Determinants of intended prevention behaviour against mosquitoes and mosquito-borne viruses in the Netherlands and Spain using the MosquitoWise survey: cross-sectional study.

BACKGROUND: Recently, Europe has seen an emergence of mosquito-borne viruses (MBVs). Understanding citizens' perceptions of and behaviours towards mosquitoes and MBVs is crucial to reduce disease risk. We investigated and compared perceptions, knowledge, and determinants of citizens' behavioural intentions related to mosquitoes and MBVs in the Netherlands and Spain, to help improve public health interventions. METHODS: Using the validated MosquitoWise survey, data was collected through participant panels in Spain (N = 475) and the Netherlands (N = 438). Health Belief Model scores measuring behavioural intent, knowledge, and information scores were calculated. Confidence Interval-Based Estimation of Relevance was used, together with potential for change indexes, to identify promising determinants for improving prevention measure use. RESULTS: Spanish participants' responses showed slightly higher intent to use prevention measures compared to those of Dutch participants (29.1 and 28.2, respectively, p 0.03). Most participants in Spain (92.2%) and the Netherlands (91.8%) indicated they used at least one prevention measure, but differences were observed in which types they used. More Spanish participants indicated to have received information on mosquitoes and MBVs compared to Dutch participants. Spanish participants preferred health professional information sources, while Dutch participants favoured government websites. Determinants for intent to use prevention measures included "Knowledge", "Reminders to Use Prevention Measures", and "Information" in the Netherlands and Spain. Determinants for repellent use included "Perceived Benefits" and "Cues to Action", with "Perceived Benefits" having a high potential for behavioural change in both countries. "Self-Efficacy" and "Knowledge" were determinants in both countries for breeding site removal. CONCLUSION: This study found differences in knowledge between the Netherlands and Spain but similarities in determinants for intent to use prevention measures, intent to use repellents and intent to remove mosquito breeding sites. Identified determinants can be the focus for future public health interventions to reduce MBV risks.

A Systematic Review of the Pulmonary Microbiome in Patients with Acute Exacerbation COPD Requiring ICU Admission.

Background: Chronic obstructive pulmonary disease (COPD) is a major health concern. Acute exacerbations (AECOPD) may require intensive care unit (ICU) admission and mechanical ventilation. Acute infections and chronic colonization of the respiratory system are known to precipitate AECOPD. Detailed knowledge of the respiratory microbiome could lead to effective treatment and prevention of exacerbations. Objective: The aim of this review is to summarize the available evidence on the respiratory microbiome of patients with a severe AECOPD requiring mechanical ventilation and intensive care admission. Methods: A systematic literature search was conducted to identify the published papers until January 2023. The collected data were then subjected to qualitative analysis. After the first analysis, a secondary focused review of the most recent publications studying the relationship between microbiome and mortality in AECOPD was performed. Results: Out of 120 screened articles six articles were included in this review. Potentially pathogenic microorganisms (PPMs) were identified in 30% to 72% of the patients with community-acquired bacteria, gram-negative enteric bacilli, Stenotrophomonas and Pseudomonas being the most frequently isolated. During hospitalization, 21% of patients experienced colonization by PPMs. Adequate antimicrobial therapy resulted in the eradication of 77% of the identified PPMs. However, 24% of the bacteria displayed multi-drug resistance leading to prolonged or failure of eradication. Conclusion: PPMs are prevalent in a significant proportion of patients experiencing an AECOPD. The most identified PPMs include community-acquired pathogens and gram-negative enteric bacilli. Notably, no differences in mortality or duration of ventilation were observed between patients with and without isolated PPMs. However, the included studies did not investigate the virome of the patients, which may influence the microbiome and the outcome of infection. Therefore, further research is essential to comprehensively investigate the complete microbial and viral composition of the lower respiratory system in COPD patients admitted to the ICU.

Development and validation of the MosquitoWise survey to assess perceptions towards mosquitoes and mosquito-borne viruses in Europe.

Due to climate change and the expanding geographical ranges of key mosquito species, several mosquito-borne viruses (MBVs) have recently emerged in Europe. Understanding people's perceptions and behaviours towards these viruses and the mosquitoes capable of transmitting them is crucial for implementing effective prevention measures and targeted communication campaigns. However, there is currently no appropriate validated survey for European populations to assess this. This study developed and validated a standardized survey, based on the Health Belief Model (HBM), to assess perceptions of mosquitoes and MBVs among Europe's residents. The survey was distributed online to United Kingdom (UK), Dutch and Spanish participants through panel providers. Survey validity and reliability were tested using confirmatory factor analysis (CFA) and Cronbach's alpha. The optimised survey was completed by 336 UK, 438 Dutch and 475 Spanish residents, respectively, and the HBM items passed our validity and reliability testing in all three countries. The final survey has 57 questions, including 19 validated HBM items, and questions to assess demographic characteristics, knowledge, prevention measures and behavioural determinants. Our MosquitoWise survey bridges researchers' understandings of European residents' perceptions and knowledge as a first step to improve preventive behaviour towards mosquitoes and MBVs and guide prevention and communication initiatives.

Transient Autoreactive PF4 and Antiphospholipid Antibodies in COVID-19 Vaccine Recipients.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare autoimmune condition associated with recombinant adenovirus (rAV)-based COVID-19 vaccines. It is thought to arise from autoantibodies targeting platelet factor 4 (aPF4), triggered by vaccine-induced inflammation and the formation of neo-antigenic complexes between PF4 and the rAV vector. To investigate the specific induction of aPF4 by rAV-based vaccines, we examined sera from rAV vaccine recipients (AZD1222, AD26.COV2.S) and messenger RNA (mRNA) based (mRNA-1273, BNT162b2) COVID-19 vaccine recipients. We compared the antibody fold change (FC) for aPF4 and for antiphospholipid antibodies (aPL) of rAV to mRNA vaccine recipients. We combined two biobanks of Dutch healthcare workers and matched rAV-vaccinated individuals to mRNA-vaccinated controls, based on age, sex and prior history of COVID-19 (AZD1222: 37, Ad26.COV2.S: 35, mRNA-1273: 47, BNT162b2: 26). We found no significant differences in aPF4 FCs after the first (0.99 vs. 1.08, mean difference (MD) = -0.11 (95% CI -0.23 to 0.057)) and second doses of AZD1222 (0.99 vs. 1.10, MD = -0.11 (95% CI -0.31 to 0.10)) and after a single dose of Ad26.COV2.S compared to mRNA-based vaccines (1.01 vs. 0.99, MD = 0.026 (95% CI -0.13 to 0.18)). The mean FCs for the aPL in rAV-based vaccine recipients were similar to those in mRNA-based vaccines. No correlation was observed between post-vaccination aPF4 levels and vaccine type (mean aPF difference -0.070 (95% CI -0.14 to 0.002) mRNA vs. rAV). In summary, our study indicates that rAV and mRNA-based COVID-19 vaccines do not substantially elevate aPF4 levels in healthy individuals.

A Transcriptomic Severity Classifier IMX-SEV-3b to Predict Mortality in Intensive Care Unit Patients with COVID-19: A Prospective Observational Pilot Study.

The prediction of disease outcomes in COVID-19 patients in the ICU is of critical importance, and the examination of host gene expressions is a promising tool. The 29-host mRNA Inflam-matix-Severity-3b (IMX-SEV-3b) classifier has been reported to predict mortality in emergency department COVID-19 patients and surgical ICU patients. The accuracy of the IMX-SEV-3b in predicting mortality in COVID-19 patients admitted to the ICU is yet unknown. Our aim was to investigate the accuracy of the IMX-SEV-3b in predicting the ICU mortality of COVID-19 patients. In addition, we assessed the predictive performance of routinely measured biomarkers and the Sequential Organ Failure Assessment (SOFA) score as well. This was a prospective observational study enrolling COVID-19 patients who received mechanical ventilation on the ICU of the Erasmus MC, the Netherlands. The IMX-SEV-3b scores were generated by amplifying 29 host response genes from blood collected in PAXgene® Blood RNA tubes. A severity score was provided, ranging from 0 to 1 for increasing disease severity. The primary outcome was the accuracy of the IMX-SEV-3b in predicting ICU mortality, and we calculated the AUROC of the IMX-SEV-3b score, the biomarkers C-reactive protein (CRP), D-dimer, ferritin, leukocyte count, interleukin-6 (IL-6), lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), procalcitonin (PCT) and the SOFA score. A total of 53 patients were included between 1 March and 30 April 2020, with 47 of them being included within 72 h of their admission to the ICU. Of these, 18 (34%) patients died during their ICU stay, and the IMX-SEV-3b scores were significantly higher in non-survivors compared to survivors (0.65 versus 0.57, p = 0.05). The Area Under the Receiver Operating Characteristic Curve (AUROC) for prediction of ICU mortality by the IMX-SEV-3b was 0.65 (0.48-0.82). The AUROCs of the biomarkers ranged from 0.52 to 0.66, and the SOFA score had an AUROC of 0.81 (0.69-0.93). The AUROC of the pooled biomarkers CRP, D-dimer, ferritin, leukocyte count, IL-6, LDH, NLR and PCT for prediction of ICU mortality was 0.81 (IQR 0.69-0.93). Further validation in a larger interventional trial of a point-of-care version of the IMX-SEV-3b classifier is warranted to determine its value for patient management.

Changes in incidence of hospitalization for cardiovascular diseases during the COVID-19 pandemic in The Netherlands in 2020.

This population-based cohort study aimed to describe changes in incidence of cardiovascular disease (CVD) hospital diagnoses during the COVID-19 pandemic in The Netherlands compared with the pre-pandemic period. We used Dutch nationwide statistics about hospitalizations to estimate incidence rate ratios (IRR) of hospital diagnoses of CVD during the first and second COVID-19 waves in The Netherlands in 2020 versus the same periods in 2019. Compared with 2019, the incidence rate of a hospital diagnosis of ischemic stroke (IRR 0.87; 95% CI 0.79-0.95), major bleeding (IRR 0.74; 95% CI 0.68-0.82), atrial fibrillation (IRR 0.73; 95% CI 0.65-0.82), myocardial infarction (IRR 0.78; 95% CI 0.72-0.84), and heart failure (IRR 0.74; 95% CI 0.65-0.85) declined during the first wave, but returned to pre-pandemic levels throughout 2020. However, the incidence rate of a hospital diagnosis of pulmonary embolism (PE) increased during both the first and second wave in 2020 compared with 2019 (IRR 1.30; 95% CI 1.15-1.48 and IRR 1.31; 95% CI 1.19-1.44, respectively). In conclusion, we observed substantial declines in incidences of CVD during the COVID-19 pandemic in The Netherlands in 2020, especially during the first wave, with an exception for an increase in incidence of PE. This study contributes to quantifying the collateral damage of the COVID-19 pandemic.

Levels of Fibrinogen Variants Are Altered in Severe COVID-19.

Background Fibrinogen variants as a result of alternative messenger RNA splicing or protein degradation can affect fibrin(ogen) functions. The levels of these variants might be altered during coronavirus disease 2019 (COVID-19), potentially affecting disease severity or the thrombosis risk. Aim To investigate the levels of fibrinogen variants in plasma of patients with COVID-19. Methods In this case-control study, we measured levels of functional fibrinogen using the Clauss assay. Enzyme-linked immunosorbent assays were used to measure antigen levels of total, intact (nondegraded Aα chain), extended Aα chain (α E ), and γ' fibrinogen in healthy controls, patients with pneumococcal infection in the intensive care unit (ICU), ward patients with COVID-19, and ICU patients with COVID-19 (with and without thrombosis, two time points). Results Healthy controls and ward patients with COVID-19 ( n = 10) showed similar fibrinogen (variant) levels. ICU patients with COVID-19 who later did ( n = 19) or did not develop thrombosis ( n = 18) and ICU patients with pneumococcal infection ( n = 6) had higher absolute levels of functional, total, intact, and α E fibrinogen than healthy controls ( n = 7). The relative α E fibrinogen levels were higher in ICU patients with COVID-19 than in healthy controls, while relative γ' fibrinogen levels were lower. After diagnosis of thrombosis, only the functional fibrinogen levels were higher in ICU patients with COVID-19 and thrombosis than in those without, while no differences were observed in the other fibrinogen variants. Conclusion Our results show that severe COVID-19 is associated with increased levels of α E fibrinogen and decreased relative levels of γ' fibrinogen, which may be a cause or consequence of severe disease, but this is not associated with the development of thrombosis.

Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis.

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

Soluble urokinase plasminogen activator receptor and procalcitonin for risk stratification in patients with a suspected infection in the emergency department: a prospective cohort study.

BACKGROUND AND IMPORTANCE: Early identification of patients at risk of clinical deterioration may improve prognosis of infected patients in the emergency department (ED). Combining clinical scoring systems with biomarkers may result in a more accurate prediction of mortality than a clinical scoring system or biomarker alone. OBJECTIVE: The objective of this study is to investigate the performance of the combination of National Early Warning Score-2 (NEWS2) and quick Sequential Organ Failure Assessment (qSOFA) score with soluble urokinase plasminogen activator receptor (suPAR) and procalcitonin to predict 30-day mortality in patients with a suspected infection in the ED. DESIGN, SETTINGS AND PARTICIPANTS: This was a single-center prospective observational study, conducted in the Netherlands. Patients with suspected infection in the ED were included in this study and followed-up for 30 days. The primary outcome of this study was all cause 30-day mortality. The association between suPAR and procalcitonin with mortality was assessed in subgroups of patients with low and high qSOFA (<1 and ≥1) and low and high NEWS2 (<7 and ≥7). MAIN RESULTS: Between March 2019 and December 2020, 958 patients were included. A total of 43 (4.5%) patients died within 30 days after ED visit. A suPAR ≥ 6 ng/ml was associated with an increased mortality risk: 5.5 vs. 0.9% ( P  < 0.01) in patients with qSOFA = 0 and 10.7 vs. 2.1% ( P  = 0.02) in patients with qSOFA ≥ 1. There was also an association between procalcitonin ≥0.25 ng/ml and mortality: 5.5 vs. 1.9% ( P  = 0.02) for qSOFA = 0 and 11.9 vs. 4.1% ( P  = 0.03) for qSOFA ≥ 1. Similar associations were found within patients with a NEWS < 7 (5.9 vs. 1.2% for suPAR and 7.0 vs. 1.7% for procalcitonin, P  < 0.001). CONCLUSION: In this prospective cohort study, suPAR and procalcitonin were associated with increased mortality in patients with either a low or high qSOFA and patients with low NEWS2.

Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia in middle-income countries.

BACKGROUND: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs. AIMS: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. METHODS: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs). RESULTS: Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20-37) versus 47 (IQR 32-58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11-40]) than in HICs (44/102 [43%, 95% CI 34-53], p = 0.039). CONCLUSIONS: The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.

Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT).

BACKGROUND: In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19. OBJECTIVE: Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19. METHODS: This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand. RESULTS: As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024. CONCLUSIONS: This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48183.

COVID-19 Screening Score for Patients without Acute Respiratory Symptoms Undergoing Emergency Medical Procedures in Indonesia.

To rule out coronavirus disease-2019 (COVID-19) in patients scheduled to undergo emergency medical procedures, SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) must be performed. In developing countries, the use of SARS-CoV-2 RT-PCR has been limited by its unavailability and long processing time. Hence, a quick screening score to predict COVID-19 may help healthcare practitioners determine which patients without acute respiratory symptoms can safely undergo an emergency medical procedure. We conducted a cross-sectional study of adult patients without acute respiratory symptoms who were admitted to the emergency department and underwent an emergency medical procedure within 24 hours after admittance. We collected baseline demographic data, COVID-19 screening variables, and SARS-CoV-2 RT-PCR as the gold standard for COVID-19 diagnosis. Bivariate and multivariate analyses were performed, and a scoring system was developed using statistically significant variables from the multivariate analysis. With data from 357 patients, multivariate backward stepwise logistic regression analysis resulted in two significant COVID-19 predictors: the presence of SARS-CoV-2-IgM antibody (adjusted odds ratio [aOR]: 7.02 [95% CI: 1.49-32.96]) and typical chest x-ray (aOR: 23.21 [95% CI: 10.01-53.78]). A scoring system was developed using these predictors with an area under the receiver operating characteristic curve of 0.71 (95% CI: 0.64-0.78). For a cutoff point of ≥ 2, the scoring system showed 42.5% sensitivity and 97.1% specificity but had poor calibration (Hosmer-Lemeshow test P value < 0.001). We believe that the development of this COVID-19 quick screening score may be helpful in a resource-limited clinical setting, but its moderate discrimination and poor calibration hinder its use as a replacement for the SARS-CoV-2 RT-PCR test for COVID-19 screening.

Association of viral kinetics, infection history, NS1 protein with plasma leakage among Indonesian dengue infected patients.

OBJECTIVES: Plasma leakage, a hallmark of disease in Dengue virus (DENV) infection, is an important clinical manifestation and is often associated with numerous factors such as viral factors. The aim of this study is to investigate the association of virus serotype, viral load kinetics, history of infection, and NS1 protein with plasma leakage. METHODS: Subjects with fever ≤ 48 hours and positive DENV infection were included. Serial laboratory tests, viral load measurements, and ultrasonography examination to assess plasma leakage were performed. RESULTS: DENV-3 was the most common serotype found in the plasma leakage group (35%). Patients with plasma leakage demonstrated a trend of higher viral load and a longer duration of viremia compared to those without. This was significantly observed on the fourth day of fever (p = 0.037). We found higher viral loads on specific days in patients with plasma leakage in both primary and secondary infections compared to those without. In addition, we also observed more rapid viral clearance in patients with secondary infection. NS1 protein, especially after 4 days of fever, was associated with higher peak viral load level, even though it was not statistically significant (p = 0.470). However, pairwise comparison demonstrated that peak viral load level in the group of patients with circulating NS1 detected for 7 days was significantly higher than the 5-day group (p = 0.037). CONCLUSION: DENV-3 was the most common serotype to cause plasma leakage. Patients with plasma leakage showed a trend of higher viral load and a longer duration of viremia. Higher level of viral load was observed significantly on day 5 in patients with primary infection and more rapid viral clearance was observed in patients with secondary infection. Longer duration of circulating NS1 protein was also seen to be positively correlated with higher peak viral load level although not statistically significant.

Monkeypox Virus Cross-Neutralizing Antibodies in Clinical Trial Participants Vaccinated With Modified Vaccinia Virus Ankara Encoding Middle East Respiratory Syndrome-Coronavirus Spike Protein.

Modified vaccinia virus Ankara (MVA) is used as a vaccine against monkeypox virus and as a viral vaccine vector. MVA-MERS-S is a vaccine candidate against Middle East respiratory syndrome (MERS)-associated coronavirus. Here, we report that cross-reactive monkeypox virus neutralizing antibodies were detectable in only a single study participant after the first dose of MVA-MERS-S vaccine, in 3 of 10 after the second dose, and in 10 of 10 after the third dose.

Dutch Healthcare Professionals' Opinion on the Allocation of Responsibilities concerning Prescribing and Administering Medically Indicated Vaccines to Immunocompromised Patients.

BACKGROUND: Specific vaccines are indicated for immunocompromised patients (ICPs) due to their vulnerability to infections. Recommendation of these vaccines by healthcare professionals (HCPs) is a crucial facilitator for vaccine uptake. Unfortunately, the responsibilities to recommend and administer these vaccines are not clearly allocated among HCPs involved in the care of adult ICPs. We aimed to evaluate HCPs' opinions on directorship and their role in facilitating the uptake of medically indicated vaccines as a basis to improve vaccination practices. METHODS: A cross-sectional survey was performed among in-hospital medical specialists (MSs), general practitioners (GPs), and public health specialists (PHSs) in the Netherlands to assess their opinion on directorship and the implementation of vaccination care. Additionally, perceived barriers, facilitators, and possible solutions to improve vaccine uptake were investigated. RESULTS: In total, 306 HCPs completed the survey. HCPs almost unanimously (98%) reported that according to them, the primary treating physician is responsible for recommending medically indicated vaccines. Administering these vaccines was seen as a more shared responsibility. The most important barriers experienced by HCPs in recommending and administering were reimbursement problems, a lack of a national vaccination registration system, insufficient collaboration among HCPs, and logistical problems. MSs, GPs and PHSs all mentioned the same three solutions as important strategies to improve vaccination practices, i.e., reimbursement of vaccines, reliable and easily accessible registration of received vaccines, and arrangements for collaboration among the different HCPs that are involved in care. CONCLUSION: The improvement in vaccination practices in ICPs should focus on better collaboration among MSs, GPs, and PHSs, who should know each other's expertise; clear agreement on responsibility; reimbursement for vaccines; and the availability of clear registration of vaccination history.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis.

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.

The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy.

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

Subcutaneous Stimulation as Add-on Therapy to Spinal Cord Stimulation in Patients With Persistent Spinal Pain Syndrome Significantly Increases the Total Electrical Charge per Second: Aspects on Stimulation Parameters and Energy Requirements of the Implanted Neurostimulators.

OBJECTIVE: In our previous multicenter randomized controlled trial, we demonstrated the clinical effectiveness of peripheral nerve field stimulation (PNFS) as add-on therapy to spinal cord stimulation (SCS) for the treatment of chronic back pain in patients with persistent spinal pain syndrome (PSPS) or failed back surgery syndrome (FBSS). To our knowledge, no previous study has investigated the effect of PNFS as an add-on to SCS on the energy consumption of the implanted neurostimulators. Therefore, in this study, we compared the specific stimulation parameters and energy requirements of a previously unreported group of patients with only SCS with those of a group of patients with SCS and add-on PNFS. We also investigated differences that might explain the need for PNFS in the treatment of chronic low back pain. MATERIALS AND METHODS: We analyzed 75 patients with complete sets of stimulation parameters, with 21 patients in the SCS-only group and 54 patients in the SCS + PNFS group. Outcome measures were average visual analog scale score, SCS parameters (voltage, frequency, and pulse width), SCS charge per second, and total charge per second. We analyzed baseline characteristics and differences between and within groups over time. RESULTS: Both groups had comparable patient characteristics at baseline and showed a significant decrease in back and leg pain. SCS charge per second did not significantly differ between the groups at baseline or at 12 months. The total charge per second was significantly higher in the active SCS + PNFS group than in the SCS-only group at baseline; in the SCS + PNFS group, this persisted for up to 12 months, and the SCS charge per second and total charge per second increased significantly over time. CONCLUSIONS: Our results show that add-on PNFS increases the total charge per second compared with SCS alone, as expected. However, further research is needed because our results do not directly explain why some patients require add-on PNFS to treat low back pain.

Spinal Cord Stimulation With Additional Peripheral Nerve/Field Stimulation Versus Spinal Cord Stimulation Alone on Back Pain and Quality of Life in Patients With Persistent Spinal Pain Syndrome.

INTRODUCTION: Persistent spinal pain syndrome (PSPS) or failed back surgery syndrome (FBSS) refers to new or persistent pain following spinal surgery for back or leg pain in a subset of patients. Spinal cord stimulation (SCS) is a neuromodulation technique that can be considered in patients with predominant leg pain refractory to conservative treatment. Patients with predominant low back pain benefit less from SCS. Another neuromodulation technique for treatment of chronic low back pain is subcutaneous stimulation or peripheral nerve field stimulation (PNFS). We investigated the effect of SCS with additional PNFS on pain and quality of life of patients with PSPS compared with that of SCS alone after 12 months. MATERIALS AND METHODS: This is a comparative study of patients with PSPS who responded to treatment with either SCS + PNFS or SCS only following a multicenter randomized clinical trial protocol. In total, 75 patients completed the 12-month follow-up: 21 in the SCS-only group and 54 in the SCS + PNFS group. Outcome measures were pain (visual analog scale), quality of life (36-Item Short Form Survey [SF-36]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), overall health (EuroQol Five-Dimension [EQ-5D]), disability (Oswestry Disability Index [ODI]), and pain assessed by the McGill questionnaire. RESULTS: There were no significant differences in baseline characteristics between the two groups. Both groups showed a significant reduction in back and leg pain at 12 months compared with baseline measurements. No significant differences were found between the groups in effect on both primary (pain) and secondary parameters (SF-36, HADS, EQ-5D, ODI, and McGill pain). CONCLUSION: In a subgroup of patients with chronic back and leg pain, SCS alone provided similar long-term pain relief and quality-of-life improvement as PNFS in addition to SCS. In patients with refractory low back pain not responding to SCS alone, adding PNFS should be recommended. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT01776749.

Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals.

In July 2022, the ongoing monkeypox (MPX) outbreak was declared a public health emergency of international concern. Modified vaccinia Ankara-Bavarian Nordic (MVA-BN, also known as Imvamune, JYNNEOS or Imvanex) is a third-generation smallpox vaccine that is authorized and in use as a vaccine against MPX. To date, there are no data showing MPX virus (MPXV)-neutralizing antibodies in vaccinated individuals nor vaccine efficacy against MPX. Here we show that MPXV-neutralizing antibodies can be detected after MPXV infection and after historic smallpox vaccination. However, a two-shot MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV-neutralizing antibodies. Dose-sparing of an MVA-based influenza vaccine leads to lower MPXV-neutralizing antibody levels, whereas a third vaccination with the same MVA-based vaccine significantly boosts the antibody response. As the role of MPXV-neutralizing antibodies as a correlate of protection against disease and transmissibility is currently unclear, we conclude that cohort studies following vaccinated individuals are necessary to assess vaccine efficacy in at-risk populations.