Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis.

Acute pulmonary embolism generally resolves within 6 months. However, if the thrombus is infected, venous thrombi transform into fibrotic vascular obstructions leading to chronic deep vein thrombosis and/or chronic thromboembolic pulmonary hypertension (CTEPH), but precise mechanisms remain unclear. Neutrophils are crucial in sequestering pathogens; therefore, we investigated the role of neutrophil extracellular traps (NETs) in chronic thrombosis. Because chronic pulmonary thrombotic obstructions are biologically identical to chronic deep venous thrombi, the murine inferior vena cava ligation model was used to study the transformation of acute to chronic thrombus. Mice with staphylococcal infection presented with larger thrombi containing more neutrophils and NETs but less resolution. Targeting NETs with DNase1 diminished fibrosis and promoted thrombus resolution. For translational studies in humans, we focused on patients with CTEPH, a severe type of deep venous and pulmonary artery fibrotic obstruction after thrombosis. Neutrophils, markers of neutrophil activation, and NET formation were increased in CTEPH patients. NETs promoted the differentiation of monocytes to activated fibroblasts with the same cellular phenotype as fibroblasts from CTEPH vascular occlusions. RNA sequencing of fibroblasts isolated from thrombo-endarterectomy specimens and pulmonary artery biopsies revealed transforming growth factor-ß (TGF-ß) as the central regulator, a phenotype which was replicated in mice with fibroblast-specific TGF-ß overactivity. Our findings uncover a role of neutrophil-mediated inflammation to enhance TGF-ß signaling, which leads to fibrotic thrombus remodeling. Targeting thrombus NETs with DNases may serve as a new therapeutic concept to treat thrombosis and prevent its sequelae.

Vaginal microbiota in pregnant women with inflammatory rheumatic and inflammatory bowel disease: A matched case-control study.

BACKGROUND: Rheumatic diseases and vaginal infections both increase the risk of preterm birth. It is unclear whether pregnant women with rheumatic disease are more likely to experience vaginal infections, which might potentially accumulate modifiable risk factors. OBJECTIVE: In this study, we sought to evaluate the vaginal microbiota of pregnant women with inflammatory rheumatic and inflammatory bowel disease. METHODS: A total of 539 asymptomatic women with singleton pregnancy were routinely screened for an abnormal vaginal microbiota between 10 + 0 and 16 + 0 gestational weeks. Vaginal smears were Gram-stained and microscopically analysed. Those with inflammatory diseases (with or without immunomodulatory therapy) were assigned to the case group and matched in a 1:3 ratio to healthy pregnant controls. RESULTS: Overall, an abnormal vaginal microbiota occurred more frequently among women of the case group, compared with those of the control group (33.8% vs 15.6%; 95% CI: 1.78-4.27, p < .001). In particular, Candida colonisation (22.3% vs 9.2%; 95% CI: 1.69-4.75, p < .001), but also bacterial vaginosis (14.9% vs 7.2%; 95% CI: 1.25-4.1, p = .006), occurred more often in the case than in the control group. No significant difference was found with regard to the occurrence of an abnormal vaginal microbiota between subgroups with and without immunomodulatory treatment (37.0% vs 27.1%; 95% CI: 0.29-1.35, p = .232). CONCLUSION: Pregnant women with inflammatory rheumatic and inflammatory bowel disease are at risk for bacterial vaginosis and Candida colonisation, which might pose a risk for preterm birth. Prospective studies are needed to further evaluate the influence of autoimmune conditions and immunosuppressive therapy on the vaginal microbiota.

Implication of baseline levels and early changes of C-reactive protein for subsequent clinical outcomes of patients with rheumatoid arthritis treated with tocilizumab.

BACKGROUND: Rheumatoid arthritis (RA) is characterised by clinical joint swelling and elevation of acute phase reactant levels, typically measured by the C-reactive protein (CRP). Clinical and inflammatory responses are usually concordant, except for inhibition of IL-6, which often disproportionally reduces the CRP due to direct inhibition of its hepatic production. We investigated whether pre-treatment CRP is a useful marker that can guide a preferential treatment choice towards IL-6 inhibition. METHODS: Data of 1126 treatment courses with tocilizumab (TCZ; early RA), 250 courses of rituximab (RTX; established RA) and 249 courses of methotrexate (MTX; established RA) were analysed. We compared clinical disease activity index (CDAI) values and change along 24 weeks' follow-up to CRP values at baseline or its early change. We validated the results using data from a separate TCZ trial in early RA. RESULTS: CRP levels in the TCZ group on average dropped by 74% within 4 weeks. Patients who attained CDAI remission at 24 weeks on TCZ had the highest baseline CRP levels while patients in high disease activity had the lowest; this association was reverse in the RTX and MTX groups. TCZ patients who achieved remission at 24 weeks showed the largest reductions of CRP levels by week 4 compared with those reaching higher disease activity states. Early CRP non-response was indicative of a risk of not achieving clinical treatment goals (p=0.038). CONCLUSION: Baseline CRP appears to have a positive association with reaching the therapeutic target on TCZ treatment, but is a negative predictor for RTX and MTX. Patients on TCZ without an early CRP response have a lower chance of achieving remission. CRP and its early course may inform, to some extent, the estimation of potential therapeutic success in patients with RA.

A new tidal breathing measurement device detects bronchial obstruction during methacholine challenge test.

PURPOSE: Bronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the methacholine challenge test (MCT). While spirometry relies on proper patients' cooperation and precise execution of forced breathing maneuvers, we conducted a comparative analysis with the portable nanomaterial-based sensing device, SenseGuard™, to non-intrusively assess tidal breathing parameters. MATERIALS AND METHODS: In this prospective study, 37 adult participants with suspected asthma underwent sequential spirometry and SenseGuard™ measurements after inhaling increasing methacholine doses. RESULTS: Among the 37 participants, 18 were MCT responders, 17 were non-responders and 2 were excluded due to uninterpretable data. The MCT responders exhibited a significant lung function difference when comparing the change from baseline to maximum response. This was evident through a notable decrease in forced expiratory volume in 1 â€‹s (FEV1) levels in spirometry, as well as in prominent changes in tidal breathing parameters as assessed by SenseGuard™, including the expiratory pause time (Trest) to total breath time (Ttot) ratio, and the expiratory time (Tex) to Ttot ratio. Notably, the ratios Trest/Ttot (∗p â€‹= â€‹0.02), Tex/Ttot (∗p â€‹= â€‹0.002), and inspiratory time (Tin) to Tex (∗p â€‹= â€‹0.04) identified MCT responders distinctly, corresponding to spirometry (∗p â€‹< â€‹0.0001). CONCLUSIONS: This study demonstrates that tidal breathing assessment using SenseGuard™ device reliably detects clinically relevant changes of respiratory parameter during the MCT. It effectively distinguishes between responders and non-responders, with strong agreement to conventional spirometry-measured FEV1. This technology holds promise for monitoring clinical respiratory changes in bronchial asthma patients pending further studies.

Asymmetric Dimethylarginine and NT-proBNP Levels Provide Synergistic Information in Pulmonary Arterial Hypertension.

BACKGROUND: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. OBJECTIVES: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. METHODS: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 µmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; rS = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; rS = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005). CONCLUSIONS: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.

Referral rates and barriers to lung transplantation based on pulmonary function criteria in interstitial lung diseases: a retrospective cohort study.

BACKGROUND: Interstitial lung diseases (ILD) unresponsive to medical therapy often require lung transplantation (LTx), which prolongs quality of life and survival. Ideal timing for referral for LTx remains challenging, with late referral associated with significant morbidity and mortality. Among other criteria, patients with ILD should be considered for LTx if forced vital capacity (FVC) is less than 80% or diffusion capacity for carbon monoxide (DLCO) is less than 40%. However, data on referral rates are lacking. OBJECTIVES: To evaluate referral rates for LTx based on pulmonary function tests (PFTs) and identify barriers associated with non-referral. DESIGN: A single-center retrospective cohort study. METHODS: The study consisted of ILD patients who performed PFT between 2014 and 2020. Patients with FVC < 80% or a DLCO < 40% were included in the study. Patients with absolute contraindications to LTx were excluded. Referral rates were computed, and a comparison was made between referred and non-referred subjects. RESULTS: Out of 114 ILD patients meeting criteria for referral to LTx, 35 were referred (30.7%), and 7 proceeded to undergo LTx. Median time from PFT to referral for assessment was 255 days [interquartile range (IQR) 35-1077]. Median time from referral to LTx was 89 days (IQR 59-143). Referred patients were younger (p = 0.003), had lower FVC (p < 0.001), DLCO (p < 0.001), and a higher rate of pulmonary hypertension (p = 0.04). Relatively better PFT, and older age, were significantly associated with non-referral of patients. CONCLUSION: There is under-referral of ILD patients who are eligible for LTx, which is associated with severe disease and missed opportunities for LTx. Further research is required to validate these findings.

Lung transplants: addressing referral gaps for lung disease patientsPatients with severe lung diseases that are unresponsive to medical treatments often require lung transplants to enhance their quality of life and survival. Determining the optimal timing for considering a transplant is challenging, as delaying it can lead to complications. Our study aimed to assess how frequently individuals with lung problems, particularly interstitial lung diseases, were referred for lung transplants based on lung function tests. We conducted a retrospective analysis of medical records for patients with lung diseases who underwent lung function tests between 2014 and 2020. We selected patients whose test results indicated impaired lung function, excluding those who were ineligible for lung transplants due to other medical reasons. Subsequently, we examined the number of patients referred for a lung transplant and compared them to those who were not referred. Our findings revealed that out of 114 patients eligible for a lung transplant, only 35 were referred, representing a referral rate of approximately 31%. Among these, only 7 patients actually underwent the transplant procedure. The time elapsed between the lung function test and the referral for a transplant assessment was notably long, averaging around 255 days. Additionally, once referred, patients waited an average of 89 days for the transplant assessment. Referred patients tended to be younger and had more severe lung disease, characterized by lower lung function test results and a higher likelihood of pulmonary hypertension. Conversely, patients who were not referred generally enjoyed better overall health and were older. This discrepancy highlights the missed opportunities for patients to improve their health and quality of life through lung transplantation. Further research is essential to verify the accuracy of these findings, but this study represents a crucial step toward ensuring that individuals with lung diseases receive the appropriate care they require.

Changes in tidal breathing biomarkers as indicators of treatment response in AECOPD patients in an acute care setting.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a complication of COPD that typically necessitates intensified treatment and hospitalization. It is linked to higher morbidity, mortality and healthcare spending. Assessment of therapy response for AECOPD is difficult due to the variability of symptoms and limitations in current measures. Hence, there is a need for new biomarkers to aid in the management of AECOPD in acute care settings. MATERIALS AND METHODS: Fifteen hospitalized AECOPD patients (GOLD 3-4) were enrolled in this study. Treatment response was assessed daily through clinical evaluations and by monitoring tidal breathing biomarkers (respiratory rate [RR], expiratory time [Tex], inspiratory time [Tin], expiratory pause [Trst], total breath time [Ttot]), using a novel, wearable nanosensor-based device (SenseGuard™). RESULTS: Patients who showed significant clinical improvement had substantial changes in ΔTex/Ttot (+14%), ΔTrst/Ttot (-18%), and ΔTin/Tex (+0.09), whereas patients who showed mild or no clinical improvement had smaller changes (+5%, +3%, and -0.03, respectively). Linear regression between change in physician's assessment score and the median change in tidal breathing parameters was significant for Tin/Tex (R2 â€‹= â€‹0.449, ∗p â€‹= â€‹0.017), Tex/Ttot (R2 â€‹= â€‹0.556, ∗p â€‹= â€‹0.005) and Trst/Ttot (R2 â€‹= â€‹0.446, ∗p â€‹= â€‹0.018), while no significant regression was observed for RR, Tin/(Trst â€‹+ â€‹Tex) and Tin/Ttot. CONCLUSIONS: Our study demonstrates the potential of the SenseGuard™ to monitor treatment response in AECOPD patients by measuring changes in tidal breathing biomarkers, which were shown to be associated with significant changes in the patients' respiratory condition as evaluated by physicians. However, further large-scale clinical studies are needed to confirm these findings.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia in Patients Treated With Anti-CD20 Monoclonal Antibodies.

We report 8 cases of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in patients previously treated with anti-CD20 monoclonal antibodies. Polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 was negative in most cases; viral cell cultures confirmed that viable SARS-Co-2 virus was present. Four patients were treated with anti-SARS-CoV-2 hyperimmune globulins with rapid resolution of disease.

Timing of Lung Transplant Referral in Patients with Severe COVID-19 Lung Injury Supported by ECMO.

Severe respiratory failure caused by COVID-19 often requires mechanical ventilation, including extracorporeal membrane oxygenation (ECMO). In rare cases, lung transplantation (LTx) may be considered as a last resort. However, uncertainties remain about patient selection and optimal timing for referral and listing. This retrospective study analyzed patients with severe COVID-19 who were supported by veno-venous ECMO and listed for LTx between July 2020 and June 2022. Out of the 20 patients in the study population, four who underwent LTx were excluded. The clinical characteristics of the remaining 16 patients were compared, including nine who recovered and seven who died while awaiting LTx. The median duration from hospitalization to listing was 85.5 days, and the median duration on the waitlist was 25.5 days. Younger age was significantly associated with a higher likelihood of recovery without LTx after a median of 59 days on ECMO, compared to those who died at a median of 99 days. In patients with severe COVID-19-induced lung damage supported by ECMO, referral to LTx should be delayed for 8-10 weeks after ECMO initiation, particularly for younger patients who have a higher probability of spontaneous recovery and may not require LTx.

Abnormal liver tests in patients with SARS-CoV-2 or influenza - prognostic similarities and temporal disparities.

BACKGROUND & AIMS: Abnormal liver tests are common in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but a possible direct role of the virus in liver injury and its association with short-term outcomes are controversial. Therefore, we aimed to compare the pattern of abnormal liver tests in patients with SARS-CoV-2 with those of patients infected with influenza, a non-hepatotropic respiratory virus, and their association with worse outcomes during hospitalisation. METHODS: We performed a retrospective cohort study of 1,737 hospitalised patients (865 with influenza and 872 with SARS-CoV-2) in a tertiary medical centre. We defined abnormal liver tests as alanine transaminase or aspartate transaminase ≥40 IU/ml at any time-point during hospitalisation. RESULTS: Abnormal liver tests were mild to moderate in most patients regardless of infection type, but the majority of patients with influenza had a transaminase peak earlier during hospitalisation compared with patients with SARS-CoV-2. Abnormal liver tests correlated with markers of severe disease in either influenza or SARS-CoV-2 infections, and were associated with death, occurring mainly in patients with severe liver test abnormalities (>200 IU/L) (38.7% and 60% of patients with influenza or SARS-CoV-2, respectively). In multivariate analysis, controlling for age, sex, lymphopaenia, and C-reactive protein, liver test abnormalities remained significantly associated with death for influenza (odds ratio 4.344; 95% CI 2.218-8.508) and SARS-CoV-2 (odds ratio 3.898; 95% CI 2.203-6.896). These results were confirmed upon propensity score matching. CONCLUSIONS: Abnormal liver tests during hospitalisation with SARS-CoV-2 or influenza infections are common, may differ in their time course, and reflect disease severity. They are associated with worse outcomes, mainly in patients with severe liver test abnormalities, regardless of infection type. LAY SUMMARY: Coronavirus disease 2019 (COVID-19) is a serious global health pandemic, the causative agent of which is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Abnormal liver tests are common among SARS-CoV-2 infected patients and are often associated with worse outcomes. Herein, we compare the pattern of abnormal liver tests and their association with disease severity between 2 major non-hepatotropic respiratory viruses: SARS-CoV-2 and influenza. We show that abnormal liver tests are common in both infections, may slightly differ in their kinetics, and are associated with worse outcomes, especially in patients with severe liver test abnormalities. These results strongly suggest that abnormal liver tests in SARS-CoV-2 patients reflect disease severity, rather than a virus-mediated direct liver injury, and should be closely followed in admitted patients.

Secondary bacterial infection in COVID-19 patients is a stronger predictor for death compared to influenza patients.

Secondary bacterial infections are a potentially fatal complication of influenza infection. We aimed to define the impact of secondary bacterial infections on the clinical course and mortality in coronavirus disease 2019 (COVID-19) patients by comparison with influenza patients. COVID-19 (n = 642) and influenza (n = 742) patients, admitted to a large tertiary center in Israel and for whom blood or sputum culture had been taken were selected for this study. Bacterial culture results, clinical parameters, and death rates were compared. COVID-19 patients had higher rates of bacterial infections than influenza patients (12.6% vs. 8.7%). Notably, the time from admission to bacterial growth was longer in COVID-19 compared to influenza patients (4 (1-8) vs. 1 (1-3) days). Late infections (> 48 h after admission) with gram-positive bacteria were more common in COVID-19 patients (28% vs. 9.5%). Secondary infection was associated with a higher risk of death in both patient groups 2.7-fold (1.22-5.83) for COVID-19, and 3.09-fold (1.11-7.38) for Influenza). The association with death remained significant upon adjustment to age and clinical parameters in COVID-19 but not in influenza infection. Secondary bacterial infection is a notable complication associated with worse outcomes in COVID-19 than influenza patients. Careful surveillance and prompt antibiotic treatment may benefit selected patients.

Efficacy and Safety of Percutaneous Pulmonary Artery Subtotal Occlusion and Chronic Total Occlusion Intervention in Chronic Thromboembolic Pulmonary Hypertension.

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Comparison of Poly (ADP-ribose) Polymerase Inhibitors (PARPis) as Maintenance Therapy for Platinum-Sensitive Ovarian Cancer: Systematic Review and Network Meta-Analysis.

BACKGROUND: Three PARPis (olaparib, niraparib and rucaparib) are currently FDA-approved as maintenance therapy in newly diagnosed and recurrent ovarian cancer. However, thus far, no trial has compared the three approved PARPis in the overall population, in patients with BRCA mutations, or in those with wild-type BRCA. METHODS: A frequentist network meta-analysis was used for indirect comparisons between the different PARPis with respect to progression free survival (PFS), overall survival (OS), and adverse events. RESULTS: Overall, six randomized clinical trials involving 2,770 patients, were included in the analysis. Results from the indirect comparisons revealed no statistically significant differences between the three PARPis with respect to PFS or OS in the entire population and in patients with mutated and wild-type BRCA, separately. Niraparib showed a statistically significant increased risk for grade 3 and 4 thrombocytopenia (risk-difference [RD] from placebo: 0.3; 95% confidence interval [CI], 0.27‒0.34) and any grade neutropenia (RD from placebo: 0.22; 95% CI, 0.18‒0.25) as compared with the other PARPis. CONCLUSION: No statistically significant difference was found between the three PARPis with respect to PFS or OS (overall and in subpopulations by BRCA status). There is, however, a statistical difference in toxicity as niraparib is associated with a greater risk for thrombocytopenia and neutropenia.

Diabetic striatopathy-Does it exist in non-Asian subjects?

BACKGROUND: Diabetic striatopathy (DS) is a rare complication of diabetes mellitus (DM). The syndrome appears in patients with uncontrolled DM and is characterized by abrupt onset of movement disorder, mainly hemichorea and accompanied by specific findings on brain imaging. It is believed that DS is unique to the Asian population and affects mainly elderly women with uncontrolled DM. METHODS: In order to define existence and characterization of DS in Western population, we reviewed the medical records of all patients admitted to the Chaim Sheba Medical Center between 2004 and 2014 and identified those with documented elevated HbA1c (>10%). The charts and imaging studies of those with elevated HbA1c and undiagnosed neurological symptoms were reviewed to diagnose DS. RESULTS: Out of 697 patients with HbA1c>10%, 328 patients had unknown neurological diagnosis. Among them, we identified 4 patients (3 women, mean age 73 and mean HbA1c of 14.8%) with hemichorea or choreoathetosis and brain imaging findings compatible with the diagnosis of DS. Only one out of the 4 patients was diagnosed during hospitalization with DS. All patients were treated with insulin with improvement of their symptoms during hospitalization. However, there was a recurrence in 2 of them and 1 died during the second episode. CONCLUSION: Diabetic striatopathy exists but underdiagnosed in the Western population. It is important to increase the awareness for this clinical syndrome in order to treat those patients properly.