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Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

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Ouderen worden vaak geconfronteerd met slikproblemen. Het is hierbij van belang een onderscheid te maken tussen enerzijds presbyfagie, dit is de invloed van het primair verouderingsproces op de slikfunctie en anderzijds dysfagie, zijnde een pathologische slikstoornis die wordt veroorzaakt door ouderdomsgerelateerde ziekteprocessen en hun behandeling. In dit literatuuroverzicht ligt de focus op presbyfagie. Hierbij wordt de impact van het natuurlijk verouderingsproces op de orofaryngeale slikfunctie en op andere lichaamsfuncties die indirect gerelateerd zijn aan het slikken besproken. Uit de literatuur blijkt dat bij het primair verouderen een aantal functies bewaard blijven, een aantal functies deterioreren, een aantal compensatoire mechanismen in werking treden, maar dat de slikveiligheid als dusdanig behouden blijft. De tekst sluit af met implicaties voor de klinisch praktijk, met name een aantal adviezen rond de detectie van slikstoornissen bij ouderen en een aantal preventieve maatregelen voor gezonde ouderen.

Background: We aimed to determine the timeliness of rabies post-exposure prophylaxis (PEP) and the proportion of individuals with an adequate antibody response post-PEP among those attending the Belgian national reference center., Methods: Retrospective analysis of patient records who attended our center from 2018 to 2023. Delay was defined as rabies immunoglobulin (RIG) and vaccine initiation beyond 2 calendar days after exposure. Antibodies were measured by rapid fluorescent focus inhibition test (RFFIT) after PEP in high-risk exposures. A titer ≥0.5 IU/ml was considered adequate., Results: We reviewed 317 patient records. Among individuals with inland exposure (n = 103), 85 % timely received PEP. Among travelers exposed abroad (n = 214), administration of RIG and vaccine initiation were timely in 30 % and 50 % of cases, respectively. An adequate antibody response was detected in 99.5 % (195/196) individuals., Conclusion: Substantial PEP delays among travelers were observed. The robust antibody responses suggest that routine serological follow-up is not necessary for all patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recent reports raise concerns on the changing epidemiology of mpox in the Democratic Republic of the Congo (DRC). High-quality genomes were generated for 337 patients from 14/26 provinces to document whether the increase in number of cases is due to zoonotic spillover events or viral evolution, with enrichment of APOBEC3 mutations linked to human adaptation. Our study highlights two patterns of transmission contributing to the source of human cases. All new sequences from the eastern South Kivu province (n = 17; 4.8%) corresponded to the recently described clade Ib, associated with sexual contact and sustained human-to-human transmission. By contrast, all other genomes are clade Ia, which exhibits high genetic diversity with low numbers of APOBEC3 mutations compared with clade Ib, suggesting multiple zoonotic introductions. The presence of multiple clade I variants in urban areas highlights the need for coordinated international response efforts and more studies on the transmission and the reservoir of mpox., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We analysed mpox cases in Burundi from July to September 2024, following the introduction of Clade Ib virus. Of 607 samples from the whole population of suspected cases, 154 were PCR-positive, of whom 85 were children under 15 years, with a higher proportion of female children testing positive. Geographical analysis demonstrates case concentration in Bujumbura Mairie (91/154). Age- and sex-specific interventions, as well as community engagement, are important for outbreak containment, as are targeted public health strategies in Burundi.

We linked 4 mpox cases in South Ubangi, Democratic Republic of the Congo, to transboundary transmission from Central African Republic. Viral genome sequencing demonstrated that the monkeypox virus sequences belonged to distinct clusters of subclade Ia. This finding demonstrates the borderless nature of mpox and highlights the need for vigilant regional surveillance.

Competing Interests: We declare no competing interests.

Outbreaks of monkeypox (mpox) have historically resulted from zoonotic spillover of clade I monkeypox virus (MPXV) in Central Africa and clade II MPXV in West Africa. In 2022, subclade IIb caused a global epidemic linked to transmission through sexual contact. Here we describe the epidemiological and genomic features of an mpox outbreak in a mining region in eastern Democratic Republic of the Congo, caused by clade I MPXV. Surveillance data collected between September 2023 and January 2024 identified 241 suspected cases. Genomic analysis demonstrates a distinct clade I lineage divergent from previously circulating strains in the Democratic Republic of the Congo. Of the 108 polymerase chain reaction-confirmed mpox cases, the median age of individuals was 22 years, 51.9% were female and 29% were sex workers, suggesting a potential role for sexual transmission. The predominance of APOBEC3-type mutations and the estimated emergence time around mid-September 2023 imply recent sustained human-to-human transmission., (© 2024. The Author(s).)

The ongoing national mpox outbreak in the Democratic Republic of the Congo has resulted in more >30,000 suspected cases in the country from January 2023 to August 2024. While these historic case totals have been driven by primarily by zoonosis, the emergence of Clade Ib monkeypox virus (MPXV), which is connected to more sustained human-to-human transmission, has been associated with increasing public health impacts in eastern DRC. First identified in South Kivu province, Clade Ib MPXV has been identified in multiple non-endemic East African countries for the first time. In DRC, there have been concerns over broader Clade Ib expansion in the country that could further complicate containment and mitigation responses. Here, we report the first introductions of Clade Ib into North Kivu province, including within internal displacement camps, with suspected close contact transmission that includes non-intimate contacts and children. These findings demonstrate that mpox case investigations and community messaging campaigns should include considerations for non-sexual contact-mediated transmission of Clade Ib that includes children <15 years., Competing Interests: COMPETING INTERESTS None of the other authors declare competing interests.

Between January and August 2024, mpox cases have been reported in nearly all provinces of the Democratic Republic of the Congo (DRC). Monkeypox virus genome sequences were obtained from 11 mpox cases' samples, collected in July-August 2024 in several health zones of Kinshasa. Characterisation of the sequences showed subclades Ia and Ib co-circulating in the Limete health zone, while phylogenetic analyses suggested multiple introductions of the two subclades in Kinshasa. This illustrates the growing complexity of Clade I mpox outbreaks in DRC.

Objectives: The 2022 mpox epidemic reached a peak in Belgium and the rest of Europe in July 2022, after which it unexpectedly subsided. This study investigates epidemiological, behavioral, and immunological factors behind the waning of the epidemic in Belgium., Methods: We investigated temporal evolutions in the characteristics and behavior of mpox patients using national surveillance data and data from a prospective registry of mpox patients in the Institute of Tropical Medicine (Antwerp). We studied behavioral changes in the population at risk using a survey among HIV-preexposure prophylaxis (PrEP) users. We determined the seroprevalence of anti-orthopoxvirus antibodies among HIV-PrEP users across four-time points in 2022., Results: Mpox patients diagnosed at the end of the epidemic had less sexual risk behavior compared to those diagnosed earlier: they engaged less in sex at mass events, had fewer sexual partners, and were less likely to belong to the sexual network's central group. Among HIV-PrEP users there were no notable changes in sexual behavior. Anti-orthopoxvirus seroprevalence did not notably increase before the start of national vaccination campaigns., Conclusion: The observed changes in group immunity and behavior in the population at greater risk of exposure to mpox seem unable to explain the waning of the mpox epidemic. A change in the profile of mpox patients might have contributed to the decline in cases., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: JBN is supported by the US National Institutes of Health (grant numbers NIH/FIC 1R25TW011217-01, NIH/FIC 1D43TW010937-01A1, NIH/FIC D43TW011827-01A1, NIH/FIC 1R21TW011706-0, and NIH/NIAID 5U01AI096299-13). FN and AZ are codirectors of the Pan-African Network on Emerging and Re-Emerging Infections funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) within the EU Horizon 2020 Framework Programme. FN and AZ also acknowledge support from the EDCTP Central Africa Clinical Research Network. AZ is a UK National Institute for Health Research senior investigator, and a Mahathir Science Award and EU-EDCTP Pascoal Mocumbi Prize laureate. JJM-T holds National Institutes of Health National Institute of Allergy and Infectious Diseases grants (number 75N91019D00024-P00001-759102000025-5). JK is supported by grant funding from the Canadian Institutes of Health Research and International Development Research Centre (grant numbers MRR-184813 and PPE-185821). ELM is supported by the US National Institutes of Health (grant number 1R01AI182082-01). All other authors declare no competing interests. We thank John L Johnson for critical review and helpful advice. The views and conclusions in this Personal View are those of the authors and do not necessarily represent the views of their institutions.

Competing Interests: The authors have declared that no competing interests exist.

This case-control study aimed to investigate the association between short-term (1 to 5 days) and medium-term (31 days) exposure to air pollutants (PM 2.5 , PM 10 , BC, NO 2 ) at home/daycare and the risk of 'severe bronchiolitis' (defined as 'requiring hospitalization for bronchiolitis') in children under 2 years in Antwerp, Belgium. We included 118 cases and 79 controls admitted to three general hospitals from October 2020 to June 2021. Exposure levels were predicted using an interpolation model based on fixed measuring stations. We used unconditional logistic regression analysis to assess associations, with adjustment for potential confounders. There were hardly any significant differences in the day-to-day air pollution values between cases and controls. Medium-term (31 days) exposure to PM 2.5 , PM 10 , and NO 2 was however significantly higher in cases than controls in univariate analysis. Logistic regression revealed an association between severe bronchiolitis and interquartile range (IQR) increases of PM 2.5 and PM 10 at home and in daycare, as well as IQR increases of NO 2 in daycare. Controls were however overrepresented in low pollution periods. Time-adjustment reduced the odds ratios significantly at home for PM 2.5 and PM 10 (aOR 1.54, 95%CI 0.51-4.65; and 2.69, 95%CI 0.94-7.69 respectively), and in daycare for. PM 2.5 (aOR 2.43, 95%CI 0.58-10.1). However, the association between severe bronchiolitis and medium-term air pollution was retained in daycare for IQR increases of PM 10 (aOR 5.13, 95%CI 1.24-21.28) and NO 2 (aOR 3.88, 95%CI 1.56-9.61) in the time-adjusted model .   Conclusion: This study suggests a possible link between severe bronchiolitis and medium-term (31 days) air pollution exposure (PM 10 and NO 2 ), particularly in daycare. Larger studies are warranted to confirm these findings. What is Known: • Bronchiolitis is a leading cause of hospitalization in infants globally and causes a yearly seasonal wave of admissions in paediatric departments worldwide. • Existing studies, mainly from the USA, show heterogeneous outcomes regarding the association between air pollution and bronchiolitis. What is New: • There is a possible link between severe bronchiolitis and medium-term (31 days) air pollution exposure (PM10 and NO2), particularly in daycare. • Larger studies are needed to validate these trends., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In September 2022, deaths of pigs manifesting pox-like lesions caused by swinepox virus were reported in Tshuapa Province, Democratic Republic of the Congo. Two human mpox cases were found concurrently in the surrounding community. Specific diagnostics and robust sequencing are needed to characterize multiple poxviruses and prevent potential poxvirus transmission.

Background: The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and become endemic several decades prior to this epidemic., Objectives: This narrative review provides an overview of mpox epidemiology since its discovery through the 2022 global outbreak., Sources: We searched PubMed for relevant literature about mpox epidemiology and transmission through 28 February 2023., Content: The emergence of human mpox is intertwined with the eradication of smallpox and the cessation of the global smallpox vaccination campaign. The first human clade I and II monkeypox virus (MPXV) infections were reported as zoonoses in Central and West Africa, respectively, around 1970 with sporadic infections reported throughout the rest of the decade. Over the next five decades, Clade I MPXV was more common and caused outbreaks of increasing size and frequency, mainly in the Democratic Republic of the Congo. Clade II MPXV was rarely observed, until its re-emergence and ongoing transmission in Nigeria, since 2017. Both clades showed a shift from zoonotic to human-to-human transmission, with potential transmission through sexual contact being observed in Nigeria. In 2022, clade II MPXV caused a large human outbreak which to date has caused over 86,000 cases in 110 countries, with strong evidence of transmission during sexual contact. By February 2023, the global epidemic has waned in most countries, but endemic regions continue to suffer from mpox., Implications: The changing epidemiology of mpox demonstrates how neglected zoonosis turned into a global health threat within a few decades. Thus, mpox pathophysiology and transmission dynamics need to be further investigated, and preventive and therapeutic interventions need to be evaluated. Outbreak response systems need to be strengthened and sustained in endemic regions to reduce the global threat of mpox., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several studies in tropical settings have reported that ∼20% of patients infected with Monkeypox virus (MPXV) also tested polymerase chain reaction (PCR) positive for Varicella zoster virus (VZV). Researchers have hypothesized that VZV infection predisposes to monkeypox (mpox), or vice versa, or that MPXV triggers the reactivation of VZV. We tested samples for VZV from a cohort of patients infected with clade IIb MPXV diagnosed between May 23 and October 14, 2022 in Antwerp, Belgium. Leftover DNA extracts of skin lesion samples from 108 mpox patients were tested with in-house PCR for VZV. No VZV infections were found. The absence of concurrent VZV-MPXV infections in our cohort indicates that VZV did not cocirculate in the population at risk for MPXV during the Belgian 2022 outbreak, but also that MPXV does not commonly trigger reactivation of latent VZV in adult men.

The 2022 global outbreak of human Mpox (formerly monkeypox) virus (MPXV) infection outside of the usual endemic zones in Africa challenged our understanding of the virus's natural history, transmission dynamics, and risk factors. This outbreak has highlighted the need for diagnostics, vaccines, therapeutics, and implementation research, all of which require more substantial investments in equitable collaborative partnerships. Global multidisciplinary networks need to tackle MPXV and other neglected emerging and reemerging zoonotic pathogens to address them locally and prevent or quickly control their worldwide spread. Political endorsement from individual countries and financial commitments to maintain control efforts will be essential for long-term sustainability.

Objective: The available epidemiological and clinical evidence from the currently ongoing monkeypox (MPX) outbreak in non-endemic areas suggests an important factor of sexual transmission. However, limited information on the behaviour and experiences of individuals with an MPX infection has to date been provided. We aimed to describe the initial phase of the MPX outbreak in Belgium, and to provide a more in-depth description of sexual behaviour and transmission contexts., Methods: We used routine national surveillance data of 139 confirmed MPX cases with date of symptom onset until 19 June 2022, complemented with 12 semistructured interviews conducted with a subsample of these cases., Results: Sexualised environments, including large festivals and cruising venues for gay men, were the suspected exposure setting for the majority of the cases in the early outbreak phase. In-depth narratives of sexual behaviour support the hypothesis of MPX transmission through close physical contact during sex. Despite awareness of the ongoing MPX outbreak, low self-perceived risk of MPX acquisition and confusing initial signs and symptoms for other STIs or skin conditions delayed early detection of an MPX infection. In addition, we describe relevant contextual factors beyond individual behaviour, related to sexual networks, interpersonal interactions and health systems. Some of these factors may complicate early MPX detection and control efforts., Conclusion: Our results highlight the role of sexual contact and networks in the transmission of MPX during the early phase of the outbreak in Belgium. Risk communication messages should consistently and transparently state the predominant sexual transmission potential of MPX virus, and prevention and control measures must be adapted to reflect multilevel factors contributing to MPX transmission risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Although transmitted mainly through direct (sexual) contact, mpox virus (MPXV) can be detected in ambient air. We explored the use of air sampling for diagnosis or (genomic) surveillance of mpox in a sexual health clinic. For six out of six patients who were infected with MPXV, all four of our ambient air PCR tests were positive. For 14 uninfected patients, PCR was positive in three ambient air samples, albeit with higher cycle threshold (C t ) values. Genomic sequencing of samples from two positive patients showed matching sequences between air and clinical samples., (© 2023. The Author(s).)

BackgroundSince May 2022, an mpox outbreak affecting primarily men who have sex with men (MSM) has occurred in numerous non-endemic countries worldwide. As MSM frequently reported multiple sexual encounters in this outbreak, reliably determining the time of infection is difficult; consequently, estimation of the incubation period is challenging.AimWe aimed to provide valid and precise estimates of the incubation period distribution of mpox by using cases associated with early outbreak settings where infection likely occurred.MethodsColleagues in European countries were invited to provide information on exposure intervals and date of symptom onset for mpox cases who attended a fetish festival in Antwerp, Belgium, a gay pride festival in Gran Canaria, Spain or a particular club in Berlin, Germany, where early mpox outbreaks occurred. Cases of these outbreaks were pooled; doubly censored models using the log-normal, Weibull and Gamma distributions were fitted to estimate the incubation period distribution.ResultsWe included data on 122 laboratory-confirmed cases from 10 European countries. Depending on the distribution used, the median incubation period ranged between 8 and 9 days, with 5th and 95th percentiles ranging from 2 to 3 and from 20 to 23 days, respectively. The shortest interval that included 50% of incubation periods spanned 8 days (4-11 days).ConclusionCurrent public health management of close contacts should consider that in approximately 5% of cases, the incubation period exceeds the commonly used monitoring period of 21 days.

The risk of infection after exposure to clade IIb mpox virus (MPXV) is unknown, and potential presymptomatic shedding of MPXV remains to be demonstrated. High-risk contacts of mpox patients were followed-up in a prospective longitudinal cohort study. Individuals reporting sexual contact, >15 min skin-to-skin contact, or living in the same household with an mpox patient were recruited in a sexual health clinic in Antwerp, Belgium. Participants kept a symptom diary, performed daily self-sampling (anorectal, genital, and saliva), and presented for weekly clinic visits for physical examination and sampling (blood and oropharyngeal). Samples were tested for MPXV by PCR. Between June 24 and July 31, 2022, 25 contacts were included, of which 12/18 (66.0%) sexual and 1/7 (14.0%) nonsexual contacts showed evidence of infection by MPXV-PCR. Six cases had typical mpox symptoms. Viral DNA was detected as early as 4 days before symptom onset in 5 of them. In 3 of these cases, replication-competent virus was demonstrated in the presymptomatic phase. These findings confirm the existence of presymptomatic shedding of replication-competent MPXV and emphasize the high risk of transmission during sexual contact. Sexual contacts of mpox cases should abstain from sex during the incubation period, irrespective of symptoms., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Aims: Severe acute respiratory syndrome coronavirus-2 infection causes COVID-19, which in severe cases evokes life-threatening acute respiratory distress syndrome (ARDS). Transcriptome signatures and the functional relevance of non-vascular cell types (e.g. immune and epithelial cells) in COVID-19 are becoming increasingly evident. However, despite its known contribution to vascular inflammation, recruitment/invasion of immune cells, vascular leakage, and perturbed haemostasis in the lungs of severe COVID-19 patients, an in-depth interrogation of the endothelial cell (EC) compartment in lethal COVID-19 is lacking. Moreover, progressive fibrotic lung disease represents one of the complications of COVID-19 pneumonia and ARDS. Analogous features between idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest partial similarities in their pathophysiology, yet, a head-to-head comparison of pulmonary cell transcriptomes between both conditions has not been implemented to date., Methods and Results: We performed single-nucleus RNA-sequencing on frozen lungs from 7 deceased COVID-19 patients, 6 IPF explant lungs, and 12 controls. The vascular fraction, comprising 38 794 nuclei, could be subclustered into 14 distinct EC subtypes. Non-vascular cell types, comprising 137 746 nuclei, were subclustered and used for EC-interactome analyses. Pulmonary ECs of deceased COVID-19 patients showed an enrichment of genes involved in cellular stress, as well as signatures suggestive of dampened immunomodulation and impaired vessel wall integrity. In addition, increased abundance of a population of systemic capillary and venous ECs was identified in COVID-19 and IPF. COVID-19 systemic ECs closely resembled their IPF counterparts, and a set of 30 genes was found congruently enriched in systemic ECs across studies. Receptor-ligand interaction analysis of ECs with non-vascular cell types in the pulmonary micro-environment revealed numerous previously unknown interactions specifically enriched/depleted in COVID-19 and/or IPF., Conclusions: This study uncovered novel insights into the abundance, expression patterns, and interactomes of EC subtypes in COVID-19 and IPF, relevant for future investigations into the progression and treatment of both lethal conditions., Competing Interests: Conflict of interest: A.D. received payments from FMC Belgium, and has a leadership/fiduciary role in the Belgian Society of Pathology (non-profit), and European Society of Pathology Nephropathology working group (non-profit). B.T. has a consulting role for ONO pharmaceutical and owns 10X genomics stocks. B.W. received payments from Hologic. L.J.C. received a research grant and consulting fees from MEDTRONIC. S.F. received support from Pfizer for congress attendance. W.W. received research grants and payment for lectures from Roche and Boehringer Ingelheim and a research grant from Galapagos. S.V. received consulting fees from Therakos and Boehringer Ingelheim. J.W. received investigator-initiated grants, consulting fees, speaker fees, and travel grants from Pfizer and Gilead., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The presentation of mpox clade IIb during the 2022 outbreak overlaps with a range of other diseases. Understanding the factors associated with mpox is important for clinical decision making., Methods: We described the characteristics of mpox patients who sought care at Belgian sexual health clinic. Furthermore we compared their characteristics to those of patients with a clinical suspicion of mpox but who tested negative on polymerase chain reaction., Results: Between May 23 and September 20, 2022, 155 patients were diagnosed with mpox, and 51 patients with suspected symptoms tested negative. All mpox patients self-identified as men and 148/155 (95.5%) as gay or bisexual MSM. Systemic symptoms were present in 116/155 (74.8%) patients. All but 10 patients (145/155, 93.5%) presented with skin lesions. Other manifestations were lymphadenopathy (72/155, 46.5%), proctitis (50/155, 32.3%), urethritis (12/155, 7.7%), tonsillitis (2/155, 1.3%). Complications involved bacterial skin infection (13/155, 8.4%) and penile oedema with or without paraphimosis (4/155, 2.6%). In multivariable logistic regression models, the presence of lymphadenopathy (OR 3.79 95% CI 1.44-11.49), skin lesions (OR 4.35 95% CI 1.15-17.57) and proctitis (OR 9.41 95% CI 2.72-47.07) were associated with the diagnosis of mpox. There were no associations with age, HIV status, childhood smallpox vaccination, number of sexual partners and international travel., Conclusions: The presence of proctitis, lymphadenopathies and skin lesions should increase clinical suspicion of mpox in patients with compatible symptoms., (© 2023 The Authors.)

Background: Infective endocarditis (IE) is characterized by an infected thrombus at the heart valves. How bacteria bypass the immune system and cause these thrombi remains unclear. Neutrophils releasing NETs (neutrophil extracellular traps) lie at this interface between host defense and coagulation. We aimed to determine the role of NETs in IE immunothrombosis., Methods: We used a murine model of Staphylococcus aureus endocarditis in which IE is provoked on inflamed heart valves and characterized IE thrombus content by immunostaining identifying NETs. Antibody-mediated neutrophil depletion and neutrophil-selective PAD4 (peptidylarginine deiminase 4)-knockout mice were used to clarify the role of neutrophils and NETs, respectively. S. aureus mutants deficient in key virulence factors related to immunothrombosis (nucleases or staphylocoagulases) were investigated., Results: Neutrophils releasing NETs were present in infected thrombi and within cellular infiltrates in the surrounding vasculature. Neutrophil depletion increased occurrence of IE, whereas neutrophil-selective impairment of NET formation did not alter IE occurrence. Absence of S. aureus nuclease, which degrades NETs, did not affect endocarditis outcome. In contrast, absence of staphylocoagulases (coagulase and von Willebrand factor binding protein) led to improved survival, decreased bacteremia, smaller infiltrates, and decreased tissue destruction. Significantly more NETs were present in these vegetations, which correlated with decreased bacteria and cell death in the adjacent vascular wall., Conclusions: Neutrophils protect against IE independent of NET release. Absence of S. aureus coagulases, but not nucleases, reduced IE severity and increased NET levels. Staphylocoagulase-induced fibrin likely hampers NETs from constraining infection and the resultant tissue damage, a hallmark of valve destruction in IE.

Objectives: We aimed at determining whether specific S. aureus strains cause infective endocarditis (IE) in the course of Staphylococcus aureus bacteraemia (SAB)., Methods: A genome-wide association study (GWAS) including 924 S. aureus genomes from IE (274) and non-IE (650) SAB patients from international cohorts was conducted, and a subset of strains was tested with two experimental animal models of IE, one investigating the early step of bacterial adhesion to inflamed mice valves, the second evaluating the local and systemic developmental process of IE on mechanically-damaged rabbit valves., Results: The genetic profile of S. aureus IE and non-IE SAB strains did not differ when considering single nucleotide polymorphisms, coding sequences, and k-mers analysed in GWAS. In the murine inflammation-induced IE model, no difference was observed between IE and non-IE SAB strains both in terms of adhesion to the cardiac valves and in the propensity to cause IE; in the mechanical IE-induced rabbit model, there was no difference between IE and non-IE SAB strains regarding the vegetation size and CFU., Conclusion: All strains of S. aureus isolated from SAB patients must be considered as capable of causing this common and lethal infection once they have accessed the bloodstream., Competing Interests: Declaration of Competing Interest FV reports research funding outside the scope of the present study by bioMérieux, two patents pending in antimicrobial resistance detection and shares in Weezion. VGF reports personal fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences. Integrated Biotherapeutics; C3J, grants from NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Basilea, Janssen, from Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm, Royalties from UpToDate; and a patent pending in sepsis diagnostics., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While mpox was well characterised during the 2022 global Clade IIb outbreak, little is known about persistent morbidity. We present interim results of a prospective cohort study of 95 mpox patients assessed 3-20 weeks post-symptom onset. Two-thirds of participants had residual morbidity, including 25 with persistent anorectal and 18 with genital symptoms. Loss of physical fitness, new-onset/worsened fatigue and mental health problems were reported in 36, 19 and 11 patients, respectively. These findings require attention by healthcare providers.

Background: Mpox (formerly monkeypox) is a viral disease caused by the mpox virus (MPXV), endemic in Central and West Africa and currently causing a global outbreak of international concern. Much remains unknown about sample types most suited for mpox laboratory diagnosis. While it is established that high viral loads can be found in active skin lesions (currently the recommended mpox laboratory confirmation specimen type), WHO mpox testing guidelines encourage the use of oropharyngeal swabs as an additional sample type for mpox diagnosis and suggest investigating the value of other specimens like blood samples., Objective: In this study, we verified the value of select alternative specimen types for mpox laboratory confirmation., Methods: We included 25 patients with MPXV-confirmed skin lesions to compare diagnostic sensitivity of MPXV PCR testing on EDTA plasma and two upper respiratory specimens: oropharyngeal swabs and saliva., Results: In our patient cohort with MPXV-confirmed skin lesions, diagnostic sensitivity of MPXV PCR was 80% in EDTA plasma, 64% in oropharyngeal swabs, and 88% in saliva. MPXV viral loads were significantly higher in saliva compared to oropharyngeal swabs and EDTA plasma., Discussion: The WHO recommendation to collect oropharyngeal swabs as an additional specimen for mpox diagnosis might need to be revised to include saliva wherever feasible. We suggest investigating saliva as a diagnostic specimen in the absence of active skin lesions or during the phase preceding skin manifestations. Moreover, the relatively high MPXV DNA content of saliva warrants elucidating its potential role in disease transmission., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Vaccination is important in containing the 2022 mpox (formerly monkeypox) epidemic. We describe five Belgian patients with localised severe symptoms of proctitis and penile oedema, occurring between 4 and 35 days after post-exposure preventive vaccination or after one- or two-dose off-label pre-exposure preventive vaccination with MVA-BN vaccine. Genome sequencing did not reveal evidence for immune escape variants. Healthcare workers and those at risk should be aware of possible infections occurring shortly after vaccination and the need for other preventive measures.

The magnitude of the 2022 multi-country monkeypox virus (MPXV) outbreak has surpassed any preceding outbreak. It is unclear whether asymptomatic or otherwise undiagnosed infections are fuelling this epidemic. In this study, we aimed to assess whether undiagnosed infections occurred among men attending a Belgian sexual health clinic in May 2022. We retrospectively screened 224 samples collected for gonorrhea and chlamydia testing using an MPXV PCR assay and identified MPXV-DNA-positive samples from four men. At the time of sampling, one man had a painful rash, and three men had reported no symptoms. Upon clinical examination 21-37 days later, these three men were free of clinical signs, and they reported not having experienced any symptoms. Serology confirmed MPXV exposure in all three men, and MPXV was cultured from two cases. These findings show that certain cases of monkeypox remain undiagnosed and suggest that testing and quarantining of individuals reporting symptoms may not suffice to contain the outbreak., (© 2022. The Author(s).)

Background: Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients., Methods: In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge., Findings: Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N  = 67 vs. SOC N  = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p  = 0.24) or mortality (intervention n  = 3 [4.6%] vs. SOC n  = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p  = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding., Conclusions: In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Recovered COVID-19 patients often display cardiac dysfunction, even after a mild infection. Most current histological results come from patients that are hospitalized and therefore represent more severe outcomes than most COVID-19 patients face. To overcome this limitation, we investigated the cardiac effects of SARS-CoV-2 infection in a hamster model. SARS-CoV-2 infected hamsters developed diastolic dysfunction after recovering from COVID-19. Histologically, increased cardiomyocyte size was present at the peak of viral load and remained at all time points investigated. As this increase is too rapid for hypertrophic remodeling, we found instead that the heart was oedemic. Moreover, cardiomyocyte swelling is associated with the presence of ischemia. Fibrin-rich microthrombi and pericyte loss were observed at the peak of viral load, resulting in increased HIF1α in cardiomyocytes. Surprisingly, SARS-CoV-2 infection inhibited the translocation of HIF1α to the nucleus both in hamster hearts, in cultured cardiomyocytes, as well as in an epithelial cell line. We propose that the observed diastolic dysfunction is the consequence of cardiac oedema, downstream of microvascular cardiac ischemia. Additionally, our data suggest that inhibition of HIF1α translocation could contribute to an exaggerated response upon SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daems, Liesenborghs, Boudewijns, Simmonds, Kraisin, Van Wauwe, Cuijpers, Raman, Geuens, Buyten, Lox, Verhamme, Van Linthout, Martinod, Heymans, Tschöpe, Neyts and Jones.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19., Methods: In this observational study, we measured plasma and tissue kallikrein hydrolytic activity, levels of kinin peptides, and myeloperoxidase (MPO)-DNA complexes as a biomarker for neutrophil extracellular traps (NETs), in bronchoalveolar lavage (BAL) fluid from patients with and without COVID-19., Findings: In BAL fluid from patients with severe COVID-19 (n = 21, of which 19 were mechanically ventilated), we observed higher tissue kallikrein activity (18·2 pM [1·2-1535·0], median [range], n = 9 vs 3·8 [0·0-22·0], n = 11; p = 0·030), higher levels of the kinin peptide bradykinin-(1-5) (89·6 [0·0-2425·0], n = 21 vs 0·0 [0·0-374·0], n = 19, p = 0·001), and higher levels of MPO-DNA complexes (699·0 ng/mL [66·0-142621·0], n = 21 vs 70·5 [9·9-960·0], n = 19, p < 0·001) compared to patients without COVID-19., Interpretation: Our observations support the hypothesis that dysregulation of the kallikrein-kinin system might occur in mechanically ventilated patients with severe pulmonary disease, which might help to explain the clinical presentation of patients with severe COVID-19 developing pulmonary oedema and thromboembolic complications. Therefore, targeting the kallikrein-kinin system should be further explored as a potential treatment option for patients with severe COVID-19., Funding: Research Foundation-Flanders (G0G4720N, 1843418N), KU Leuven COVID research fund., Competing Interests: Declaration of interests M.V., B.N., H.C., and J.H.M.F. are employees of Oxurion NV. Oxurion NV and KU Leuven LRD submitted a patent on kallikrein inhibitors. K.M. is an inventor on the granted patent US9642822 awarded to Children's Medical Center Corporation covering the targeting of NETs in thrombosis and lung injury and the pending patent WO20180271953A1. She reports issued patent US9642822B2 and pending patents US2019167680A1. K.M. also reports consulting fees from PEEL Therapeutics. She holds a grant from Flanders Research Foundation (FWO) and a Horizon 2020 grant, as well as a grant from the International Society on Thrombosis and Haemostasis. T.V. is a board member and vice-president of the Belgian Society for Thrombosis and Haemostasis. P.V. and T.V. are co-holders of a research chair for clinical research with Trasylol (DAWN-AntiCo). P.V. holds an institutional grant funded by Bayer AG and by BMS/Pfizer. He reports consulting fees from Anthos Therapeutics, Bayer AG, Boehringer,BMS, Pfizer, Daiichi Sankyo, and Portola/Actelion, and honoraria as a speaker from Bayer, BMS, Pfizer, Daiichi Sankyo, and Leo Pharma. P.V. has participated in a DSMB for clinical trials sponsored by Bayer and Boehringer Ingelheim. R.V. and A.V. report participation in advisory board for Takeda and involvement in ERS, ESOT/ECTTA boards. J.W. is a holder of research grants funded by MSD, Pfizer, and Gilead. He reports speakers fees and support for attending meetings from Gilead, MSD, and Pfizer, and participation on an advisory board for Gilead. He has received study medication for clinical trials from MSD. The other authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Following an outbreak of cases of vesicular-pustular rash with fever, evocative of human monkeypox, in Bas-Uélé province, Democratic Republic of Congo, surveillance was strengthened., Methods: Households with at least one active generalized vesicular-pustular rash case were visited, and contact and clinical history information were collected from all household members. Whenever possible, skin lesions were screened by polymerase chain reaction for the monkeypox virus, followed by the varicella-zoster virus, when negative for the former., Results: Polymerase chain reaction results were obtained for 77 suspected cases, distributed in 138 households, of which 27.3% were positive for monkeypox, 58.4% positive for chickenpox, and 14.3% negative for both. Confirmed monkeypox cases presented more often with monomorphic skin lesions on the palms of the hands and on the soles of the feet. Integrating these three features into the case definition raised the specificity to 85% but would miss 50% of true monkeypox cases. A predictive model fit on patient demographics and symptoms had 97% specificity and 80% sensitivity but only 80% and 33% in predicting out-of-sample cases., Conclusion: Few discriminating features were identified and the performance of clinical case definitions was suboptimal. Rapid field diagnostics are needed to optimize worldwide early detection and surveillance of monkeypox., (Published by Elsevier Ltd.)