Influence Disease Severity Research Articles

Timing patterns of initial respiratory syncytial virus infection and factors influencing disease severity in hospitalized infants with different health status.

This study aimed to determine the timing patterns of the initial respiratory syncytial virus (RSV) infection and to identify the factors influencing disease severity in infants of varying health status. A retrospective study was conducted at the Affiliated Children's Hospital of Chongqing Medical University from 2012 to 2022. The timing of the first RSV infection was estimated in infants with differing health status using correlation analysis, considering their birth time. Logistic regression was utilized to identify factors influencing severe RSV infection in these infants.RSV detection primarily occurred in the winter and spring. Epidemic season and peak timing of RSV were not significantly affected by health status or the COVID-19 pandemic. A strong positive correlation was observed between the age at RSV infection and the interval from birth to the RSV peak season. Infants born during the RSV epidemic season exhibited a higher likelihood of infection within the first 2 months postbirth. In contrast, those born outside the RSV epidemic season were more susceptible to infection during the subsequent peak. Notably, infants with pre-existing health conditions contracted RSV at an earlier age compared to their healthy counterparts. Among healthy infants, severe RSV infection was associated with sex, age, and timing of infection. For infants with underlying conditions, severe RSV infection was primarily related to age and timing of infection. The initial timing of RSV infection in infants varied depending on their health status. Young age and infection timing during the RSV epidemic season were significant risk factors for severe RSV infection. These findings provide a theoretical basis for optimizing immunization strategies for infants with diverse health conditions.

P116 How does the 4005+2T>C CFTR variant influence disease severity in the Norwegian cystic fibrosis population

P116 How does the 4005+2T>C CFTR variant influence disease severity in the Norwegian cystic fibrosis population

The endocannabinoid ARA-S acts as an endogenous rescuing factor of Kv7.1/KCNE1 carrying Long QT syndrome mutations and paves the way for drug development strategies

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation program Long QT Syndrome (LQTS) is a cardiac arrhythmia characterized by delayed ventricular repolarization. LQTS occurs when there are loss-of-function mutations in genes encoding for voltage-gated channels and their beta subunits that contribute to the cardiac action potential. Among them, the most mutated channel is Kv7.1/KCNE1, which encodes for the slowly activating component of the delayed rectifier K+ current (IKs). Families with inherited mutations in the Kv7.1/KCNE1 exhibit inconsistent correlations between genotypes and phenotypes making the clinical management of LQTS challenging. A possible strategy to help guide clinical approaches involves exploring endogenous compounds capable of modulating the Kv7.1/KCNE1 channel function, acting as potential disease modifiers. Using the two-electrode voltage clamp technique, we previously found that the endogenous endocannabinoid-like compound ARA-S, which has an arachidonic acid tail and a serine head group, facilitates activation of the wild-type Kv7.1/KCNE1 channel expressed in Xenopus oocytes. This is seen as a left shift in the voltage dependence of channel opening and an increase in conductance. Moreover, we showed that ARA-S restores a physiological QT interval in isolated guinea pig hearts suffering from drug-induced LQTS. Hence, ARA-S is an interesting endogenous Kv7.1/KCNE1 channel modulator that may influence disease severity. However, it is uncertain whether ARA-S also activates the Kv7.1/KCNE1 when it carries LQTS-associated mutations. Therefore, the current study involves studying the effect of ARA-S on mutated Kv7.1/KCNE1 channels using two-electrode voltage clamp electrophysiology. We find that ARA-S facilitates the activation of all tested LQTS mutants. However, the magnitude of the effect varies among them, suggesting that the compound´s effect is dependent on the genetic background. To understand why ARA-S has different effects, we use computational simulation approaches to study how mutations in the putative ARA-S binding sites change ARA-S efficacy. This understanding aids in developing new substances that can activate different mutations, by, for example, modifying the ARA-S tail to enhance its efficacy. We also try to understand the concentration of ARA-S required to restore a wild-type-like function of each mutant, considering the mutant's intrinsic behavior and the apparent affinity of ARA-S for the specific mutant. Altogether, this work finds ARA-S to be an efficient activator of LQTS-associated mutant Kv7.1/KCNE1 channels and is a first step towards understanding how the genetic background determines the effect of this endogenous modulator.

SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression.

The virus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, is the causative agent of the current COVID-19 pandemic. It possesses a large 30 kilobase (kb) genome that encodes structural, non-structural, and accessory proteins. Although not necessary to cause disease, these accessory proteins are known to influence viral replication and pathogenesis. Through the synthesis of novel infectious clones of SARS-CoV-2 that lack one or more of the accessory proteins of the virus, we have found that one of these accessory proteins, ORF8, is critical for the modulation of the host inflammatory response. Mice infected with a SARS-CoV-2 virus lacking ORF8 exhibit increased weight loss and exacerbated macrophage infiltration into the lungs. Additionally, infection of mice with recombinant SARS-CoV-2 viruses encoding ORF8 mutations found in variants of concern reveal that naturally occurring mutations in this protein influence disease severity. Our studies with a virus lacking this ORF8 protein and viruses possessing naturally occurring point mutations in this protein demonstrate that this protein impacts pathogenesis.

Body composition impacts outcome of bronchoscopic lung volume reduction in patients with severe emphysema: a fully automated CT-based analysis

Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive and irreversible airflow limitation, with individual body composition influencing disease severity. Severe emphysema worsens symptoms through hyperinflation, which can be relieved by bronchoscopic lung volume reduction (BLVR). To investigate how body composition, assessed through CT scans, impacts outcomes in emphysema patients undergoing BLVR. Fully automated CT-based body composition analysis (BCA) was performed in patients with end-stage emphysema receiving BLVR with valves. Post-interventional muscle and adipose tissues were quantified, body size-adjusted, and compared to baseline parameters. Between January 2015 and December 2022, 300 patients with severe emphysema underwent endobronchial valve treatment. Significant improvements were seen in outcome parameters, which were defined as changes in pulmonary function, physical performance, and quality of life (QoL) post-treatment. Muscle volume remained stable (1.632 vs. 1.635 for muscle bone adjusted ratio (BAR) at baseline and after 6 months respectively), while bone adjusted adipose tissue volumes, especially total and pericardial adipose tissue, showed significant increase (2.86 vs. 3.00 and 0.16 vs. 0.17, respectively). Moderate to strong correlations between bone adjusted muscle volume and weaker correlations between adipose tissue volumes and outcome parameters (pulmonary function, QoL and physical performance) were observed. Particularly after 6-month, bone adjusted muscle volume changes positively corresponded to improved outcomes (ΔForced expiratory volume in 1 s [FEV1], r = 0.440; ΔInspiratory vital capacity [IVC], r = 0.397; Δ6Minute walking distance [6MWD], r = 0.509 and ΔCOPD assessment test [CAT], r = −0.324; all p < 0.001). Group stratification by bone adjusted muscle volume changes revealed that groups with substantial muscle gain experienced a greater clinical benefit in pulmonary function improvements, QoL and physical performance (ΔFEV1%, 5.5 vs. 39.5; ΔIVC%, 4.3 vs. 28.4; Δ6MWDm, 14 vs. 110; ΔCATpts, −2 vs. −3.5 for groups with ΔMuscle, BAR% < –10 vs. > 10, respectively). BCA results among patients divided by the minimal clinically important difference for forced expiratory volume of the first second (FEV1) showed significant differences in bone-adjusted muscle and intramuscular adipose tissue (IMAT) volumes and their respective changes after 6 months (ΔMuscle, BAR% −5 vs. 3.4 and ΔIMAT, BAR% −0.62 vs. 0.60 for groups with ΔFEV1 ≤ 100 mL vs > 100 mL). Altered body composition, especially increased muscle volume, is associated with functional improvements in BLVR-treated patients.

The complex landscape of DMD mutations: moving towards personalized medicine.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.

Gaucher’s Disease – current state of knowledge and future perspectives?

Introduction and purpose: Gaucher's Disease (GD), a rare genetic disorder, is a difficult challenge in genetic and metabolic disorders. The aim of this review is to provide an exploration of GD, spanning its pathophysiology to the latest advancements in diagnostic and therapeutic innovations. In this review we aimed to underscore the challenges it presents and the ongoing efforts to overcome them. State of knowledge: GD, characterized by the accumulation of glucocerebroside, involves molecular, cellular, and systemic dysfunctions. At the molecular level, mutations in the GBA gene give rise to diverse manifestations, influencing disease severity. Cellular disruptions lead to lysosomal dysfunction, altered calcium homeostasis, and chronic inflammation, impacting various organ systems. Diagnostic approaches involve biomarkers, genetic testing, and imaging studies, each playing a crucial role in confirming the disease type and assessing its grade. Summary: Management and treatment strategies for GD have evolved, with enzyme replacement therapy and substrate reduction therapy serving as the basics. However, challenges persist, including limited efficacy in treating neurological symptoms and the high cost of treatments. The review highlights ongoing research and future perspectives in GD therapy.

The interaction between general or abdominal obesity and hypertension on the risk of type 2 diabetes mellitus: a cross-sectional analysis in Iranian adults from the RaNCD cohort study

BackgroundInteractions between risk factors may influence disease severity. Knowing this relationship is important for preventive interventions and disease control. The purpose of this study was to determine the interactions effects of obesity and hypertension on the risk of type 2 diabetes mellitus (T2DM).MethodsThe data of 9,283 adults 35 to 65 years were examined from the cohort study of Ravansar Non-Communicable Disease (RaNCD). Waist circumference (WC) was used to identify both general and abdominal obesity based on body mass index (BMI). To assess the interaction between hypertension and obesity (general/abdominal) and the risk of T2DM, the additive interaction was calculated.ResultsThe adjusted odds ratios for T2DM were 2.38 (1.67, 3.41) in men and 4.02 (2.47, 6.47) in women for the combinations of hypertension and abdominal obesity. The adjusted odds ratios for T2DM were 2.53 (1.63, 3.82) in men and 2.66 (1.92, 3.70) in women for the combinations of hypertension and general obesity. The results of the additive interaction indicators were inconsistent with gender. The relative excess risk due to interaction (interaction between hypertension and central obesity) (RERI), attributable proportion due to interaction (AP) and synergy index (SI) were0.27 (-1.01, 1.54), 0.11 (-0.41, 0.63) and 1.23 (0.41, 3.68) in male and were 0.61 (-1.12, 2.33), 0.23 (0.08, 0.37) and 1.26 (0.60, 2.61) in female, respectively.ConclusionGeneral/abdominal obesity and hypertension have a synergistic effect on the risk of T2DM. The recommendation for preventing T2DM is lifestyle modification. Large longitudinal studies are necessary to investigate causal relationships.

Long-Term Persistence of COVID-Induced Hyperglycemia: A Cohort Study.

Although the short-term mortality of patients with COVID-19 infection and hyperglycemia has been well documented, there is little available data regarding longer-term prognosis. The presence of diabetes has not only influenced disease severity but has also impacted its transmission dynamics. In this study, we followed a historical cohort of patients without previous history of diabetes who presented with moderate to severe COVID-19 and were found to have hyperglycemia (random blood glucose >140 mg/dL) at the time of admission. We evaluated the need for antidiabetic therapy in these patients at the end of 6 months and the risk factors associated with persistent hyperglycemia determined by monthly values of self-monitored blood glucose. Of the seventy participants who were followed telephonically, 54 (77%) continued to receive antidiabetic therapy or have persistent hyperglycemia (>140 mg/dL) at the end of 6 months. Persistent hyperglycemia at the end of follow-up, was found to be associated with a higher blood glucose at presentation.

Obesity and diabetes mellitus are associated with SARS-CoV-2 outcomes without influencing signature genes of extrapulmonary immune compartments at the RNA level

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for eliciting Coronavirus disease 2019 (COVID-19) still challenges healthcare services worldwide. While many patients only suffer from mild symptoms, patients with some pre-existing medical conditions are at a higher risk for a detrimental course of disease. However, the underlying mechanisms determining disease course are only partially understood. One key factor influencing disease severity is described to be immune-mediated. In this report, we describe a post-mortem analysis of 45 individuals who died from SARS-CoV-2 infection. We could show that although sociodemographic factors and premedical conditions such as obesity and diabetes mellitus reduced survival time in our cohort, they were not associated with changes in the expression of immune-related signature genes at the RNA level in the blood, the gut, or the liver between these different groups. Our data indicate that obesity and diabetes mellitus influence SARS-CoV-2-related mortality, without influencing the extrapulmonary gene expression of immunity-related signature genes at the RNA level.

Evaluation of lumbar paraspinal muscles degeneration and fatty infiltration in dynamic sagittal imbalance based on magnetic resonance imaging.

To explore degeneration and fatty infiltration (FI) of lumbar paraspinal muscles in patients with dynamic sagittal imbalance (DSI) and the relationship between lumbar paraspinal muscles degeneration, fatty infiltration and severity of the disease. We recruited 41 DSI patients and selected 22 lumbar spinal stenosis (LSS) patients without osphyalgia as controls. All patients received magnetic resonance imaging (MRI) scan and DSI patients also received pre-walk and post-walk X-rays. DSI patients were divided into 2 subgroups according to their symptom improvement after conservative treatment. We calculated rmCSA and FI of the lumbar paraspinal muscles. The rmCSA and FI between DSI and control and between DSI subgroups were compared by t test. The regression analysis was used to explore the risk factors influencing disease severity. Receiver operating characteristic (ROC) curves and area under curves (AUCs) were used to evaluate the severity of the disease. In comparison of rmCSA and FI between DSI and control, there are significant differences of most muscles. In comparison of rmCSA between two subgroups, there are significant differences of most muscles, while in comparison of FI, only muscles in L4 segment have significant different. In logistic regression analysis, total rmCSA and total FI are risk factors influencing disease severity. ROC curves shows that total rmCSA and total FI both achieve an AUC greater than 0.7. Compared with control, DSI patients have degeneration and fatty infiltration of the lumbar paraspinal muscles. The degeneration and fatty infiltration are risk factors influencing disease severity. The total rmCSA and total FI can be used as an indicator to determine whether a patient has severe DSI.

Efficacy and Safety of Luspatercept in Patients with HbE/β-Thalassemia from the BELIEVE Study: A Subgroup Analysis

Background: Thalassemias are a group of inherited blood disorders caused by impaired production of the globin chains of hemoglobin (Hb), resulting in anemia. HbE/β-thalassemia results from the co-inheritance of a specific point mutation in the β-globin gene with a second β-thalassemia mutation. The combination of mutations influences disease severity, ranging from mild to severe, with HbE/β-thalassemia accounting for about half of all cases of severe thalassemia. Patients (pts) with severe disease have higher red blood cell (RBC) transfusion requirements, which can be associated with increased risk of related morbidities. Treatments that can reduce dependence on RBC transfusions are needed to improve pt outcomes. Primary results from the BELIEVE study (NCT02604433) demonstrated the efficacy and safety of luspatercept to treat anemia in transfusion-dependent pts with β-thalassemia across genotypes including HbE (Cappellini MD, et al. HemaSphere 2020;4[S1]:108-109). A subsequent analysis of the final BELIEVE data for pts with β 0/β 0 mutations, a form of severe β-thalassemia, demonstrated similar results with longer treatment in this subgroup (Sheth S, et al. Blood 2022;140 [S1]:1946-1948). The aim of this post hoc sub-analysis was to investigate the efficacy and safety of longer-term luspatercept treatment in pts in the BELIEVE trial with HbE/β-thalassemia. Methods: The BELIEVE trial included adult pts with β-thalassemia or HbE/β-thalassemia (compound heterozygous β-thalassemia with mutation and/or multiplication of α-globin genes allowed) who required regular RBC transfusions (6-20 RBC units in the 24 wk before randomization with no transfusion-free period &amp;gt; 35 days). Pts were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk and evaluated for response (defined as reduction in RBC transfusion burden ≥ 33% or ≥ 50% from baseline during any 12-wk interval over the entire study) and safety. Data were evaluated up to the final pt visit (Jan 5, 2021). Results: The BELIEVE trial enrolled 336 pts, 52 (15.5%) of whom had HbE/β-thalassemia; 31 were randomized to the luspatercept group of the overall intent-to-treat (ITT) population (13.8%; N = 224). At baseline, pts receiving luspatercept with HbE/β-thalassemia were similar in age compared with the overall ITT population (median 32 y vs 30 y, respectively) and had similar transfusion burden (median 13.0 units vs 14.0 units over 24 wk), but had higher median fetal Hb (6.1% vs 5.1%), higher median serum ferritin (2087.0 vs 1441.3 μg/L), and higher median liver iron content (10.8 vs 6.1 mg/g dry weight). The median (range) duration of luspatercept treatment for pts with HbE/β-thalassemia was similar to the overall ITT population (157.7 [51.0-207.1] wk vs 153.6 [1.7-215.0] wk). A similar proportion of pts with HbE/β-thalassemia as in the overall ITT population achieved ≥ 33% reduction in transfusion burden (83.9% vs 77.2%) and ≥ 50% reduction in transfusion burden (61.3% vs 50.0%) over any 12-wk interval with luspatercept treatment (Figure A). Median total duration of ≥ 33% reduction in transfusion burden response was longer for HbE/β-thalassemia pts versus the overall ITT population (722.0 days vs 586.0 days). In the HbE/β-thalassemia subgroup, 67.6% of pts experienced ≥ 1 treatment-emergent adverse event (TEAE) related to treatment versus 60.5% of pts in the overall luspatercept safety population. The proportion of pts experiencing grade ≥ 3 treatment-related TEAEs was 25.8% in the HbE/β-thalassemia subgroup and 12.1% in the overall safety population. Treatment-related TEAEs resulted in discontinuation of luspatercept in 6.5% and 9.0% of the HbE/β-thalassemia and overall safety populations, respectively. No treatment-related TEAEs resulted in death in either group (Figure B). Summary: The HbE/β-thalassemia sub-group of the BELIEVE study had rates of response that were consistent with the larger ITT population. Furthermore, pts with HbE/β-thalassemia experienced a longer median total duration of response compared with the overall ITT population with a similar safety profile. Additional evaluation of the efficacy and safety of luspatercept in a larger population of HbE/β-thalassemia pts would be valuable as the number of pts in this sub-analysis was small, yet these results suggest that luspatercept is as safe and effective for this subgroup of pts as for the wider β-thalassemia population.

Analysis of factors affecting enoxaparin effectiveness on coagulation, inflammation, and clinical outcomes in patients with COVID-19

Context: Hypercoagulopathy is a COVID-19 extra-pulmonary manifestation has drawn the attention of the scientists due to its risk of thromboembolism. Enoxaparin is an anticoagulant used to prevent hypercoagulopathy. Many factors have been associated with enoxaparin effectiveness. Aims: To analyze factors affecting enoxaparin effectiveness on coagulation, inflammation, and clinical outcomes. Methods: This retrospective cohort study involved hospitalized adult patients with COVID-19 from November 2020 to April 2021. Patients’ age, gender, body mass index (BMI), comorbidity, and laboratory results were extracted from medical records. Factors influencing enoxaparin efficacy on coagulation, inflammation, and clinical outcomes were analyzed using path analysis with SmartPLS 3.0 software. D-dimer and platelet values was determined as coagulation outcomes and C-reactive protein (CRP) value as an inflammation outcome. Clinical outcomes comprised of mortality, ventilator usage, and length of stay. Results: A total of 269 patients fulfilled the inclusion criteria. Most of the subjects were male (58%), 66% had comorbidities, 48.3% were aged ≥60 years old, and 65.8% had a BMI ≥ 25 kg/m2. Path analysis showed that age, BMI, and comorbidity affected disease severity (p&lt;0.05). Disease severity strongly influenced enoxaparin dosage (p=0.000). Dosage affected platelet value, ventilator usage, and mortality (p&lt;0.05). Gender did not influence disease severity, and dosage displayed no significant effect on length of stay, CRP, and D-dimer (p&gt;0.05). Conclusions: Dosage is the main factor influencing enoxaparin efficacy on coagulation, inflammation, and clinical outcomes. The dosage is strongly affected by disease severity, in which is predominantly influenced by age, BMI, and comorbidity.

Timing of BNT162b2 vaccine prior to COVID-19 infection, influence disease severity in patients with hematologic malignancies: Results from a cohort study.

The COVID-19 pandemic continues to pose challenges to the treatment of hemato-oncology patients. Emergence of COVID-19 variants, availability of vaccine boosters and antiviral treatments could impact their outcome. We retrospectively studied patients with hematologic malignancies and confirmed COVID-19 during the Omicron outbreak. Of 116 evaluated patients, 16% developed severe or critical COVID-19. Diagnosis of chronic lymphocytic leukemia (CLL) was significantly associated with severe COVID-19 (p = 0.01). The vaccine effectiveness was related to the timing of the vaccine, with patients who received a mRNA vaccine within 7-90 days prior to COVID-19 being less likely to develop severe disease compared to all other patients (p = 0.019). There was no correlation between disease severity and antiviral therapies. Importantly, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID-19. In conclusion, patients with hematologic malignancies are at a considerable risk for severe COVID-19 during the Omicron outbreak, with patients with CLL being the most vulnerable. mRNA vaccines have the potential to protect hematological patients from severe COVID-19 if administered within the previous 3 months. Hematological treatment interruption is a frequent adverse outcome of COVID-19 infection.

Characteristics of the pulmonary microbiota in patients with mild and severe pulmonary infection.

Lung infection is a global health problem associated with high morbidity and mortality and increasing rates of hospitalization. The correlation between pulmonary microecology and infection severity remains unclear. Therefore, the purpose of this study was to investigate the differences in lung microecology and potential biomarkers in patients with mild and severe pulmonary infection. Patients with pulmonary infection or suspected infection were divided into the mild group (140 cases) and the severe group (80 cases) according to pneomonia severity index (PSI) scores. Here, we used metagenomic next-generation sequencing (mNGS) to detect DNA mainly from bronchoalveolar lavage fluid (BALF) collected from patients to analyze changes in the lung microbiome of patients with different disease severity. We used the mNGS to analyze the pulmonary microecological composition in patients with pulmonary infection. The results of alpha diversity and beta diversity analysis showed that the microbial composition between mild and severe groups was similar on the whole. The dominant bacteria were Acinetobacter, Bacillus, Mycobacterium, Staphylococcus, and Prevotella, among others. Linear discriminant analysis effect size (LEfSe) results showed that there were significant differences in virus composition between the mild and severe patients, especially Simplexvirus and Cytomegalovirus, which were prominent in the severe group. The random forest model screened 14 kinds of pulmonary infection-related pathogens including Corynebacterium, Mycobacterium, Streptococcus, Klebsiella, and Acinetobacter. In addition, it was found that Rothia was negatively correlated with Acinetobacter, Mycobacterium, Bacillus, Enterococcus, and Klebsiella in the mild group through co-occurrence network, while no significant correlation was found in the severe group. Here, we describe the composition and diversity of the pulmonary microbiome in patients with pulmonary infection. A significant increase in viral replication was found in the severe group, as well as a significant difference in microbial interactions between patients with mild and severe lung infections, particularly the association between the common pathogenic bacteria and Rothia. This suggests that both pathogen co-viral infection and microbial interactions may influence the course of disease. Of course, more research is needed to further explore the specific mechanisms by which microbial interactions influence disease severity.

Superior resistance to Phytophthora infestans in new pre-breeding potato clones under different nitrogen fertilisation regimes used in organic agriculture

ABSTRACT Late blight caused by Phytophthora infestans is the most devastating disease for cultivated potatoes, causing considerable financial loss annually due to loss of yield and costs of fungicide applications. For organic farming especially, the strict limitations on the use of fungicides makes research necessary to investigate factors that influence disease severity. Therefore, effects of nitrogen fertiliser rates on leaf and tuber blight in organically grown potato cultivars and pre-breeding clones were evaluated in the present study. It was found that the foliage of the pre-breeding clones was little, or not at all, affected by P. infestans, irrespectively of the nitrogen application rate, while the cultivars reacted differently with mild to strong late blight symptoms. Only some of the clones and cultivars showed increased infection of tubers at the higher nitrogen application rates, whilst most showed no significant differences between the N rates. Overall, the present study showed that the use of new resistant cultivars could be a suitable approach to reduce late blight in organic farming, where soil nitrogen levels may vary due to the use of different forms of nutrient inputs with varying mineralisation rates.

Antimicrobial activity of coral-associated beneficial bacteria against coral disease-causing microbial pathogens.

Microbial infection of immune-compromised corals influences disease severity, resulting in coral mortality. However, coral-associated beneficial bacteria are known to produce antimicrobial compounds that prevent the growth of potential pathogens and invading microbes. Hence, beneficial bacteria associated with coral Porites lutea were isolated and antimicrobial protein and bioactive secondary metabolites were extracted and tested for their antimicrobial activity against putative prokaryotic and eukaryotic coral pathogens. Bioactive secondary metabolites exhibited remarkable antagonism against various coral pathogens such as Serratia marcescens, Vibrio species, and Aspergillus sydowii. Besides, the metabolites of Cobetia marina, Cobetia amphilecti, Pseudoalteromonas neustonica, and Virgibacillus halodenitrificans manifested notable inhibition against the protozoan ciliates (Uronema marinum, Holosticha diademata, Cohnilembus verminus, and Euplotes vannus) and zooplankton that are known to be involved in the secondary pathogenesis in coral diseased lesion progression. Thus, the present study may benefit in understanding coral-associated beneficial bacteria for their antagonistic interactions with microbial pathogens, as well as their potential involvement in reducing coral disease severity.

Gene Polymorphisms of Epithelial Cell-Derived Alarmins and Their Effects on Protein Levels and Disease Severity in Patients with COVID-19.

The immune response in COVID-19 is characterized by the release of alarmin cytokines, which play crucial roles in immune activation and inflammation. The interplay between these cytokines and genetic variations may influence disease severity and outcomes, while sex differences might further contribute to variations in the immune response. We measured the levels of alarmin cytokines in a cohort of COVID-19 and non-COVID-19 patients using a sensitive Meso Scale Discovery system. Additionally, we conducted an SNP analysis to identify genetic variations within the IL-33 and TSLP genes. The association between these genetic variations, cytokine production, and COVID-19 severity was examined. Our findings revealed elevated levels of IL-33 and IL-25 in COVID-19-positive patients compared to COVID-19-negative patients (p < 0.05), indicating their potential as therapeutic targets for disease modulation. Moreover, a minor allele within the IL-33 gene (rs3939286) was found to be associated with a protective effect against severe COVID-19 (p < 0.05), and minor alleles of the TSLP gene (rs2289276 and rs13806933) were found to significantly reduce TSLP protein levels in serum (p < 0.05). Sex-specific effects of TSLP and IL-33 SNPs were observed, suggesting a potential influence of sex hormones and genetic variations on the regulation of cytokine production. The present study highlights the importance of alarmin cytokines and genetic variations in COVID-19 severity, providing valuable insights into personalized treatment approaches. Our results suggest that targeting alarmin cytokines may offer potential therapeutic benefits in managing COVID-19. Furthermore, the sex-specific effects of genetic variations emphasize the need to consider individual genetic profiles and sex differences when designing targeted interventions.

A novel gut microbiome–immune axis influencing pathology in HCMV infected infants with neonatal cholestasis

The interplay of active HCMV infection with gut dysbiosis in the immunopathology of cholestasis in neonates and infants remains unexplored. In this study, we evaluated gut microbiome profiles and immune dysfunction in a cohort of HCMV infected cholestatic infants (IgM positive, N = 21; IgM negative, N = 25) compared to healthy infants, N = 10. HCMV infected IgM positive individuals exhibited increased clinical severity in terms of liver dysfunction, altered CD4+: CD8+ ratio, and elevated Granzyme B levels in cellular immune subsets. Gut microbiome analysis revealed distinct and differential diversity and composition within infected groups aligned with clinical severity reflected through the increased abundance of Gammaproteobacteria, reduced Bifidobacteria, and a unique signature mapping to the HCMV infected IgM negative group. Correlation analyses revealed associations between Bifidobacterium breve, Gammaproteobacteria, Firmicutes, Clostridia, Finegoldia magna, Veillonella dispar, and Granzyme B expressing immune cell subsets. Our study describes a novel gut microbiome–immune axis that may influence disease severity in cholestatic infants with active HCMV infection.

Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval.

Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel KV7.1/KCNE1, which is the most frequently mutated ion channel in LQTS. We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts. We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate KV7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval. We consider the endocannabinoids as an interesting class of hKV7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts. ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.