Listeria monocytogenes-associated spontaneous bacterial peritonitis in France: a nationwide observational study of 208 cases.

BACKGROUND: Listeriosis is a foodborne infection caused by Listeria monocytogenes. Three main forms of listeriosis are well characterised, but little is known about L monocytogenes-associated spontaneous bacterial peritonitis. We used data from the French national surveillance of listeriosis to perform a nationwide retrospective study. METHODS: All patients with L monocytogenes isolated by culture from a peritoneal fluid sample in France between April 1, 1993, and Dec 31, 2022, were included. Individuals for whom bacterial peritonitis was not confirmed and those who also had another type of invasive listeriosis were excluded. A standardised checklist was used to collect demographic, clinical, and biological data as well as antibiotic treatment and follow-up data. The primary outcome was to determine the characteristics of L monocytogenes-associated spontaneous bacterial peritonitis. We did descriptive analyses and assessed risk factors for 1-month mortality using an exploratory multivariable Cox model analysis. FINDINGS: Among the 8768 L monocytogenes cases reported, 208 (2%) were patients with L monocytogenes-associated spontaneous bacterial peritonitis. Mean age was 65 years (SD 13), 50 (24%) of 208 patients were female, and 158 (76%) were male (no data on race or ethnicity were available). 200 (98%) of 205 patients with L monocytogenes-associated spontaneous bacterial peritonitis with available data had immunosuppressive comorbidities, including cirrhosis (148 [74%] of 201 with available data), ongoing alcoholism (58 [62%] of 94), and ongoing neoplasia (60 [31%] of 195). Causes of ascites included cirrhosis (146 [70%] of 208), ongoing neoplasia (26 [13%]), end-stage heart failure (13 [6%]), and peritoneal dialysis (11 [5%]). Among those with available data, presentation was pauci-symptomatic and non-specific; only 67 (50%) of 135 patients presented with fever, 49 (37%) of 132 with abdominal pain, and 27 (21%) of 129 with diarrhoea. 61 (29%) of 208 patients were dead at 1 month, 92 (44%) were dead at 3 months, and 109 (52%) were dead at 6 months after diagnosis. Ongoing neoplasia (hazard ratio 2·42 [95% CI 1·05-5·56]; p=0·039), septic shock (8·03 [2·66-24·02]; p=0·0021), and high blood leukocyte count (1·05 [1·00-1·09]; p=0·045) were independently associated with 1-month mortality. INTERPRETATION: Despite the non-specific and mild presentation of L monocytogenes-associated spontaneous bacterial peritonitis, the outcome is poor and similar to that of neurolisteriosis, and so identification of L monocytogenes in ascitic fluid samples requires urgent parenteral amoxicillin-based treatment to avoid a fatal outcome. FUNDING: Institut Pasteur, Inserm, and French Public Health Agency. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Cuffless Blood Pressure in clinical practice: challenges, opportunities and current limits.

Background: Cuffless blood pressure measurement technologies have attracted significant attention for their potential to transform cardiovascular monitoring.Methods: This updated narrative review thoroughly examines the challenges, opportunities, and limitations associated with the implementation of cuffless blood pressure monitoring systems.Results: Diverse technologies, including photoplethysmography, tonometry, and ECG analysis, enable cuffless blood pressure measurement and are integrated into devices like smartphones and smartwatches. Signal processing emerges as a critical aspect, dictating the accuracy and reliability of readings. Despite its potential, the integration of cuffless technologies into clinical practice faces obstacles, including the need to address concerns related to accuracy, calibration, and standardization across diverse devices and patient populations. The development of robust algorithms to mitigate artifacts and environmental disturbances is essential for extracting clear physiological signals. Based on extensive research, this review emphasizes the necessity for standardized protocols, validation studies, and regulatory frameworks to ensure the reliability and safety of cuffless blood pressure monitoring devices and their implementation in mainstream medical practice. Interdisciplinary collaborations between engineers, clinicians, and regulatory bodies are crucial to address technical, clinical, and regulatory complexities during implementation. In conclusion, while cuffless blood pressure monitoring holds immense potential to transform cardiovascular care. The resolution of existing challenges and the establishment of rigorous standards are imperative for its seamless incorporation into routine clinical practice.Conclusion: The emergence of these new technologies shifts the paradigm of cardiovascular health management, presenting a new possibility for non-invasive continuous and dynamic monitoring. The concept of cuffless blood pressure measurement is viable and more finely tuned devices are expected to enter the market, which could redefine our understanding of blood pressure and hypertension.

This review explores cuffless blood pressure technologies and their impact on clinical practice, highlighting innovative devices that offer non-invasive, continuous and non-continuous monitoring without a cuff. Signal processing is essential for ensuring accurate readings, as it filters out unwanted artifacts and environmental disturbances which could make the reading inaccurate. While these advancements show great potential for transforming cardiovascular care, there are still several challenges to overcome, including the need for standardized protocols and validation studies to ensure their reliability and safety in clinical settings. Collaborative efforts between engineers, clinicians, and regulatory bodies are needed to address the technical and regulatory complexities surrounding the implementation of these technologies. These cuffless blood pressure measurement devices have the potential to reshape how we understand and manage blood pressure and hypertension.

Critically Ill Patients with Visceral Nocardia Infection, France and Belgium, 2004-2023.

We studied 50 patients with invasive nocardiosis treated during 2004-2023 in intensive care centers in France and Belgium. Most (65%) died in the intensive care unit or in the year after admission. Nocardia infections should be included in the differential diagnoses for patients in the intensive care setting.

Susceptibility to malaria in fulani, Bariba, Otamari and gando individuals living in sympatry in Benin: Role of opsonizing antibodies to Plasmodium falciparum merozoites.

Objectives: Fulani in Africa are known to be less susceptible to Plasmodium falciparum (Pf) malaria. This study explored a potential involvement of antibody-mediated merozoite phagocytosis mechanism in this natural protection against malaria. Methods: Before the start of the malaria transmission season (MTS) in Benin, the functionality of antibodies against Pf merozoites was determined by the opsonic phagocytosis (OP) assay in plasma samples from Fulani, Bariba, Otamari and Gando groups. These individuals were actively followed-up for malaria detection from the beginning to the end of MTS. Anti-GLURP Immunoglobulin G antibody quantification, malaria Rapid Diagnostic Test (RDT) and spleen palpation were performed before and after MTS. Results: In Bariba, Otamari and Gando, but not in Fulani, plasma from adults promoted higher levels of OP than the children (P = 0.003; P = 0.012; P = 0.031 and P = 0.122). A high proportion of Fulani children had higher OP and anti-GLURP (P < 0.0001) antibody levels as compared to non-Fulani children; whereas this was not observed for Fulani adults (P = 0.223). High OP levels before MTS were significantly related to negative RDT after MTS (P = 0.011). Conclusion: Our results highlight the ability of opsonizing antibodies to potentially enhance natural protection of young Fulani individuals against Pf malaria in Benin.

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria.

BACKGROUND: In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anaemia and splenomegaly. The mechanisms underlying this phenotype remain elusive. METHODS: In a cohort study set up in Benin, West Africa, after a careful evaluation of malaria-related phenotypes, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Heritability of erythrocytes deformability was calculated, followed by a genome-wide association study (GWAS) of the same phenotype. FINDINGS: Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity. INTERPRETATION: In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anaemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases. FUNDING: ANR, National Geographic Society, IMEA, IRD, and Région Ile-de-France.

Antifungals influence the immune-related transcriptomic landscape of human monocytes after Aspergillus fumigatus infection.

The heterogeneity of clinical responses to antifungals in aspergillosis is partially understood. We hypothesized that besides direct antifungal effects, these discrepancies may be related to different immunomodulatory profiles. Human THP-1 monocytes were coincubated in vitro with Aspergillus fumigatus and variable concentrations of voriconazole (0.5, 1 and 2 mg/l), caspofungin (1 and 2 mg/l), amphotericin B deoxycholate (0.25, 0.5 and 1 mg/l) and liposomal amphotericin B (1, 2 and 3 mg/l). After 6 h of coincubation, total cellular RNA was extracted, converted into cDNA, and transcription of 84 genes involved in antifungal immunity was measured through RT-qPCR. The presence of A. fumigatus was the main driver of the global immune-related transcriptomic response. After Aspergillus infection, thirty genes were upregulated, while 19 genes were downregulated. Discrepancies across antifungals were also evident; voriconazole-containing conditions showed similar reaction to natural infection, while the use of liposomal Amphotericin B significantly decreased the inflammatory response. Chemokines (notably CCL20 and CXCL2) and pro-inflammatory cytokines (IL1A, IL1B, IL23, G-CSF) exhibited the most pronounced differences across antifungals. Pattern recognition receptors and adaptor protein transcription were minimally affected. Protein-protein-interaction network analysis showed that IL23A played a dominant role in upregulated genes. Pathway enrichment analysis indicated that cytokine-cytokine receptor integration, TNF signaling pathways and Toll-like receptor pathways were highly involved. This exploratory study confirms the heterogeneous immunomodulatory role of antifungals. Overall, voriconazole appears to maintain an early pro-inflammatory response seen in natural infection. Assessment of immunomodulatory response with clinical response may provide a better rationale for differences observed across antifungals.

SARS-CoV-2 Circulation, Guinea, March 2020-July 2021.

This overview of severe acute respiratory syndrome coronavirus 2 circulation over 1.5 years in Guinea demonstrates that virus clades and variants of interest and concern were progressively introduced, mostly by travellers through Conakry, before spreading through the country. Sequencing is key to following virus evolution and establishing efficient control strategies.

Emergence of SARS-CoV-2 resistance mutations in a patient who received anti-SARS-COV2 spike protein monoclonal antibodies: a case report.

BACKGROUND: To manage severe or potentially severe cases of CoronaVirus Disease 2019 (COVID-19), therapeutic monoclonal antibodies targeting Spike protein of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) have been designed. It has been noted in vitro that upon exposure to these treatments, mutations could be selected. CASE PRESENTATION: We here report the case of an immunosuppressed patient infected with a B.1.1.7 variant, who received a combination of monoclonal antibodies, and subsequently selected mutations K417N, E484K and Q493R on Spike protein of SARS-CoV-2. CONCLUSIONS: Our case raises the importance of monitoring SARS-CoV-2 mutations in patients receiving monoclonal antibodies and having persistent excretion of the virus, in order to offer optimal management of their infection, and strengthen prevention measures to avoid subsequent transmission of these selected variants.

Risk of Lung Allograft Dysfunction Associated With Aspergillus Infection.

We sought to determine whether invasive aspergillosis (IA) during the first year after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD). METHODS: We retrospectively reviewed the records of 191 patients who underwent lung transplantation at our institution between January 2013 and December 2017. Screening for Aspergillus was with bronchial aspirates, bronchoalveolar lavage if indicated or during surveillance bronchoscopy, radiography, and computed tomography. We used Fine and Gray multivariable regression to identify potential risk factors for CLAD. RESULTS: During the first posttransplant year, 72 patients had at least 1 deep-airway sample positive for Aspergillus; 63 were classified as having IA and were included in the study. Median number of endoscopies per patient during the first year was 9 (range, 1-44). Median time from transplantation to first Aspergillus-positive sample was 121 d. Bronchial aspirate samples and bronchoalveolar lavage fluid were positive in 71 and 44 patients, respectively. Aspergillus fumigatus (n = 36, 50%) predominated; bacterial samples were also positive in 22 (31%) patients. IA within 4 mo after transplantation was independently associated with CLAD development (subdistribution hazard ratio, 3.75; 95% confidence interval [CI], 1.61-8.73; P < 0.01) by regression analysis. Survival at 3 and 5 y conditional on 1-y CLAD-free survival was 37% (95% CI, 24%-58%), and 24% (95% CI, 11%-52%) in the IA <4 mo group compared to 65% (95% CI, 57%-73%) and 54% (95% CI, 43%-66%) in the non-IA group and to 69% (95% CI, 58%-83%) and 54% (95% CI, 35%-82%) in the IA ≥4 mo group, respectively (P < 0.01, logrank test). CONCLUSIONS: Our evaluation of de novo IA showed that this infection was most strongly associated with CLAD when found within 4 mo after transplantation.

Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study.

BACKGROUND: A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. METHODS AND FINDINGS: We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. CONCLUSIONS: Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.

Invasive Mold Infections in FLT3-Mutated Acute Myeloid Leukemia.

BACKGROUND: The incidence and risk factors for invasive mold infections (IMI) in acute myeloid leukemia (AML) patients carrying FLT3 mutations have not been addressed. PATIENTS AND METHODS: This retrospective cohort included FLT3-mutated AML patients (2008-2018). Primary outcome was IMI incidence within 6 months after first induction or salvage therapy. RESULTS: We included 108 patients receiving fluconazole or micafungin prophylaxis. IMI incidence after induction and salvage therapy was 4.8% and 14.8%, respectively, and did not differ between patients receiving 3+7 regimen or 3+7 plus midostaurin (4.3% vs 4.5%). In a bivariate analysis, age (odds ratio, 1.11; P = .027) and FLT3 ITD mutation (odds ratio, 0.05; P = .023) were independently associated with IMI after induction chemotherapy. Gilteritinib was more frequently prescribed in patients with relapsed/refractory disease who developed IMI (50% vs 27.3%, P = .563). CONCLUSION: FLT3 ITD mutation may be a preventive factor for IMI. Neither midostaurin nor salvage gilteritinib significantly increased the risk of IMI in this population.

Rapid clearance of storage-induced microerythrocytes alters transfusion recovery.

Permanent availability of red blood cells (RBCs) for transfusion depends on refrigerated storage, during which morphologically altered RBCs accumulate. Among these, a subpopulation of small RBCs, comprising type III echinocytes, spheroechinocytes, and spherocytes and defined as storage-induced microerythrocytes (SMEs), could be rapidly cleared from circulation posttransfusion. We quantified the proportion of SMEs in RBC concentrates from healthy human volunteers and assessed correlation with transfusion recovery, investigated the fate of SMEs upon perfusion through human spleen ex vivo, and explored where and how SMEs are cleared in a mouse model of blood storage and transfusion. In healthy human volunteers, high proportion of SMEs in long-stored RBC concentrates correlated with poor transfusion recovery. When perfused through human spleen, 15% and 61% of long-stored RBCs and SMEs were cleared in 70 minutes, respectively. High initial proportion of SMEs also correlated with high retention of RBCs by perfused human spleen. In the mouse model, SMEs accumulated during storage. Transfusion of long-stored RBCs resulted in reduced posttransfusion recovery, mostly due to SME clearance. After transfusion in mice, long-stored RBCs accumulated predominantly in spleen and were ingested mainly by splenic and hepatic macrophages. In macrophage-depleted mice, splenic accumulation and SME clearance were delayed, and transfusion recovery was improved. In healthy hosts, SMEs were cleared predominantly by macrophages in spleen and liver. When this well-demarcated subpopulation of altered RBCs was abundant in RBC concentrates, transfusion recovery was diminished. SME quantification has the potential to improve blood product quality assessment. This trial was registered at www.clinicaltrials.gov as #NCT02889133.

Intravenous Artesunate for the Treatment of Severe Imported Malaria: Implementation, Efficacy, and Safety in 1391 Patients.

BACKGROUND: Intravenous artesunate is the World Health Organization-recommended first-line treatment for severe malaria worldwide, but it is still not fully licensed in Europe. Observational studies documenting its safety and efficacy in imported malaria are thus essential. METHODS: We prospectively collected clinical and epidemiological features of 1391 artesunate-treated patients among 110 participant centers during the first 7 years (2011-2017) of a national program implemented by the French Drug Agency. RESULTS: Artesunate became the most frequent treatment for severe malaria in France, rising from 9.9% in 2011 to 71.4% in 2017. Mortality was estimated at 4.1%. Treatment failure was recorded in 27 patients, but mutations in the Kelch-13 gene were not observed. Main reported adverse events (AEs) were anemia (136 cases), cardiac events (24, including 20 episodes of conduction disorders and/or arrhythmia), and liver enzyme elevation (23). Mortality and AEs were similar in the general population and in people with human immunodeficiency virus, who were overweight, or were pregnant, but the only pregnant woman treated in the first trimester experimented a hemorrhagic miscarriage. The incidence of post-artesunate-delayed hemolysis (PADH) was 42.8% when specifically assessed in a 98-patient subgroup, but was not associated with fatal outcomes or sequelae. PADH was twice as frequent in patients of European compared with African origin. CONCLUSIONS: Artesunate was rapidly deployed and displayed a robust clinical benefit in patients with severe imported malaria, despite a high frequency of mild to moderate PADH. Further explorations in the context of importation should assess outcomes during the first trimester of pregnancy and collect rare but potentially severe cardiac AEs.

CYP51A polymorphisms of Aspergillus fumigatus in lung transplant recipients: Prevalence, correlation with phenotype, and impact on outcomes.

Azole resistance in Aspergillus fumigatus is increasing worldwide and can affect prognosis. It is mostly mediated by cytochrome P51 (CYP51) mutations. In lung transplant recipients (LTR), little is known regarding the prevalence and clinical impact of CYP51 mutations. One hundred thirty-one consecutive A. fumigatus isolates from 103 patients were subjected to CYP51A genotyping through PCR and sequencing. Antifungal susceptibility testing was performed using the Sensititre YeastOne YO-9© broth microdilution technique. Correlations between genotype, phenotype, clinical manifestations of Aspergillus infection, and clinical outcomes were made. Thirty-four (26%) isolates harbored mutations of CYP51A; N248K (n = 14) and A9T (n = 12) were the most frequent. Three isolates displayed multiple point mutations. No significant influences of mutational status were identified regarding azole MICs, the clinical presentation of Aspergillus disease, 1-year all-cause mortality, and clinical outcomes of invasive forms. In the specific context of lung transplant recipients, non-hotspot CYP51A-mutated isolates are regularly encountered; this does not result in major clinical consequences or therapeutic challenges. LAY SUMMARY: In 131 isolates of Aspergillus fumigatus isolates originating from 103 lung transplant recipients, the CYP51A polymorphism rate was 26%, mostly represented by N248K and A9T mutations. These mutations, however, did not significantly impact azoles minimal inhibitory concentrations or clinical outcomes.

The Human Spleen in Malaria: Filter or Shelter?

The human spleen is an immune sentinel and controls red blood cell (RBC) quality. By mechanically retaining subsets of infected RBCs, the spleen may reduce the pace at which the parasite biomass increases before the adaptive immune response operates. Conversely, the spleen may contribute to malaria pathogenesis, particularly anemia that is associated with splenomegaly. Large spleens may also shelter parasites in chronic carriers. Upon treatment with artemisinins, the spleen clears circulating parasites by pitting and releases 'once-infected' RBCs in circulation. This triggers postartesunate delayed hemolysis and explains the long post-treatment positivity of histidine-rich protein 2 (HRP2)-based dipsticks. Importantly, splenic retention of RBCs also applies to gametocytes, the clearance of which may be enhanced by stiffening them with drugs, a potential way to block malaria transmission.

Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis.

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.