changes in plasma RvD1 levels in each group before and after treatment with Belimumab were analyzed, and their correlation with various activity indicators of SLE was checked too. Results: A total of 81 patients were included, of which 15 were male and 66 were female, with an average age of (33.14±8.27) years. At baseline, plasma RvD1 levels in SLE patients were negatively correlated with SLEDAI scores (r=-0.642, P<0.001) and anti dsDNA antibody levels (r=-0.623, P=0.012). There was no significant difference in plasma RvD1 level [M(Q1, Q3)] between SLE patients with renal involvement (n=50) and those without renal involvement (n=31) [73.27 (45.16, 122.12) ng/L vs 58.32 (32.29, 94.33) ng/L, P=0.365]. There was no significant difference in plasma RvD1 level between SLE patients with hematological involvement (n=40) and those without hematological involvement (n=41) [74.78 (47.01, 121.67) ng/L vs 42.88 (30.05, 76.76) ng/L, P=0.277]. The plasma RvD1 level in the moderate activity group (n=51) was significantly higher than that in the severe activity group (n=30) [104.76 (65.65, 135.34) ng/L vs 55.86 (37.53, 81.35) ng/L, P=0.002]. After 24 weeks of treatment with Belimumab, plasma RvD1 levels in the complete remission group (n=10) were both significantly higher than those in the low disease activity group (n=61) and the non-remission group (n=10) [196.48 (123.08, 236.33) ng/L vs 98.87 (63.35, 110.23) ng/L and 77.68 (41.73, 128.55) ng/L, respectively, P=0.001]. After the treatment, the plasma RvD1 levels in both the complete remission group and the low disease activity group increased significantly when compared to those before the treatment [98.23 (40.45, 107.19) ng/L vs 176.48 (123.08, 226.33) ng/L and 65.27 (31.76, 94.35) ng/L vs 98.87 (63.35, 110.23) ng/L, both P<0.05]. Further analysis revealed that all the patients of complete remission group after treatment were from the moderate disease activity group before treatment, and the plasma RvD1 level in the complete remission group was significantly higher than that in the low disease activity group before the treatment [98.23 (40.45, 127.19) vs 65.27 (31.76, 94.35) ng/L] (P=0.022). Conclusions: The plasma RvD1 level significantly increased after treatment with Belimumab in SLE patients, patients with higher plasma RvD1 level before treatment have better efficacy with Belimumab.

Association between Helicobacter pylori, reflux and chronic rhinosinusitis: a systematic review.

The prevalence, role, and clinical relevance of Helicobacter Pylori (HP) in sinonasal tissues of patients with chronic rhinosinusitis remain unclear. To investigate the prevalence and clinical relevance of Helicobacter Pylori (HP) in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and without nasal polyps (CRSSNP). Three investigators conducted a PubMed, Scopus, and Cochrane Library systematic review of the prevalence and clinical relevance of HP infection in CRS patients through the PRISMA framework. A bias analysis was conducted to identify potential heterogeneity and biases across studies. Of the 42 identified studies, 20 met the inclusion criteria, accounting for 741 CRS patients and 368 controls. HP was detected in 37.1% (n = 127/342) of polyps of CRSwNP patients with the polymerase chain reaction (PCR) and 32.7% (n = 37/113) of polyp tissue with the immunohistochemistry (IHC). Controls reported a nasal PCR and IHC detection rates of 14.8% (n = 36/243) and 3.6% (n = 3/84), respectively. The HP rate did not differ between CRSwNP and CRSsNP. Among patients with CRS, the enzyme-linked immunosorbent assay testing detected blood HP antigens in 48.7% (n = 74/152) of CRS patients and 41.6% (n = 37/89) of controls. The detection of HP in polyps was associated with the severity of gastroesophageal reflux disease (GERD). There was an important heterogeneity between studies for the inclusion criteria, methods of HP detection, and reflux outcomes. Helicobacter Pylori can be detected in one-third of sinonasal tissues from patients with CRS and can be considered a biomarker of GERD. The potential role of HP in the development of CRS remains unclear. The heterogeneity between studies limits the drawing of valid conclusions.

A pilot study for speech assessment to detect the severity of Parkinson's disease: An ensemble approach.

Changes in voice are a symptom of Parkinson's disease and used to assess the progression of the condition. However, natural differences in the voices of people can make this challenging. Computerized binary speech classification can identify people with PD (PwPD), but its multiclass application to detect the severity of the disease remains difficult. This study investigated six diadochokinetic (DDK) tasks, four features (phonation, articulation, prosody, and their fusion), and three machine learning models for four severity levels of PwPD. The four binary classifications were: (i) Normal vs Not Normal, (ii) Slight vs Not Slight, (iii) Mild vs Not Mild and (iv) Moderate vs. Not Moderate. The best task and features for each class were identified and the models were ensembled to develop a multiclass model to distinguish between Normal vs. Slight vs. Mild vs. Moderate. For Normal vs Not-normal, logistic regression (LR) using the prosody from "ka-ka-ka" task, Random Forest (RF) using articulation from "petaka" for Slight vs Not Slight, RF for the fusion from "ka-ka-ka" for Mild vs Not Mild and Gradient Boosting (GB) using prosody from "ta-ta-ta" for Moderate vs Not Moderate gave the best results. Combining these using LR achieved an accuracy of 72%. Dividing the multiclass problem into four binary problems gives the optimum speech features for each class. This pilot study, conducted on a small public dataset, shows the potential of computerized speech analysis using DDK to evaluate the severity of Parkinson's disease voice symptoms.

Translation, Cross-Cultural Adaptation and Validation of the Karaduman Chewing Performance Scale for the Italian Paediatric Population.

Chewing is a fundamental motor activity, but there is no specific assessment tool in Italian for paediatric rehabilitation. The Karaduman Chewing Performance Scale (KCPS) is a performance-based assessment tool that allow to classify chewing performance in childhood. To translate, culturally adapt and assess reliability, criterion validity and cross-cultural validity of the KCPS into Italian in a paediatric population. Following international guidelines, the KCPS was translated and culturally adapted into Italian. Inter-rater reliability was measured using the intraclass correlation coefficient (ICC), the criterion validity using the Pearson correlation coefficient comparing KCPS score with the Paediatric Screening-Priority Evaluation Dysphagia (PS-PED), and cross-cultural validity was examined across diagnostic groups. The study included 165 children with a mean age of 6.33 with different health conditions, namely autism spectrum disorder, cerebral palsy and genetic syndromes. The analysis revealed that KCPS was reliable measure with a ICC 0.93, and a moderate positive linear correlation with the PS-PED (Pearson 0.48) was found. In each diagnostic group, chewing performance disorders were found, highlighting specific characteristics. Despite limited sample in reliability analysis and the need of exploring the relationship with chewing abilities and severity of diseases, the KCPS was found a reliable and valid tool for determining the level of chewing performance in paediatric population. Now Italian clinicians can use it with more confidence in their clinical practice and research.

Cerebrospinal fluid biomarkers as predictors of multiple sclerosis severity.

Prognostic biomarkers at multiple sclerosis (MS) onset to predict disease severity may help guide initial therapy selection for people with MS. Over 20 disease-modifying treatments (DMTs) of varying levels of risk and efficacy now exist. The ability to predict MS severity would help to identify those patients at higher risk where a highly effective, but potentially risky, therapy would be optimal. The goal of this project was to determine if cerebrospinal fluid (CSF) soluble markers obtained near time of diagnosis can predict disease severity in people with relapsing remitting MS (RRMS). We identified 42 RRMS subjects with 4 or more years of clinical follow-up at our center, 8 subjects with other inflammatory neurological diseases (OIND), and 4 subjects with non-inflammatory neurological diseases (NIND) who had donated CSF samples collected for disease diagnosis. This study evaluated soluble CSF biomarkers chosen to reflect neuroinflammation (chemokine ligand 13 - CXCL13), microglia activity (soluble triggering receptor expressed on myeloid cells 2 - sTREM2), demyelination (myelin basic protein -MBP), axon injury and loss (neurofilament light, heavy, and intermediate chains - NFL, NFH, internexin-alpha - INT-α) and neuronal loss (parvalbumin - PVALB) to determine whether any of these CSF factors might predict future MS disease severity. The main outcome measure was MS Severity Score (MSSS), which takes into account disability accumulation (expanded disability status scale - EDSS) and duration of disease. EDSS at last clinical visit was a secondary outcome measure. Univariate and multivariable regression models were used for analysis. Spearman correlations were performed to evaluate correlation between laboratory and clinical variables. Forty-two RRMS patients with mean 9.4 years follow-up since lumbar puncture (LP) contributed data. Higher NFH, NFL, and sTREM2 each predicted worse MSSS using both univariate and multivariable regression models. Older age at the time of LP predicted worse MSSS both in the univariate and multivariable models. NFL correlated with NFH, and both were positively correlated with sTREM2 and CXCL13. In the combined OIND and NIND comparator group, NFH correlated with both NFL and CXCL13. These data support that CSF sTREM2, NFH, and NFL are predictors of MSSS, a measure of MS disease aggressiveness. This study adds to a growing literature implicating microglial activity and axonal injury in MS progression, starting from early stages of the disease.

OPG and BAFF as predictive biomarkers of the severity of SARS-CoV-2 infection.

Molecules of the tumour necrosis factor superfamily (TNFSF) are key players in immune regulation; an increase in some TNFSF molecules has been reported during severe COVID-19. In this study, we profiled and evaluated TNFSF members in the serum of COVID-19 vaccine-naïve patients to identify potential biomarkers associated with disease severity. Our data show that TRAIL serum levels are lower in severely affected patients than those mildly affected by COVID-19 (AUC 0.8, p = 0.0003). On the contrary, OPG and BAFF serum levels are higher in severe COVID-19 compared to mild COVID-19 cases (AUC 0.8, p = 0.0001; AUC 0.7, p = 0.0012; respectively) and moderate COVID-19 cases (OPG p < 0.01), BAFF (p < 0.05). At the transcriptional level, TRAIL, OPG and BAFF are elevated in severe compared to mild COVID-19 cases, with OPG and BAFF also higher in moderate compared to mild COVID-19 patients. Additionally, we found that APRIL, LIGHT, CD30L and CD40L protein-levels are higher in COVID-19 patients compared to healthy donors but not significantly different between various COVID-19 clinical statuses. Finally, we found that TNF-α, TNF-β, RANKL and TWEAK protein levels were not affected during COVID-19. Our work identifies OPG and BAFF as potential biomarkers and therapeutic targets for preventing severe COVID-19. Due to the opposite contradictory levels of TRAIL (protein/transcriptional level), its role during COVID-19 should be elucidated and clarified with more in-depth studies.

An Australian Single-center Cohort of Pediatric Empyema: Incidence, Pathogens and Disease Severity, and the Interaction of the COVID-19 Pandemic.

Empyema is the most common complication of pediatric community-acquired pneumonia, posing a significant morbidity to children. Clinicians have observed an increase in empyema rates and acuity in the years following the COVID-19 pandemic. This retrospective analysis of children managed for empyema in a tertiary pediatric hospital, aimed to compare the incidence and describe the clinical characteristics prepandemic and postpandemic (2017-2023). There were 222 empyema cases, with a median age of 3 years (0.3-15 years). The majority (87.8%) of cases were managed with a chest drain and fibrinolytics. The remaining underwent minimally invasive video-assisted thoracoscopic surgery. Admissions postpandemic were associated with significantly longer lengths of stays (14 vs 12 days, P ≤ 0.001), higher rates of pediatric intensive care unit admissions (32% vs 26%, P = 0.045), and they required higher level of care (inotropes, noninvasive and invasive ventilation). There were also significantly higher rates of Streptococcus pyogenes (28% vs 7%, P ≤ 0.001), while rates of other organisms were not significantly different. We also noted a significant reduction in immunization rates post-pandemic (95.8% vs 83.1%, P < 0.01); however, there was no significant difference in S. pneumoniae serotypes between epochs. This study demonstrates an increased rate and severity of pediatric empyemas in the post-pandemic period. We propose that the increase was secondary to the increased rates of S. pyogenes seen in the postpandemic period. This rise in infection rates may be alleviated with nonpharmacologic measures aimed at reducing transmission; however, such measures are not sustainable and should be avoided.

Nucleated red blood cells for characterization of systemic inflammatory response syndrome in dogs.

Nucleated red blood cells (nRBCs) are increased by disease processes and hematopoietic stress. To evaluate the utility of nRBCs as a marker of disease severity and prognosis in dogs with systemic inflammatory response syndrome (SIRS). Sixty-two client-owned dogs met the criteria of SIRS without anemia. nRBC-positive (nRBCs: ≥5/500, n = 32) and nRBC-negative (nRBCs: <5/500, n = 30) dogs were classified, and clinicopathological data, Acute Patient Physiologic and Laboratory Evaluation (APPLEfast) scores, cytokines, 2- and 4-weeks survival were compared. The median WBC (17.63, interquartile range [IQR]: 11.72-20.24 × 109/L), neutrophils (12.28, IQR: 7.17-16.88 × 109/L), band neutrophils (1288.5, IQR: 252.5-2575 cells/μL), serum IL-6 (731.80, IQR: 299.79-5522.05 pg/mL), and plasma C-reactive protein (4.10, IQR: 1.00-8.58 mg/L) were significantly higher in nRBC-positive dogs than negative dogs (11.27, IQR: 7.63-15.13 × 109/L; 7.57, IQR: 4.96-11.71 × 109/L; 62.5, IQR: 0-350.25 cells/μL; 232.30, IQR: 99.33-447.01 pg/mL; 0.40, IQR: 0.10-3.00 mg/L, respectively; P < .05). The median reticulocyte count (87.95, IQR: 52.45-130.55 × 103/μL) and serum IL-3 (40.94, IQR: 29.85-53.52 ng/L) were also significantly greater in nRBC-positive dogs than nRBC-negative dogs (46.00, IQR: 26.43-68.15 × 103/μL; 25.24, IQR: 21.65-37.40 ng/L, respectively; P < .01). The presence of circulating nRBCs, but not the reticulocyte count, at admission was predictive of death in dogs with SIRS at 2 weeks (P = .01, AUC: 0.729) and 4 weeks (P = .002, AUC: 0.731). The overall survival time was shorter in nRBC-positive dogs (95% CI, 47.35-113.90) than nRBC-negative dogs (95% CI, 90.92-135.55; P = .03). Measuring peripheral nRBCs in dogs with SIRS is rapid and clinically applicable, reflecting disease severity and associated prognosis.

Left Atrial Markers in Diagnosing and Prognosticating Non-Ischemic Cardiomyopathies: Ready for Prime Time?

The left atrium (LA) is pivotal in cardiac hemodynamics, serving as a dynamic indicator of left ventricular (LV) compliance and diastolic function. The LA undergoes structural and functional adaptations in response to hemodynamic stress, infiltrative processes, myocardial injury, and arrhythmic triggers. Remodeling of the LA in response to these stressors directly impacts pulmonary circulation, eventually leading to pulmonary capillary involvement, pulmonary artery hypertension, and eventually right ventricular failure. LA dysfunction and fibrosis also contribute to the future risk of atrial arrhythmias and mitral regurgitation. The parameters of LA size and function are being recognized as robust markers for the progression of several cardiac pathologies as well as important tools for prognostication. In this article, we briefly describe the different modalities and markers used to evaluate LA pathology in patients with nonischemic cardiomyopathies (NICM). We then provide an overview of the studies that compared the association of the different LA parameters with disease severity and future prognosis. We also identify the gaps in knowledge before these LA parameters make a case for clinical adoption.

Association of systemic inflammatory markers with white matter hyperintensities and microstructural injury: an analysis of UK Biobank data.

White matter damage is closely associated with cognitive and psychiatric symptoms and is prevalent in cerebral small vessel disease (CSVD); although the pathophysiological mechanisms involved in CSVD remain elusive, inflammation plays a crucial role. We sought to investigate the relationship between systemic inflammation markers and imaging markers of CVSD, namely white matter hyperintensity (WMH) and microstructural injury. We conducted a study involving both cross-sectional and longitudinal data from the UK Biobank Cohort. We performed multiple linear regression analyses, adjusted for potential confounders, to explore the associations between systemic inflammation markers (e.g., systemic immune-inflammation index [SII], neutrophil-to-lymphocyte ratio [NLR], C-reactive protein [CRP] levels, monocyte count, neutrophil count) and macro- and microstructural white matter injury, as markers of CSVD. We performed Mendelian randomization analysis to investigate the genetically predictive effect of monocytes on WMH, as well as mediation analysis to clarify whether inflammatory markers affected cognitive function via white matter injury. We included 36 411 participants (mean age 54.8 ± 7.5 yr, 51.9% female) from the UK Biobank Cohort. We found that SII was significantly associated with both WMH and microstructural injury markers (fractional anisotropy, mean diffusivity, intracellular volume fraction, and isotropic compartment volume fraction [ISOVF]), and the neutrophil-to-lymphocyte ratio was significantly associated with WMH and some markers of microstructural injury (mean diffusivity and ISOVF). Our analysis revealed that the CRP level was significantly associated with WMH and WMH progression but not with microstructural injury. We also demonstrated that monocyte count was significantly associated with WMH and ISOVF, and that neutrophil count was significantly associated with WMH, mean diffusivity, and ISOVF. In 2-sample Mendelian randomization analyses, we found positive associations between genetic determinants of monocytes and WMH. The mediating role of WMH suggested that a higher SII value and monocyte count could contribute to cognitive impairment through white matter injury. Although the study includes both cross-sectional and longitudinal components, the sample size for the longitudinal aspect is limited, and the use of blood biomarkers from a single timepoint is also a limitation of this research. The SII and neutrophil-to-lymphocyte ratio may be early detection markers for white matter damage in patients with CSVD, whereas the CRP level is more closely associated with disease severity and progression. Our findings highlight the clinical relevance of systemic inflammation markers with white matter macro- and microstructural injuries, revealing that systemic inflammation is likely involved in the mechanism of early white matter injury among patients with CSVD.

Impact of SARS-CoV-2 inactivated vaccine on symptoms following omicron variant breakthrough infection.

The SARS-CoV-2 Omicron variant and its sublineages continue to circulate widely. Clinical outcomes with this variant differ among individuals, primarily influenced by host immunity. Previous studies have explored the relationship between immune responses and severe diseases in infected or convalescent patients. However, the impact of vaccine-induced immune responses on disease severity, especially in cases of mild infection following breakthrough infection, remains unclear. This is primarily due to the lack of assessment of immune status in vaccinated individuals before infection. In this study, we aimed to elucidate the causality between virus-specific cellular and humoral immune responses and the severity of symptoms in breakthrough infected patients from a long-term follow-up post-vaccination cohort. A questionnaire survey was conducted to collect general symptoms upon breakthrough infection with the Omicron variants. Plasma levels of specific antibodies (neutralizing antibodies, anti-S IgG, and anti-N IgG) and T cell responses induced by inactivated SARS-CoV-2 vaccine were evaluated. The findings revealed that individuals with milder symptoms, particularly lower peak fever temperatures, exhibited higher antibody levels and enhanced T cell activation and responses prior to infection. This suggests that cellular and humoral immunity induced by inactivated vaccines may provide protection against severe clinical symptoms following breakthrough infection.

The Relationship between the Clinical Course of SARS-CoV-2 Infections and Expression of Bruton's Tyrosine Kinase.

Bruton's Tyrosine Kinase (BTK), an important element for the production of several inflammatory cytokines, may play a role in the pathogenesis of COVID-19. This study aimed to assess BTK gene expression levels in COVID-19 cases based on disease severity and outcome. In this study, 33 hospitalized patients with COVID-19 were recruited and divided into two groups based on the severity of the disease: "mild to moderate" and "severe to critical". A blood sample was taken from each patient, peripheral blood mononuclear cells (PBMCs) were extracted, and BTK gene expression was measured. The level of BTK gene expression was compared based on the demographic data, laboratory results, and the severity and outcome of the disease. Among the 33 patients, 22 (66.7%) were male, with nearly half having at least one underlying condition. The severity groups comprised 12 patients in the "mild to moderate" category and 21 in the "severe to critical" category, with eight (24.2%) experiencing fatal outcomes. Age, weight, and BMI showed no significant associations with BTK expression. BTK expression was notably lower in "severe to critical" and ICU-admitted cases, as well as in individuals with low O2 saturation. However, no significant difference in BTK expression was observed between cured and deceased patients (p = 0.117). BTK gene expression in PBMCs exhibited an inverse correlation with COVID- 19 severity. However, no difference was found between BTK expression and disease outcome.

High-Throughput Screening of Plant Extracts for Targeted Control of Burkholderia glumae, Causing Rice Sheath and Panicle Blight

Rice (&lt;i&gt;Oryza sativa&lt;/i&gt;), a staple crop worldwide, is severely threatened by bacterial panicle blight caused by &lt;i&gt;Burkholderia glumae&lt;/i&gt;, leading to substantial yield losses. The lack of effective chemical treatments and resistant rice cultivars highlights the urgent need for alternative solutions. In this study, 1,134 plant extracts were screened for antibacterial activity against &lt;i&gt;B. glumae&lt;/i&gt; using agar disc diffusion and liquid broth assays. Thirty-three extracts exhibited significant growth inhibition on agar plates. These 33 extracts were further tested in Luria- Bertani broth, where five showed notable activity, and two extracts—&lt;i&gt;Trapa japonica&lt;/i&gt; (FBCC-EP312) and &lt;i&gt;Rumex crispus&lt;/i&gt; (FBCC-EP487)—were selected for detailed analysis. Both extracts significantly reduced bacterial motility and disease severity in rice, while having no effect on non-target bacteria such as &lt;i&gt;Escherichia coli&lt;/i&gt;. These findings highlight the potential of these plant-derived compounds as effective biocontrol agents, offering an eco-friendly alternative to synthetic pesticides and promising applications in sustainable agriculture.

Comparison of clinical variables and outcome of 2 natural equine herpesvirus myeloencephalopathy outbreaks induced by equine herpesvirus-1 A2254/N752 strain in sport horses.

Understanding of equine herpesvirus-1 (EHV-1) myeloencephalopathy (EHM) is complicated by disparities among studies. Compare clinical findings and outcome in horses involved in 2 recent EHM outbreaks. Twenty-five and 10 horses affected during 2 natural EHM outbreaks were admitted to a veterinary teaching hospital (VTH) in 2021 and 2023, respectively. Data collected from the VTH and surveys completed by riders and horse owners were analyzed retrospectively. No risk factors associated with EHM development showed significant differences between the outbreaks; both outbreaks were caused by A2254/N752 strains. Treatments administered for EHM were not significantly different, whereas the duration was longer in 2021 for flunixin meglumine (P = .01) and dimethyl sulfoxide (P < .001). In 2021, more horses required hospitalization (P = .02), and fatality rate was 32%, whereas in 2023, no patient died. Hospitalization duration was longer in 2021 than in 2023 (P = .06) and 11.7% of horses from 2021 returned to competition within 6 months, whereas 100% in 2023 did (P < .001). Ataxia grade upon admission was equivalent in 2021 and 2023, but factors related to poor prognosis, such as simultaneous development of urinary and vascular complications, occurred in 2021 but not in 2023 (P = .01). Two EHM outbreaks caused by the A2254/N752 strain differed in disease severity. Urinary complications and systemic signs of vasculitis were important clinical variables associated with prognosis. Systemic complications in horses with EHM lead to a worse prognosis.

Severe Liver-Related Outcomes in Patients With Hepatitis Delta: Results From a Multi-Ethnic Multicenter Long-Term Follow-Up Study.

Hepatitis B virus (HBV)-hepatitis delta virus (HDV) coinfection is the most severe form of chronic viral hepatitis, but the factors that determine disease progression and severity are incompletely characterised. This long-term follow-up study aims to identify risk factors for severe liver-related outcomes. In this multicentre national cohort study, data from admission until the last visit between 2001 and 2023 was retrospectively collected from 162 HBV-HDV coinfected patients. The inclusion criteria were HBsAg or HBV DNA positivity, anti-HDV or HDV RNA positivity, and at least one follow-up visit. The median follow-up was 6.2 years (IQR 3.3-10.2). At baseline, 68/152 (44.7%) patients were diagnosed with advanced liver fibrosis. Forty patients (24.7%) had at least one severe liver-related outcome during follow-up. HDV viremia was detectable in 92 patients (64.3%) at last evaluation and was more frequently detectable in patients of European origin (p < 0.001). HDV RNA-positive patients had a 4.7-fold higher risk for severe liver-related outcomes (p < 0.001) and were more frequently diagnosed with advanced fibrosis at baseline (p = 0.007) compared to HDV RNA-negative patients. Multivariate analyses identified HDV RNA positivity, as well as several markers for liver disease severity, such as INR, platelet count, and advanced fibrosis at baseline, and age at admission as independent risk factors for severe liver-related outcomes. In conclusion, almost one in four HBV-HDV coinfected patients developed a severe liver-related outcome during follow-up. Several markers for liver disease severity and HDV RNA positivity were the strongest predictors for outcomes.

Evaluation of Fungicides, Host-plant Defense Inducer, and Anti-transpirant in Management of Boxwood Blight

Boxwood, valued at over $140.9 million annually in the United States, faces a significant threat from boxwood blight disease. This study evaluated 24 treatment combinations involving three fungicides (Daconil Weatherstik, Postiva, and F6123-1), a disinfectant/fungicide (KleenGrow), a host-plant defense inducer (Actigard), and an anti-transpirant (Vapor Gard) for managing boxwood blight. Preventive applications were performed 24 h before pathogen inoculation, while curative treatments were applied at 14-d intervals, starting 14 d after inoculation. The disease severity (0% to 100% plant affected), area under disease progress curve (AUDPC), plant growth, defoliation (0% to 100%), and stem water potential (MPa) were assessed. All the applications significantly reduced disease severity and AUDPC compared with the non-treated, inoculated control. Preventative applications of Actigard alternated (alt.) with Vapor Gard and Actigard alone consistently reduced the disease progression, while Actigard alt. with Vapor Gard reduced the disease severity. Curative application of the low rate of Postiva exhibited the highest disease suppression, comparable to applications of F6123-1 alt. with Vapor Gard and the high rate of Postiva alt. with Vapor Gard. The preventative and curative application of the high rate of Postiva alt. with Vapor Gard was the most effective in reducing disease severity and slowing disease progression. Preventive and curative application of Daconil Weatherstik, KleenGrow, and Daconil Weatherstik alt. with KleenGrow were also effective. None of the preventive treatments significantly reduced defoliation. However, curative applications of F6123-1 alt. with Vapor Gard and preventive and curative treatments of the high rate of Postiva alt. with Vapor Gard consistently reduced the defoliation. Preventive application of Actigard alt. with Vapor Gard, curative application of the low rate of Postiva alt. Vapor Gard, and preventive and curative treatments of the high rate of Postiva alt. Vapor Gard, as well as Vapor Gard alone, resulted in the highest stem water potential among treated plants. A weak positive correlation was observed between stem water potential and disease development. The identified combinations and application strategies provide options for effective boxwood blight management when combined with other management strategies.

Friedreich Ataxia: An (Almost) 30-Year History After Gene Discovery.

In the late 1800s, Nikolaus Friedreich first described "degenerative atrophy of the posterior columns of the spinal cord," noting its connection to progressive ataxia, sensory loss, and muscle weakness, now recognized as Friedreich ataxia (FRDA). Renewed interest in the disease in the 1970s and 80s by the Quebec Cooperative Group and by Anita Harding led to the development of clinical diagnostic criteria and insights into associated biochemical abnormalities, although the primary defect remained unknown. In 1988, Susan Chamberlain mapped FRDA's location on chromosome 9. In the early 90s, collaborative research, including work by the author's team, identified a gene, later named FXN, containing an expanded GAA repeat-confirming it as the FRDA mutation. This discovery established a diagnostic foundation for FRDA, advancing genetic testing and opening new research avenues. These new areas of study included the characteristics, origin, and pathogenicity of the GAA repeat expansion; the characterization of frataxin, the encoded protein, including its subcellular localization, structure, and function; the identification of cellular pathways disrupted by frataxin deficiency; and the redefinition of FRDA phenotypes based on genetic testing, along with the study of FRDA's natural history. In addition, efforts focused on the search for biomarkers to reflect diagnosis, disease severity, and progression and, most importantly, the identification and development of therapeutic approaches in both preclinical and clinical settings. The creation of cellular and animal models was crucial to this progress, as was the formation of consortia to collaboratively drive basic and clinical research forward. Now, 28 years after the gene discovery, although much remains to be understood about the disease's mechanisms and the development of effective therapies, the progress is undeniable. A thriving community has emerged, uniting researchers, health care providers, industry professionals, individuals with FRDA, their families, and dedicated volunteers. With this collective effort, a cure is within reach.

Abstract TP347: Sex differences of immunosuppression and phagocytosis after stroke as a correlative measure for post-stroke functional recovery

Background: Stroke remains a leading cause of death globally, with significant sex differences in post-stroke outcomes. Additionally, post-stroke infections and sepsis are linked to differences in innate immune responses. The glycosidase, Chitotriosidase 1 (CHIT1), has emerged as an important regulator of innate immunity and lower levels of CHIT1 and chitinases-like proteins are associated with disease severity and progression including multiple sclerosis. However, whether CHIT1 plays a role in the response to acute ischemic stroke is unknown. Hypothesis: We hypothesized that sex-specific alterations in pro-inflammatory factors, including CHIT1, contribute to differential patterns of phagocytosis and post-stroke outcomes. Methods: We examined the effects of acute ischemic stroke (AIS) in older men and women, specifically circulatory cytokine production, circulatory phagocytosis assessment utilizing fluorescent bead engulfment assay, and if these correlated with post-stroke complications in peripheral blood mononuclear cells (PBMCs). We examined relationships with stroke severity, as measured by the NIH Stroke Scale (NIHSS) in patients with a NIHSS&gt;6. Results: Our findings reveal that older women exhibit lower levels of CHIT1 activity correlating with poorer survival outcomes in AIS (p&lt;0.05, n=7-11/grp) compared to men (ns, n=21-22/grp). Female presented a robust phagocytic capability and CHIT1 depression on peripheral monocytes (p&lt;0.05, n=7-11/grp). This effect is not observed in men, who exhibit greater phagocytic capacity after 1 day after stroke (p&lt;0.01, n=21-22/grp) measured by bead uptake assay using flow cytometry. Variations in CHIT1 levels in PBMCs correlated with stroke severity and infection risk, underscoring its potential role in sex-dependent outcomes. Conclusion: Our data suggests that peripheral reduction of CHIT1 levels impairs phagocytosis and increases susceptibility to infections as a risk factor for poorer stroke outcomes. CHIT1 appears to be a novel mediator of sex differences in post-stroke immune suppression. Targeting the anti-fungal response protein CHIT1 could help normalize phagocytic responses in older women, potentially reducing infection rates and improving post-stroke outcomes. Further research into CHIT1's interaction with pathogen-associated molecular patterns could provide new therapeutic strategies for stroke management.

Quantification of antibiotic usage against Streptococcus suis in weaner pigs in The Netherlands between 2017-2021

Streptococcus suis is an important pig pathogen that can cause severe disease in the post-weaning period. As there are no commercial vaccines available in the Netherlands, antibiotic treatment is often necessary to control disease. S. suis is regarded as one of the major causes of antibiotic prescription in weaned pigs, but scientific studies supporting this claim with quantitative data are lacking. The aim of this study was to obtain insight in, and to quantify usage of, antibiotics against S. suis in weaner pigs at sow farms in the Netherlands. Three sources of data were used, including 1) total antibiotic usage in weaner pigs in the Netherlands, as yearly reported by the Netherlands Veterinary Medicines Institute (SDa), and estimates from 2) pig veterinarians and 3) pig farmers on the relative amount of antibiotics prescribed against S. suis, via questionnaires. Information from the SDa on the total amount of antibiotic usage was combined with the estimates of the veterinarians to estimate the antibiotic usage against S. suis in weaner pigs. Our study shows that ~90% of the total amount of amoxicillin (AMOX) and ampicillin (AMPI) prescribed in weaner pigs is used for treatment of disease caused by S. suis (S. suis disease). Of all orally prescribed antibiotics against S. suis, AMOX comprises 85% of the total absolute usage expressed by the mean defined daily dosage per animal farm (3.2 – 5.4 mean DDDAF). Furthermore, veterinarians reported that at farms with structural S. suis disease problems second choice antibiotics (AMOX, AMPI) are more often prescribed than at farms with incidental S. suis disease. All together, we estimated that S. suis disease accounts for about 1/3rd of the total antibiotic usage in weaner pigs. This study is the first to quantify antibiotic usage against S. suis in weaner pigs and shows that S. suis is a hotspot of antibiotic usage. This underlines the severity and relevance of S. suis disease and the need for alternative control measures.

The glutathione S-transferase BnGSTU12 enhances the resistance of Brassica napus to Sclerotinia sclerotiorum through reactive oxygen species homeostasis and jasmonic acid signaling.

Sclerotinia sclerotiorum is a severe disease that affects rapeseed (Brassica napus), resulting in significant yield losses. In previous study, we identified the candidate GLUTATHIONE S-TRANSFERASE (GST) gene, BnGSTU12, associated with sclerotiorum stem resistance and the expression levels of BnGSTU12 in resistant lines were higher than that in susceptible lines. We analyzed the function of the BnGSTU12 during S. sclerotiorum infection in this study. BnGSTU12 expression was induced by S. sclerotiorum, with a strong increase 24h after onset of infection. Transgenic functional analysis indicated that overexpression of BnGSTU12 in Arabidopsis thaliana and B. napus enhanced resistance to S. sclerotiorum, whereas BnGSTU12 silencing decreased S. sclerotiorum resistance. The inoculated BnGSTU12-OE A. thaliana and B. napus plants showed higher antioxidant enzyme activity and lower H2O2 contents than the wild type. As BnGSTU12 was rapidly induced by the phytohormones salicylic acid (SA), ethylene, and methyl jasmonate (MeJA), we investigated the involvement of the JA and SA pathways in GSTU12-mediated S. sclerotiorum resistance. JA content was higher in infected BnGSTU12-OE plants than in the wild type, whereas their SA contents were comparable. In addition, the expression levels of JASMONATE RESISTANT (JAR) involved in JA-Ile biosynthesis and those of JA-responsive genes were higher, the expression of JAZ gene repressing JA signaling was less in OE plants than WT after 12 and 24h inoculation with S. sclerotiorum. Our results show that BnGSTU12 enhances resistance to S. sclerotiorum through ROS homeostasis and JA signaling.