•Typhoid fever (TF) is a systemic illness and disseminated intravascular coagulation may occur.•This study includes 2 patients groups, blood culture-positive and PCR-positive patients.•The ...coagulation system is strongly activated in most TF patients involving all 3 major pathways.•A fifth of TF patients had marked thrombocytopenia, a proposed marker for severity of disease.
Typhoid fever caused by Salmonella Typhi remains a major burden worldwide. Gastrointestinal bleeding can be seen in up to 10 percent of patients and may be fatal. The coagulopathy, which may be the driver of this severe complication in patients with typhoid fever, however is ill defined. The aim of this study was to evaluate the activation of coagulation, anticoagulation, and fibrinolysis in patients with acute typhoid fever.
Parameters of coagulation and fibrinolysis were measured in 28 hospitalized patients with culture-confirmed or PCR-confirmed typhoid fever and compared to 38 age- and sex-matched healthy volunteers.
Patients demonstrated activation of the coagulation system, as reflected by elevated in vitro thrombin generation and high plasma levels of fibrinogen, D-dimer and prothrombin fragment F1 + 2 in concert with consumption of coagulation factors resulting in a prolonged prothrombin-time and activated-partial-thromboplastin-time. Concurrently, the anticoagulant proteins, protein C and antithrombin, were significantly lower in comparison to healthy controls. Patients also demonstrated evidence of activation and inhibition of fibrinolysis and a marked activation of endothelial cells. The extent of coagulation activation was associated with the course of the disease, repeated testing during convalescence showed a return toward normal values.
Activation of coagulation is an important clinical feature of typhoid fever and is associated with severity of disease.
Objective
To determine the diagnostic accuracy of three rapid diagnostic tests (RDTs) for typhoid fever in febrile hospitalised patients in Bangladesh.
Methods
Febrile adults and children admitted to ...Chittagong Medical College Hospital, Bangladesh, were investigated with Bact/Alert® blood cultures and real‐time PCR to detect Salmonella enterica Typhi and Paratyphi A and assays for Rickettsia, leptospirosis and dengue fever. Acute serum samples were examined with the LifeAssay (LA) Test‐it™ Typhoid IgM lateral flow assay detecting IgM antibodies against S. Typhi O antigen, CTKBiotech Onsite Typhoid IgG/IgM Combo Rapid‐test cassette lateral flow assay detecting IgG and IgM antibodies against S. Typhi O and H antigens and SD Bioline line assay for IgG and IgM antibodies against S. Typhi proteins.
Results
In 300 malaria smear‐negative febrile patients median (IQR) age of 13.5 (5–31) years, 34 (11.3%) had confirmed typhoid fever: 19 positive by blood culture for S. Typhi (three blood PCR positive) and 15 blood culture negative but PCR positive for S. Typhi in blood. The respective sensitivity and specificity of the three RDTs in patients using a composite reference standard of blood culture and/or PCR‐confirmed typhoid fever were 59% and 61% for LifeAssay, 59% and 74% for the CTK IgM and/or IgG, and 24% and 96% for the SD Bioline RDT IgM and/or IgG. The LifeAssay RDT had a sensitivity of 63% and a specificity of 91% when modified with a positive cut‐off of ≥2+ and analysed using a Bayesian latent class model.
Conclusions
These typhoid RDTs demonstrated moderate diagnostic accuracies, and better tests are needed.
Objectif
Déterminer la précision diagnostique de trois tests de diagnostic rapide (TDR) pour la fièvre typhoïde chez les patients fébriles hospitalisés au Bangladesh.
Méthodes
Les adultes et enfants fébriles admis à l'hôpital de Chittagong Medical College, au Bangladesh ont été investigués avec: BactAlert® pour les cultures de sang, la PCR en temps réel pour détecter S. enterica typhi et paratyphi A et les tests pour Rickettsia, la leptospirose et la fièvre de la dengue. Des échantillons de sérum prélevé en phase aiguë ont été examinés avec le test LifeAssay (LA) Test‐it™ Typhoïd IgM à écoulement latéral détectant les anticorps IgM contre l'antigène O de S. typhi, le test CTKBiotech Onsite Typhoïd IgG/IgM Combo Rapid‐test cassette à écoulement latéral détectant les anticorps IgG et IgM contre antigènes O et H de S. typhi et le test SD Bioline pour les anticorps IgG et IgM contre les protéines de S. typhi.
Résultats
Sur 300 patients fébriles avec à frottis négatif pour le paludisme (âge médian (IQR): 13,5 ans (5 à 31)), 34 (11,3%) ont eu la fièvre typhoïde confirmée: 19 positifs par la culture de sang pour S. typhi (3 échantillons de sang positif avec la PCR) et 15 hémocultures négatives, mais positives pour S. typhi par la PCR sur le sang. La sensibilité et la spécificité respectives des trois TDR chez les patients, en utilisant un standard de référence composé de la culture de sang et/ou la PCR pour confirmer la fièvre typhoïde, était de 36% et 89% pour le LifeAssay, 54% et 74% pour le CTK IgM et/ou IgG et 21% et 97% pour le SD Bioline IgM et/ou IgG. Le TDR LifeAssay avait une sensibilité de 63% et une spécificité de 91% lorsqu'il était modifié pour un seuil de positivité fixé à ≥ 2+ et analysé en utilisant un modèle de structure latente bayésienne.
Conclusions
Ces TDR pour la typhoïde ont démontré des précisions diagnostiques modérées; de meilleurs tests sont donc toujours nécessaires.
Objetivo
Determinar la precisión diagnóstica de tres pruebas de diagnóstico rápido (PDR) para la fiebre tifoidea en pacientes hospitalizados y con fiebre en Bangladesh.
Métodos
A pacientes adultos y niños, febriles y hospitalizados en el Hospital Universitario de Chittagong, se les realizaron las siguientes pruebas: hemocultivo con BactAlert®; PCR a tiempo real para detectar S.enterica typhi y paratyphi A; y pruebas para Rickettsia, leptospirosis y fiebre del dengue. A las muestras de suero de pacientes en fase aguda se les realizaron las siguientes pruebas: detección de anticuerpos IgM frente a al antígeno O de S.typhi con el inmunoensayo de flujo lateral LifeAssay (LA) Test‐it™; la prueba rápida CTKBiotech Onsite Tifoidea IgG/IgM Combo en casete para la detección de anticuerpos IgG e IgM frente a los antígenos O y H de S. typhi; y la prueba rápida SD Bioline para detección de anticuerpos IgG e IgM frente a proteínas de S. typhi.
Resultados
De 300 pacientes febriles con resultados negativos para malaria (edad media de 13.5 (5‐31) años), 34 (11.3%) tenían fiebre tifoidea confirmada: 19 con cultivo positivo para S. typhi (3 con PCR positiva en sangre); 15 con hemocultivo negativo pero con resultados positivo para la PCR de S. typhi en sangre. La sensibilidad y especificidad respectiva para las tres PDRs en pacientes, utilizando un estándar de referencia compuesto de fiebre tifoidea confirmada por hemocultivo y/o PCR eran 36% y 89% para LifeAssay, 54% y 74% para CTK IgM y/o IgG y 21% y 97% para la PDR de SD Bioline IgM y/o IgG. La PDR de LifeAssay tenía una sensibilidad del 63% y una especificidad del 91% cuando se modificaba con un punto de corte positivo de ≥2+ y se analizaba utilizando un modelo Bayesiano de clases latentes.
Conclusiones
Estas PDR para fiebre tifoidea demuestran una precisión diagnóstica moderada y se necesitan mejores pruebas.
Abstract
Background
We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in ...women.
Methods
This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2–5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6–10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449).
Results
After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference RD, 9.6%; 95% confidence interval CI: –8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6–10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, –16.2%; 95% CI: –32.7 to –0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively.
Conclusions
Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events.
Clinical Trial Registration
Trial NL6275 (NTR6449).
Fosfomycin is noninferior to ciprofloxacin regarding clinical cure as a targeted oral step-down treatment for Escherichia colifebrile urinary tract infections in women. Its use could prevent extended hospitalization in cases of resistance, intolerance, or allergies to existing step-down antibiotics.
Abstract
Background
The 2023 Duke-ISCVID criteria for IE were recently introduced to improve classification of IE for research and clinical purposes (Table 1). We compared the diagnostic accuracy of ...the new criteria with the 2000 modified Duke criteria, the 2015 European Society of Cardiology (ESC) criteria and a clinically adjudicated reference standard by a panel of international experts on IE.Table 1:Overview of changes in criteria from 2000 modified Duke to 2023 Duke-ISCVIDAdapted from: Fowler et al, Clinical Infectious Diseases, 2023
Methods
The study population consisted of consecutively enrolled patients suspected to have IE and discussed by the IE team of the Amsterdam University Medical Center (AMC) between October 2016 and March 2021. A panel of international experts on IE assigned a final diagnosis, which served as the reference standard. We compared the definite classification of the 2023 Duke-ISCVID criteria against this reference standard. We also evaluated accuracy of the new criteria, excluding data obtained from cardiac surgery and pathology (“Clinical Criteria”). Lastly, we quantified the added value of the proposed changes to the criteria, and compared the 2023 Duke-ISCVID to previous criteria using the McNemar test. We performed sensitivity analyses in patients who underwent cardiac surgery and patients who underwent TEE.
Results
595 patients with suspected IE were included, of whom 399 (67%) were adjudicated as having IE. 111 patients (19%) had prosthetic valve IE, 48 (8%) had cardiac implantable electronic device IE. The 2023 Duke-ISCVID criteria were more sensitive than the modified Duke or ESC criteria (84.2 vs 74.9 vs 80%,respectively, p < 0.001 for ISCVID vs ESC criteria) without significant loss of specificity (Table 2). After excluding cardiac surgery/pathology results, the 2023 Duke-ISCVID Clinical Criteria also had significantly better sensitivity than the modified Duke and ESC criteria, again without losing specificity. The changes in the 'major microbiological' and 'imaging' criteria had the most impact (Figure 1). Findings were robust in sensitivity analyses (Table 3). When classifying ‘definite’ and ‘possible’ IE as a positive test, the 2023 Duke-ISCVID criteria had 99% sensitivity compared to the reference standard, but specificity decreased to 21%.Table 2:Diagnostic accuracy of modified Duke, ESC and Duke-ISCVID criteria
Sensitivity and specificity are against the reference standard (adjudication panel). The Clinical Criteria classification is the Duke-ISCVID classification when results from surgery or post-mortem studies are not used to determine classification.Table 3:Sensitivity analyses of accuracy of Duke-ISCVID criteria
In the Definite + Possible analysis, patients with possible IE according to the Duke-ISCVID criteria were also considered as having IE. All comparisons are against the reference standard (adjudication panel).
Conclusion
In this cohort, the 2023 Duke-ISCVID criteria represent a significant advance in the diagnostic classification of patients suspected of IE.
Added value of new Duke-ISCVID criteria compared to modified Duke criteria
Each point (red square for sensitivity, blue circle for specificity) provides the diagnostic accuracy measure for the 2000 modified Duke Criteria with addition of a specific change from the Duke-ISCVID criteria. The horizontal bars represent the 95% confidence interval for the point estimate. The top points represent the modified Duke criteria without addition, the bottom points are the complete Duke-ISCVID criteria.
Disclosures
Larry M. Baddour, MD, Boston Scientific: Advisor/Consultant|Roivant Sciences: Advisor/Consultant Arnold S. Bayer, MD, Akagera Medicines: Grant/Research Support|ContraFect Corporation: Grant/Research Support Emanuele Durante Mangoni, MD,, PhD, Advanz pharma: Advisor/Consultant|Advanz pharma: Grant/Research Support|Advanz pharma: Honoraria|Angelini: Grant/Research Support|Angelini: Honoraria|Genentech: Advisor/Consultant|Genentech: Board Member|Genentech: Honoraria|Infectopharm: Grant/Research Support|Menarini: Board Member|Menarini: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Roche: Advisor/Consultant|Roche: Board Member|Roche: Honoraria Thomas L. Holland, MD, Aridis: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|Karius: Advisor/Consultant|Lysovant: Advisor/Consultant Adolf W. Karchmer, MD, Karius: Grant/Research Support|Up To Date: Honoraria Vance G. Fowler, MD, MHS, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, Astra Zeneca: Advisor/Consultant|Genentech, Regeneron, Deep Blue, Basilea, Janssen;: Grant/Research Support|Infectious Diseases Society of America: Honoraria|MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius;: Grant/Research Support|Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny,: Advisor/Consultant|Sepsis diagnostic: Patent pending|UpToDate: Royalties|Valanbio and ArcBio: Stock Options
Nitric oxide in exhaled air is thought to reflect airway inflammation. No data have been reported so far on circadian changes in NO in subjects with nocturnal asthma. To determine whether exhaled NO ...shows a circadian rhythm inverse to the circadian rhythm in airway obstruction in subjects with nocturnal asthma, we conducted a study involving six healthy controls, eight individuals without nocturnal asthma (4-h to 16-h variation in peak expiratory flow PEF <= 15%), and six individuals with nocturnal asthma (4-h to 16-h PEF variation > 15%). Smoking, use of corticosteroids, and recent respiratory infections were excluded. NO concentrations were measured at 12, 16, 20, and 24 h, and at 4, 8, and 12 h of the next day, using the single-breath method. At the same times, FEV1 and PEF were also measured. Mean NO concentrations were significantly higher in subjects with nocturnal asthma than in subjects without nocturnal asthma, and higher in both groups than in healthy controls at all time points. Mean exhaled NO levels over 24 h correlated with the 4-h to 16-h variation in PEF (r = 0.61, p < 0.01). Exhaled NO did not show a significant circadian variation in any of the three groups as assessed with cosinor analysis, in contrast to the FEV1 in both asthma groups (p < 0.05). At 4 h, mean +/- SD NO levels were higher than at 16 h in subjects with nocturnal asthma; at 50 +/- 20 ppb versus 42 +/- 15 ppb (p < 0.05); other measurements at all time points were similar. Differences in NO and FEV1 from 4 h to 16 h did not correlate with one another. We conclude that subjects with nocturnal asthma exhale NO at higher levels both at night and during the day, which may reflect more severe diurnal airway-wall inflammation. A circadian rhythm in exhaled NO was not observed. NO levels did not correspond to the circadian rhythm in airway obstruction. The small increase in NO at 4 h may indicate an aspect of inflammation, but it is not associated with increased nocturnal airway obstruction.
Background: Gender incongruent children report lower self-perception compared to the norm population. This study explored differences in self-perception between children living in their gender role ...assigned at birth and children living in their experienced gender role.
Method: The self-perception questionnaire was administered to 312 children referred to the Center of Expertise on Gender Dysphoria ‘Amsterdam UMC’. Social transition status was determined by parental interviews. 2 (social transition) by 2 (sex assigned at birth) ANCOVA’s were conducted.
Results: Children living in their assigned gender role reported comparable self-perception to children living in their experienced gender role. Birth assigned girls living in their assigned gender role reported poorer self-perception on ‘athletic competence’, compared to girls living in their experienced gender role. Birth assigned boys living in their assigned gender role reported poorer on ‘scholastic competence’ and ‘behavioral conduct’ compared to boys living in their experienced gender role.
Conclusions: Social transition did not show to affect self-perception. Self-perception was poorer for birth assigned boys living in their experienced gender role. For birth assigned girls this was reversed. Future studies should give more insight in the role of social transitions in relation to child development and focus on other aspects related to self-perception.
Abstract
The interplay between three-dimensional chromosome organisation and genomic processes such as replication and transcription necessitates in vivo studies of chromosome dynamics. Fluorescent ...organic dyes are often used for chromosome labelling in vivo. The mode of binding of these dyes to DNA cause its distortion, elongation, and partial unwinding. The structural changes induce DNA damage and interfere with the binding dynamics of chromatin-associated proteins, consequently perturbing gene expression, genome replication, and cell cycle progression. We have developed a minimally-perturbing, genetically encoded fluorescent DNA label consisting of a (photo-switchable) fluorescent protein fused to the DNA-binding domain of H-NS — a bacterial nucleoid-associated protein. We show that this DNA label, abbreviated as HI-NESS (H-NS-based indicator for nucleic acid stainings), is minimally-perturbing to genomic processes and labels chromosomes in eukaryotic cells in culture, and in zebrafish embryos with preferential binding to AT-rich chromatin.
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