Favorable Course Of Disease Research Articles

Efficacy of Doxorubicin in the Adjuvant Treatment of Canine Splenic Visceral Hemangiosarcoma

Introduction. Splenic hemangiosarcoma is a highly malignant neoplasm that affects geriatric patients. The incidence in dogs is 45–50% of all splenic tumours and about 2% of all oncological pathologies. The visceral form of splenic hemangiosarcoma is characterised by the most aggressive course of the disease and early metastasis to other organs. The average life expectancy of animals after splenectomy, according to various scientific data, is from 20 to 90 days. The article studies the efficacy of additional doxorubicin-based adjuvant chemotherapy to increase the life expectancy of dogs at different stages of the disease.Materials and Methods. To compare the life expectancy, the patients were divided into 4 groups receiving different treatments for splenic hemangiosarcoma. Examination of patients, visual diagnostics and pathomorphological diagnostics were used for making a diagnosis, determining the stage of the disease and prescribing treatment. Treatment efficacy was assessed based on the median relapse-free period, median life expectancy and survival rate of patients after 3, 6, and 12 month periods. Statistical analysis was performed using the Fisher's exact test.Results. The obtained data demonstrated a more favourable course of disease in dogs with the stage I tumour process. Splenectomy made it possible to increase the life expectancy of patients to 243 days with a 6–month survival rate in 62.5% of patients. Postoperative chemotherapy treatment combined with doxorubicin significantly improved the longterm prognosis and led to more than twofold increase in life expectancy of dogs (up to 475 days) with a one-year survival rate in 83.3% of patients. However, no substantial statistical significance was determined in the studied groups (p=0.7).Discussion and Conclusion. The results of the research have revealed the efficacy of adjuvant doxorubicin-based chemotherapy in dogs with the visceral forms of splenic hemangiosarcoma. In animals with early stages of the disease, a significant increase in life expectancy has been discovered. The development of hemagdomain and/or the presence of metastasis to abdominal organs indicate the unfavourable course of the disease and, as a consequence, early metastasis. Nevertheless, even at these stages, doxorubicin can increase the life expectancy of patients.

The Effect of Corticosteroids on the Progression and Outcomes of Polytrauma in Children

Polytrauma in children are among the most common causes of death in the pediatric intensive care unit (ICU).The aim of this study was to evaluate the effect of systemic corticosteroids (SCS) on the progression, laboratory parameters, and outcomes of severe multiple injuries in children requiring ICU.Materials and methods. A retrospective, observational, multicenter (case-control and cross-sectional) study included 203 patients from pediatric ICUs across the Russian Federation. The Abbreviated Injury Scale (AIS) score was 36.81 (25–48), and the Pediatric Trauma Score (PTS) was 5.2 (2–8). SCS were administered to 113 (55.7%) children, 19 (9.36%) of whom died.Results. The most severe changes in laboratory parameters, such as an increase in amylase (35.3 vs. 18.3; P0.001) and activated partial thromboplastin time (APTT) (28.9 vs. 25.8; P0.001), were documented upon admission of children with multiple traumatic injuries to the hospital compared with subsequent days of treatment in the ICU. The average fluid volume (as a percentage of age-related fluid requirements) on the first day of treatment in the ICU was 118.53% and did not exceed 84.42% on subsequent days (P0.001). Higher systolic blood pressure (SBP) during the first three days of ICU treatment was observed in children treated without SCS. SBP tended to decrease by day 5, and then a tendency toward arterial hypertension emerged on days 6–7. In children treated with SCS, blood pressure remained stable during the first seven days in the ICU, contributing to a favorable outcome.Conclusion. The use of SCS in children with severe polytrauma from the first day of ICU treatment contributed to the stabilization of hemodynamic parameters and improved control of shock signs. A positive response to SCS in these patients can be considered a marker for a favorable disease course during ICU treatment.

Clinical characteristics and long-term disease course in patients with Crohn's disease as diagnosed by video capsule endoscopy: a multicenter retrospective matched case-control study.

Video capsule endoscopy is rarely used to diagnose Crohn's disease in patients with negative ileocolonoscopy or cross-sectional image findings. We evaluated clinical characteristics and long-term outcomes of these rare cases. This multicenter study included patients with Crohn's disease from 3 tertiary hospitals from January 2007 to October 2022. Patients with normal findings on ileocolonoscopy and computed tomography (CT)/magnetic resonance (MR) enterography but had ulcerations at the small bowel detected by video capsule endoscopy were included. The controls were patients with abnormal findings on endoscopy or CT/MR enterography. Controls were case-matched in a ratio of 3:1 for sex, calendar year of diagnosis, and age at diagnosis. Among 3,752 patients, 24 (0.6%) were diagnosed with Crohn's disease using video capsule endoscopy findings. The disease location (P< 0.001) and behavior at diagnosis (P= 0.013) of the cases significantly differed from that of controls. The perianal fistula modifier (25.0% vs. 33.3%, P= 0.446) did not differ significantly between the 2 groups. Initial disease activity and C-reactive protein and fecal calprotectin levels were significantly lower in cases versus controls. The median Lewis score was 838 (interquartile range, 393-1,803). Over 10 years of follow-up, the cases showed significantly lower cumulative risk of complicated behavior, biologics use, Crohn's disease-related hospitalization, and surgeries (log-rank test P< 0.05). Patients with Crohn's disease whose lesions were observed only by video capsule endoscopy were rare, and exhibit different clinical characteristics and a more favorable long-term disease course compared to those who were conventionally diagnosed.

Clinical features of breast cancer in Ashkenazi Jewish carriers of the two founder BRCA1 pathogenic variants.

e12557 Background: Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Carriers have a significantly elevated risk of developing breast cancer (BC) and ovarian cancer (OC) compared to the general female population. Two prevalent PVs in Ashkenazi Jews (AJ) in the BRCA1 gene are 185delAG and 5382insC. This study aims to compare clinical features of disease between the PV carrier groups. Methods: Data was collected retrospectively on 282 BC patients who were carriers of 5382insC or 185delAG, treated in Hadassah and Shaare Zedek Medical Centers between the years 1978 and 2021. Data collected included features such as age at disease onset, staging at diagnosis, additional malignancies or recurrence of disease, pathological features such as hormone receptor status and HER2 status (tumor subtype), and treatments. Disease characteristics and outcomes were compared. Results: There were 207 carriers of the 185delAG PV, while 75 carried the 5382insC PV. Amongst carriers of 185delAG, vs. 5382InsC, 58.1% vs. 35.8% (p&lt;0.01) had triple negative BC (TNBC), while 28.2% vs. 52.6% (p&lt;0.01) had hormone positive BC, respectively (Table). There was no significant difference in disease-free or overall survival, even after adjusting for age, stage and other potential confounders. Although it appeared that 5382insC carriers suffered a higher rate of OC (14% vs. 9.6%), and that 185delAG had a higher rate of non-OC malignancies (8.2% vs. 4%), these differences did not reach statistical significance. Conclusions: Our study suggests that 5382insC and 185delAG differ in their patterns of disease. Despite the lower rates of TNBC, 5382insC carriers had similar survival to 185delAG carriers. This could suggest that the hormone receptor positive disease amongst 5382InsC carriers had a less favorable course of disease, with a similar outcome as in those with TNBC. Further studies are warranted to better understand this pattern of disease aggression. [Table: see text]

Diabetes as a risk factor for pneumococcal disease and severe related outcomes and efficacy/effectiveness of vaccination in diabetic population. Results from meta-analysis of observational studies

AimsTo collect all available evidence on the effect of diabetes mellitus (DM) as a risk factor for pneumococcal disease incidence and related complications, and on the efficacy/effectiveness of vaccines in patients with DM.MethodsTwo distinct systematic searches on MEDLINE, Cochrane, ClinicalTrials.gov and EMBASE databases were performed, one for each meta-analysis, collecting all observational (cohort and case–control) studies and randomized clinical trials performed on humans up to June 1st, 2023.ResultsWe retrieved 36 observational studies comparing risk for pneumococcal disease and related complications in people with or without DM, and 11 studies (1 randomized clinical trial and 10 observational studies) assessing conjugated and polysaccaridic vaccines efficacy/effectiveness on preventing such outcomes. People with DM were at higher risk for Invasive Pneumococcal Disease (unadjusted OR 2.42 [2.00; 2.92]); Case-Fatality Rate (unadjusted OR 1.61 [1.25; 2.07], Pneumococcal pneumonia (unadjusted OR 2.98 [2.76; 3.22), and Intensive care unit admission for pneumococcal disease (unadjusted OR 2.09 [1.20; 3.66]). In diabetic individuals vaccinated with conjugated vaccine, incidence of pneumonia specific for vaccine type in a clinical trial (OR 0.237 [0.008; 0.704]), and hospitalization for overall pneumonia during the year following the polysaccharide vaccination in observational studies (unadjusted OR 0.63 [0.45–0.89]) were significantly lower in comparison with unvaccinated DM subjects, with no significant differences for other outcomes.ConclusionsPeople with diabetes mellitus are at higher risk for less favourable course of pneumococcal disease and should be therefore targeted in vaccination campaigns; more evidence needs to be collected on vaccination outcomes in people with diabetes.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. The genotype frequencies of rs28371582, a 21-bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p .009; Del/Del genotype 16.8% vs. 7.7%, p .005, odds ratio: 2.43 [1.27-4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040-0.490, p .019). The presence of CD59 rs141385724 was associated with less severe pre-diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083-1.80, p .032). MMN susceptibility is associated with a 21-bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long-term disease outcome. Taken together, these results point out the relevance of the pre-C5 level of the complement cascade in the inflammatory processes underlying MMN.

MET receptor serves as a promising target in melanoma brain metastases

The development of brain metastases hallmarks disease progression in 20–40% of melanoma patients and is a serious obstacle to therapy. Understanding the processes involved in the development and maintenance of melanoma brain metastases (MBM) is critical for the discovery of novel therapeutic strategies. Here, we generated transcriptome and methylome profiles of MBM showing high or low abundance of infiltrated Iba1high tumor-associated microglia and macrophages (TAMs). Our survey identified potential prognostic markers of favorable disease course and response to immune checkpoint inhibitor (ICi) therapy, among them APBB1IP and the interferon-responsive gene ITGB7. In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score. Signature-based deconvolution of MBM via single sample GSEA revealed enrichment of interferon-response and immune signatures and revealed inflammation, stress and MET receptor signaling. MET receptor phosphorylation/activation maybe elicited by inflammatory processes in brain metastatic melanoma cells via stroma cell-released HGF. We found phospho-METY1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival.

Navigating the discontinuation of multiple sclerosis first line treatments: A paradigm shift in patient care

BackgroundThis retrospective study, conducted between 2005 and 2016, investigated the outcomes of patients with multiple sclerosis (MS) who discontinued injectable first-line disease-modifying therapies (DMTs). The study aimed to identify factors influencing treatment discontinuation and assess the impact of discontinuation on disease progression. MethodsData was collected from 2,270 patients who received injectable DMTs for at least two years and subsequently discontinued treatment due to clinical and MRI remission, side effects, or noncompliance. Patients were categorized into two groups: those stable after discontinuation (SAD) and those with relapse after discontinuation (RAD). Survival analysis and logistic regression were employed to assess factors influencing treatment discontinuation. ResultsOf the 60 patients who discontinued DMTs, one-third (n = 20) remained stable, while 40 patients experienced clinical and/or MRI activity during follow-up. The SAD group had a significantly later age at treatment discontinuation compared to RAD patients (35.9 ± 11.1 vs. 30.7 ± 6.1, p = 0.025). Patients below 40 years old had a higher likelihood of experiencing worsening (75 %), while those over 50 years old demonstrated an 80 % stability rate. SAD patients used DMTs for a more extended period than RAD patients (69.1 ± 47.3 vs. 46.6 ± 20.3 months, p = 0.012). A notable proportion (42.9 %) of worsened patients discontinued DMTs without consulting a physician, emphasizing potential challenges in treatment adherence. After treatment discontinuation, RAD patients experienced relapses after a median of 21.0 months. Survival analysis suggested a more favorable disease course for patients who discontinued treatment after achieving a stable period (p = 0.237), with evidence of differentiation between groups after four years. Regression analysis indicated that older age at discontinuation had a favorable impact on relapse probability (HR: 0.904; p = 0.031; 95 % CI: 0.825, 0.991). Reasons for discontinuation unrelated to disease stability showed a positive but imprecise effect on relapse probability. ConclusionThis study provides insights into the outcomes of MS patients discontinuing injectable DMTs, emphasizing the importance of age at discontinuation and reasons for treatment cessation in predicting disease progression. The findings suggest that discontinuation after achieving stability may lead to more favorable outcomes, highlighting the need for personalized treatment decisions in MS management. Further research is warranted to validate these findings and inform clinical practices.

Low-intensity inflammation as a manifestation of comorbidity and a factor in the unfavorable clinical course of heart failure with preserved ejection fraction

Aim. To analyze the prognostic significance of clinical, anamnestic and paraclinical parameters in patients with heart failure with preserved ejection fraction (HFpEF) and non-obstructive coronary artery disease.Material and methods. The study included 54 patients. Cardiac and lung ultrasound was performed. In addition, the level of N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukin-1β, interleukin-18, growth differentiation factor 15 (GDF-15), and cryopyrin was determined. The level of quality of life, anxiety and depression, and adherence to treatment were analyzed.Results. The patients were divided into 2 following groups: group 1 (n=22) with an unfavorable course and group 2 (n=32) with a favorable disease course. Basic echocardiographic parameters, as well as the number of B-lines in lungs, were comparable in both groups. An unfavorable HFpEF course was associated with a longer history of hypertension — 17,5 [10;20] and 7 [5;15] years (p=0,03), smoking — 36,4 and 9,4% (p=0,035), impaired carbohydrate metabolism — 54,5 and 15,6% (p=0,003) and lower adherence to treatment (p=0,02). In group 1, GDF-15 levels were higher than in group 2 — 1841 [1237;3552] vs 1709,5 [1158;2492] pg/ml (p=0,026).Conclusion. Low-intensity subclinical inflammation, the predisposing factors of which are smoking, impaired carbohydrate metabolism, and a long history of hypertension, is associated with higher GDF-15 values in patients with HFpEF and, along with low patient adherence to treatment, has an adverse effect on the clinical course of heart failure.

P259 Clinical characteristics and long-term disease course in patients with Crohn’s disease diagnosed by video capsule endoscopy; A retrospective multicentre matched case-control study

Abstract Background Video capsule endoscopy (VCE) is a non-invasive and accurate diagnostic modality that allows for direct visualization of the small intestinal mucosa in Crohn’s disease (CD). In rare cases, lesions not detected by other diagnostic modalities in patients suspected to have CD are solely identified through VCE. We aim to evaluate the clinical characteristics and long-term outcomes of these rare cases. Methods A retrospective multicentre matched case-control analysis was conducted in patients with CD across three hospitals in Korea, from January 2007 to April 2023. To perform a matched case-control study, we defined cases (VCE group) as patients with normal findings at colonoscopy and cross-sectional imaging, ultimately diagnosed with CD by VCE; the controls were patients with CD diagnosed with specific findings at endoscopy or cross-sectional imaging (non-VCE group). Controls were matched to cases with a ratio of 3:1 for sex, calendar year of diagnosis, and age at diagnosis. Clinical characteristics and outcomes between the two groups were compared. Results Of the 3,137 patients diagnosed with CD during the study period, 24 were diagnosed solely by VCE. When compared to 72 matched patients with CD, the mean duration from symptom onset to diagnosis did not significantly differ (27.2 months [SD 10.2] vs. 25.3 months [SD 8.9], p=0.394). There was a significant difference in the proportion of Montreal behaviour (p&amp;lt;0.001). In the VCE group, non-stricturing and non-penetrating (B1) type and stricturing (B2) type accounted for 91.7 and 8.3%, respectively. However, there was no significant difference in the perianal fistula modifier (25% vs. 33.3%, p=0.446). Within the VCE group, 45.8% underwent the examination due to abdominal pain with diarrhoea, followed by 25.0% with perianal disease, and 20.8% with unexplained iron deficiency anaemia. Regarding capsule findings, the ileum was mostly involved (87.5%), while the jejunum and duodenum were affected in 70.8 and 16.7% of cases, respectively. Fifteen patients had two or three segments affected. The Median Lewis score was 838 [IQR 393–1803]. Concerning the cumulative incidence of clinical outcomes over 10 years, complicated behaviour, need for biologics, and CD-related hospitalization and surgery were all significantly lower in the VCE group than in the non-VCE group (p&amp;lt;0.005). Conclusion Patients diagnosed with CD solely by VCE are rare. In this study, they exhibited different clinical characteristics and a more favourable long-term disease course compared to the general population of patients with CD. This included a lower incidence of complicated behaviour, reduced need for biologics, and CD-related hospitalization and surgery.

ОСОБЕННОСТИ ТЕЧЕНИЯ МИКОБАКТЕРИОЗА ЛЕГКИХ В ЗАВИСИМОСТИ ОТ ВЫЯВЛЕНИЯ ВОЗБУДИТЕЛЯ В МОКРОТЕ

Objective: to evaluate treatment effectiveness in patients with mycobacterial pulmonary disease and its association with mycobacteria detection in sputum. Materials and methods. The study enrolled 196 patients with confirmed mycobacterial pulmonary disease. The diagnosis was established as per ATS/IDSA criteria (2007). The patients were divided into two groups: group 1 consisted of 108 patients with nontuberculous mycobacteria (NTM) detected in sputum; group 2 consisted of 60 patients with NTM detected in BAL and/or lung tissue samples. Female patients prevailed (78.6%). The average patients’ age was 56.9 ± 11.3 years. The time period from diagnosing pulmonary mycobacterial disease to commencementof combination antibacterial therapy varied from one month to 3.5 years. Patients were followed up during one year after treatment completion. Results. The most commonly identified NTM were MAC (M. аvium, M. intracellulare) and M. kansasii. The combination antibacterial therapy was administered to 168 (85.7%) patients. Clinical cure was more frequently achieved in the patients of group 2 compared to group 1 (21.7 and 3.7% respectively, р &lt; 0.01). The frequency of clinical improvement without conversion of biological samples did not significantly differ between the groups (40 and 54.6% respectively, …). The frequency of relapse was similar in both groups and did not exceed 5%. Conclusion. The presence of NTM in BAL while the absence of NTM in sputum allows predicting more favourable disease course and better response to treatment.

Diagnostics, Management, and Outcomes in Patients with Pyogenic Spinal Intra- or Epidural Abscess.

Owing to the lack of evidence on the diagnostics, clinical course, treatment, and outcomes of patients with extremely rare spinal intradural abscess (SIA) and spinal epidural abscess (SEA), we retrospectively analyzed and compared a cohort of patients to determine the phenotyping of both entities. Over a period of 20 years, we retrospectively analyzed the electronic medical records of 78 patients with SIA and SEA. The patients with SIA showed worse motor scores (MS scores) on admission (SIA: 20 ± 26 vs. SEA: 75 ± 34, p < 0.001), more often with an ataxic gait (SIA: 100% vs. SEA: 31.8%, p < 0.001), and more frequent bladder or bowel dysfunction (SIA: 91.7% vs. SEA: 27.3%, p < 0.001) compared to the SEA patients. Intraoperative specimens showed a higher diagnostic sensitivity in the SEA patients than the SIA patients (SIA: 66.7% vs. SEA: 95.2%, p = 0.024), but various pathogens such as Staphylococcus aureus (SIA 33.3% vs. SEA: 69.4%) and Streptococci and Enterococci (SIA 33.3% vs. SEA: 8.1%, p = 0.038) were detected in both entities. The patients with SIA developed sepsis more often (SIA: 75.0% vs. SEA: 18.2%, p < 0.001), septic embolism (SIA: 33.3% vs. SEA: 8.3%, p = 0.043), signs of meningism (SIA: 100% vs. 18.5%, p < 0.001), ventriculitis or cerebral abscesses (SIA: 41.7% vs. SEA: 3.0%, p < 0.001), and pneumonia (SIA: 58.3% vs. SEA: 13.6%, p = 0.002). The mean MS score improved in both patient groups after surgery (SIA: 20 to 35 vs. SEA: 75 to 90); however, the SIA patients showed a poorer MS score at discharge (SIA: 35 ± 44 vs. SEA: 90 ± 20, p < 0.001). C-reactive protein (CrP) (SIA: 159 to 49 vs. SEA: 189 to 27) and leukocyte count (SIA: 15 to 9 vs. SEA: 14 to 7) were reduced at discharge. The SIA patients had higher rates of disease-related mortality (SIA: 33.3% vs. SEA: 1.5%, p = 0.002), had more pleural empyema (SIA: 58.3% vs. SEA: 13.6%, p = 0.002), required more than one surgery (SIA: 33.3% vs. SEA 13.6%, p = 0.009), were treated longer with intravenous antibiotics (7 ± 4 w vs. 3 ± 2 w, p < 0.001) and antibiotics overall (12 ± 10 w vs. 7 ± 3 w, p = 0.022), and spent more time in the hospital (SIA: 58 ± 36 vs. SEA: 26 ± 20, p < 0.001) and in the intensive care unit (SIA: 14 ± 18 vs. SEA: 4 ± 8, p = 0.002). Our study highlighted distinct clinical phenotypes and outcomes between both entities, with SIA patients displaying a markedly less favorable disease course in terms of complications and outcomes.

COVID-19 prognosis in systemic lupus erythematosus compared with rheumatoid arthritis and spondyloarthritis: results from the CONTROL-19 Study by the Italian Society for Rheumatology

IntroductionData concerning SARS-CoV-2 in patients affected by SLE are contradicting.The aim of this study was to investigate disease-related differences in COVID-19 prognosis of patients affected by rheumatic diseases before vaccination;...

Antiphospholipid antibody carriers and patients with quiescent antiphospholipid syndrome show persistent subclinical complement activation.

Complement activation has been advocated as one mechanism by which aPLs can induce thrombosis. In patients with catastrophic APS or re-thrombosis, enhanced complement activation has been shown, even in the quiescent phase of the disease. We aimed to assess complement activation and to investigate its association with clinical variables in aPL-positive patients with a favourable disease course. Subjects with at least two consecutive positive aPL results obtained ≥12 weeks apart were enrolled. They were subjects without a history of thrombosis or pregnancy morbidity (aPL carriers), patients with pregnancy morbidity alone, i.e. obstetric APS patients (OAPS patients), and/or patients with arterial, venous, or small-vessel thrombotic APS (TAPS patients); for enrolment, all patients were required to have been free of symptoms for ≥2 years. Patients affected with systemic autoimmune diseases were excluded. Healthy age- and sex-matched subjects were included as controls. Plasma C5a and C5b-9 levels were assessed by commercially available ELISA assays. The non-parametric Mann-Whitney test and Spearman's correlation were applied. Thirty-seven OAPS patients, 38 TAPS patients, 42 aPL carriers and 30 healthy subjects were enrolled. The median C5a and C5b-9 levels were significantly higher in quiescent aPL-positive patients (OAPS, TAPS, aPL carriers) compared with controls: C5a ng/ml 10.61 [interquartile range (IQR) 6.87-15.46] vs 4.06 (2.66-7.35), P < 0.001; C5b-9 ng/ml 283.95 (175.8-439.40) vs 165.90 (124.23-236.8), P < 0.001. Similar C5a and C5b-9 levels were observed in OAPS and TAPS patients and aPL carriers. A positive correlation between the median C5b-9 levels and the number of aPL-positive tests was found (P = 0.002). The persistence of aPL antibodies is associated with a persistent subclinical activation of the complement cascade.

Antibodies against angiotensin II receptor type 1 and endothelin A receptor are increased in COVID-19 patients.

Increased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms. Antibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause. Significantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up. In patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.

Characterization of extracellular vesicles in COVID-19 infection during pregnancy.

Introduction: SARS-CoV-2 infection may cause a severe inflammatory response, inflicting severe morbidity and mortality. This risk is modestly increased in pregnant patients. Despite the hypercoagulability and immunosuppression associated with pregnancy, most pregnant women experience a mild COVID-19 infection. Maternal extracellular vesicles (EVs) may interact with endothelial and immune components to facilitate a favorable disease course. This pilot study aimed to explore the characteristics of EVs released during COVID-19 infection occurring during the third trimester of pregnancy. Methods: In this prospective study, blood samples were obtained from 16 healthy non-pregnant (NP), 18 healthy-pregnant (HP), and 22 COVID-19 positive pregnant subjects (CoV-P). Disease course and pregnancy outcomes were assessed and EVs were characterized. Of note, limited volumes of sample acquired from the subjects made it necessary to use smaller and different subsets of samples for each analysis. Results: The majority (91%) of the COVID-19-pregnant subjects (18 mild and 2 moderate disease) experienced good pregnancy-related outcomes. EV concentrations were higher in healthy-pregnant subjects compared to non-pregnant subjects (p = 0.0041) and lower in COVID-19-pregnant subjects compared to healthy-pregnant subjects (p = 0.0150). CD63 exosome marker expression was higher in EVs of healthy-pregnant subjects and COVID-19-pregnant subjects compared to EVs of non-pregnant subjects (p = 0.0149, p = 0.0028, respectively). Similar levels of SARS-CoV-2 entry proteins (ACE-2 and TMPRSS2) were found in all three groups. Cytokine content increased in healthy-pregnant subject-EVs compared to non-pregnant EVs, while IL-2 and IL-6 levels were decreased in COVID-19-pregnant subject-EVs compared to healthy-pregnant subject-EVs (p = 0.043, p = 0.0390, respectively). CD8+, cytotoxic T-cell marker, was lower in non-pregnant EVs compared to healthy-pregnant subject-EVs and to COVID-19-pregnant subjects (p = 0.0108, p < 0.0001, respectively). COVID-19- pregnant subject-EVs demonstrated higher levels of platelet activation marker (CD62P) than non-pregnant (p = 0.0327) and healthy-pregnant subjects (p = 0.0365). Endothelial marker EV-CD144+ was lower in healthy-pregnant subjects versus non-pregnant subjects (p = 0.0093), but similar in COVID-19-pregnant and non-pregnant subjects. Other EVs' coagulation markers/activity, D-Dimer and fibrinogen levels were similar in healthy-pregnant subjects and COVID-19 positive pregnant subjects. Conclusion: COVID-19 positive pregnant subjects' EVs demonstrated an attenuated inflammatory response, with no additional activation of the coagulation system.

Hereditary Liver Diseases: Wilson's Disease and Hemochromatosis

Wilson's disease and HFE-hemochromatosis are autosomal-recessively inherited metabolic diseases of the liver. Copper overload in case of Wilson's disease and iron overload in case of hemochromatosis lead to organ damage of the liver and other organs. In order to diagnose these diseases at an early stage and introduce therapy, knowledge of the symptoms and diagnostic criteria of these diseases is important. Iron overload in hemochromatosis patients is treated with phlebotomies and copper overload in Wilson's disease patients with either chelating medications (D-penicillamine or trientine) or zinc salts. After introduction of lifelong therapy both diseases typically have a favorable disease course and further development of organ-damage can be prevented, especially with respect to liver-damage.

GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis.

Widespread dysregulation of long non-coding RNAs [lncRNAs] including a reduction in GATA6-AS1 was noted in inflammatory bowel disease [IBD]. We previously reported a prominent inhibition of epithelial mitochondrial functions in ulcerative colitis [UC]. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not defined. Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment-naïve independent human cohorts [n=673]. RNA pull-down followed by mass spectrometry was used to determine the GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2 cells were used to elaborate on GATA6-AS1 functions. GATA6-AS1 showed predominant expression in gut epithelia using single cell datasets. GATA6-AS1 levels were reduced in Crohn's disease [CD] ileum and UC rectum in independent cohorts. Reduced GATA6-AS1 lncRNA was further linked to a more severe UC form, and to a less favourable UC course. The GATA6-AS1 interactome showed robust enrichment for mitochondrial proteins, and included TGM2, an autoantigen in coeliac disease that is induced in UC, CD and coeliac disease, in contrast to GATA6-AS1 reduction in these cohorts. GATA6-AS1 silencing resulted in induction of TGM2, and this was coupled with a reduction in mitochondrial membrane potential and mitochondrial respiration, as well as in a reduction of metabolites linked to aerobic respiration relevant to mucosal inflammation. TGM2 knockdown in GATA6-AS1-deficient cells rescued mitochondrial respiration. GATA6-AS1 levels are reduced in UC, CD and coeliac disease, and in more severe UC forms. We highlight GATA6-AS1 as a target regulating epithelial mitochondrial functions, potentially through controlling TGM2 levels.

Clinical phenotyping of spondylodiscitis and isolated spinal epidural empyema: a 20-year experience and cohort study.

The incidence of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) has been increasing in the last decades, but the distinct differences between both entities are poorly understood. We aimed to evaluate the clinical phenotypes and long-term outcomes of SD and ISEE in depth. We performed a chart review and analyzed data from our cohorts of consecutive SD and ISEE patients who were treated and assessed in detail for demographic, clinical, imaging, laboratory, and microbiologic characteristics at a university neurosurgical center in Germany from 2002 to 2021. Between-group comparisons were performed to identify meaningful differences in both entities. We included 208 patients (72 females: age 75 [75 32-90] y vs. 136 males: 65 [23-87] y, median [interquartile range], p < 0.001), of which 142 (68.3%) had SD and 66 (31.7%) had ISEE. Patients with SD were older than ISEE (ISEE: 62 y vs. SD: 70 y, p = 0.001). While SD was more common in males than females (males: n = 101, 71.1% vs. females: n = 41, 28.9%, p < 0.001), there was no sex-related difference in ISEE (males: n = 35, 53.0% vs. females: n = 31, 47.0%, p = 0.71). Obesity was more frequent in ISEE than in SD (ISEE: n = 29, 43.9% vs. SD: n = 37, 26.1%, p = 0.016). However, there were no between-group differences in rates of diabetes and immunodeficiency. In the entire study population, a causative pathogen was identified in 192 (92.3%) patients, with methicillin-susceptible staphylococcus aureus being most frequent (n = 100, 52.1%) and being more frequent in ISEE than SD (ISEE: n = 43, 65.2% vs. SD: n = 57, 40.1%, p = 0.003). SD and ISEE occurred most frequently in the lumbar spine, with no between-group differences (ISEE: n = 25, 37.9% vs. SD: n = 65, 45.8%, p = 0.297). Primary infectious sources were identified in 145 patients (69.7%) and among this skin infection was most common in both entities (ISEE: n = 14, 31.8% vs. SD: n = 25, 24.8%, p = 0.418). Furthermore, epidural administration was more frequent the primary cause of infection in ISEE than SD (ISEE: n = 12, 27.3% vs. SD: n = 5, 4.9%, p < 0.001). The most common surgical procedure in SD was instrumentation (n = 87, 61%) and in ISEE abscess evacuation (n = 63, 95%). Patients with ISEE displayed lower in-hospital complication rates compared to SD for sepsis (ISEE: n = 12, 18.2% vs. SD: n = 94, 66.2%, p < 0.001), septic embolism (ISEE: n = 4/48 cases, 8.3% vs. SD: n = 52/117 cases, 44.4%, p < 0.001), endocarditis (ISEE: n = 1/52 cases, 1.9% vs. SD: n = 23/125 cases, 18.4%, p = 0.003), relapse rate (ISEE: n = 4/46, 8.7% vs. SD: n = 27/92, 29.3%, p = 0.004), and disease-related mortality (ISEE: n = 1, 1.5% vs. SD: n = 11, 7.7%, p = 0.108). Patients with SD showed prolonged length of hospital stay (ISEE: 22 [15, 30] d vs. SD: 38 [29, 53] d, p < 0.001) and extended intensive care unit stay (ISEE: 0 [0, 4] d vs. SD: 3 [0, 12] d, p < 0.002). Our 20-year experience and cohort analysis on the clinical management of SD and ISEE unveiled distinct clinical phenotypes and outcomes in both entities, with ISEE displaying a more favorable disease course with respect to complications and relapse rates as well as disease-related mortality.

The roles of tertiary lymphoid structures in chronic diseases.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues that drive antigen-specific immune responses at sites of chronic inflammation. Unlike secondary lymphoid organs such as lymph nodes, TLSs lack capsules and have their own unique characteristics and functions. The presumed influence of TLSs on the disease course has led to widespread interest in obtaining a better understanding of their biology and function. Studies using single-cell analyses have suggested heterogeneity in TLS composition and phenotype, and consequently, functional correlates with disease progression are sometimes conflicting. The presence of TLSs correlates with a favourable disease course in cancer and infection. Conversely, in autoimmune diseases and chronic age-related inflammatory diseases including chronic kidney disease, the presence of TLSs is associated with a more severe disease course. However, the detailed mechanisms that underlie these clinical associations are not fully understood. To what extent the mechanisms of TLS development and maturation are shared across organs and diseases is also still obscure. Improved understanding of TLS development and function at the cellular and molecular levels may enable the exploitation of these structures to improve therapies for chronic diseases, including chronic kidney disease.