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A century has passed since the 1918 influenza pandemic, the deadliest epidemic in human history, that killed 50–100 million people in a matter of months, causing more deaths than World War 1. Today, with influenza vaccinations available and established health-care systems, we might feel that the events and stories of the 1918 pandemic are distant from our everyday lives. Yet, the fear that a new pandemic could occur exists, and in our globalised world the risk of spread is extreme. Researchers and international health organisations are committed to constant investigation and surveillance to prevent such a risk from becoming a reality, but how have they reached this milestone?
Michael P Casaer, Greet Van den Berghe, Jan Gunst
Philipp Schuetz and colleagues1 should be applauded for investigating a multifaceted nutritional intervention in 2088 older patients who were acutely ill, continued beyond hospital discharge in 24% of intervention patients.1 Oral nutritional supplements substantially increased protein and caloric intake in the intervention group, with only 20 patients requiring enteral or parenteral nutrition.
Otake, T., Fujimoto, M., Hoshino, Y., Ishihara, T., Haneda, T., Okada, N., Miki, T.
The twin-arginine translocation (Tat) system is involved in not only a wide array of cellular processes but also pathogenesis in many bacterial pathogens; thus this system is expected to become a novel therapeutic target to treat infections. To the best of our knowledge, involvement of the Tat system has not been reported in the gut infection caused by Citrobacter rodentium. Here, we studied the role of Tat in C. rodentium gut infection, which resembles human infection with enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). A C. rodentium Tat loss-of-functional mutant displayed prolonged gut colonization, which was explained by reduced inflammatory responses and particularly neutrophil infiltration. Further, the Tat-mutant had colonization defects upon co-infection with the wild-type strain of C. rodentium. The Tat-mutant also became hypersensitive to bile acids, and an increase in fecal bile acids fostered C. rodentium clearance from the gut lumen. Finally, we show that the chain form of C. rodentium cells, induced by a Tat-dependent cell division defect, exhibits impaired resistance to bile acids. Our findings indicate that the Tat system is involved in gut colonization by C. rodentium, which is associated with neutrophil infiltration and resistance to bile acids. Interventions that target the Tat system, as well as luminal bile acids, might thus be promising therapeutic strategies to treat human EHEC and EPEC infections.
Srisaowakarn, C., Pudla, M., Ponpuak, M., Utaisincharoen, P.
Melioidosis is an infectious disease with a high mortality rate responsible for community-acquired sepsis in Southeast Asia and Northern Australia. The causative agent of this disease is Burkholderia pseudomallei, a gram-negative bacterium that resides in soil and contaminated natural water. After entering into host cells, the bacteria escape into the cytoplasm which has numerous cytosolic sensors, including the non-canonical inflammatory caspases. Although the non-canonical inflammasome (caspase-11) has been investigated in a murine model of B. pseudomallei infection, its role in human, particularly in lung epithelial cells, remains unknown. We, therefore, investigated the function of caspase-4 (ortholog of murine caspase-11) in intracellular killing of B. pseudomallei. The results showed that B. pseudomallei induced caspase-4 activation at 12 hr post-infection in human alveolar epithelial A549 cells. The number of intracellular B. pseudomallei was increased in the absence of caspase-4, suggesting its function in intracellular bacterial restriction. In contrast, a high level of caspase-4 processing was observed when cells were infected with LPS-mutant B. pseudomallei. The enhanced bacterial clearance in LPS mutant-infected cells is also correlated with a higher degree of caspase-4 activation. These results highlight the susceptibility of LPS mutant to the caspase-4-mediated intracellular bacterial killing.
Sunuwar, L., Yin, J., Kasendra, M., Karalis, K., Kaper, J., Fleckenstein, J., Donowitz, M.
Modeling host-pathogen interactions with human intestinal epithelia using enteroid monolayers on permeable supports (such as Transwells) represents an alternative to animal studies or use of colon cancer-derived cell lines. However, the static monolayer model does not expose epithelial cells to mechanical forces normally present in the intestine, including luminal flow and serosal blood flow (shear force) or peristaltic forces. To determine the contribution of mechanical forces in the functional response of human small intestine to a virulence factor of a pathogenic intestinal bacteria, human jejunal enteroids were cultured as monolayers in microengineered fluidic-based Organ-Chips (Intestine-Chips), exposed to enterotoxigenic E. coli heat-stable enterotoxin A (ST), and evaluated under conditions of static fluid, apical and basolateral flow, and flow plus repetitive stretch. Application of flow increased epithelial cell height, and apical and basolateral secretion of cGMP under baseline, unstimulated conditions. Addition of ST under flow conditions increased apical and basolateral secretion of cGMP relative to static conditions, but did not enhance intracellular cGMP accumulation. Cyclic stretch did not have any significant effect beyond that contributed by flow. This study demonstrates that fluid flow application initiates changes in intestinal epithelial cell characteristics relative to static culture conditions under both baseline conditions and with exposure to ST enterotoxin, and suggests that further investigations of application of these mechanical forces will provide insights into physiology and pathophysiology that more closely resembles intact intestine than study under static conditions.
Chakraborti, S., Gulati, S., Zheng, B., Beurskens, F. J., Schuurman, J., Rice, P. A., Ram, S.
The sialylatable lacto-N-neotetraose (LNnT; Gal-GlcNAc-Gal-Glc) moiety from heptose I (HepI) of the lipooligosaccharide (LOS) of Neisseria gonorrhoeae undergoes positive selection during human infection. Lactose (Gal-Glc) from HepII, although phase-variable, is commonly expressed in humans; loss of HepII lactose compromises gonococcal fitness in mice. Anti-LOS monoclonal antibody (mAb) 2C7, a promising anti-gonococcal immunotherapeutic that elicits complement-dependent bactericidal activity and attenuates gonococcal colonization in mice, recognizes an epitope that comprises lactoses expressed simultaneously from HepI and HepII. Glycan extensions beyond lactose on HepI modulate binding and function of mAb 2C7 in vitro. Here, four gonococcal LOS mutants, each with lactose from HepII, but fixed (unable to phase-vary) LOS HepI glycans extended beyond the lactose substitution of HepI (lactose alone, Gal-lactose, LNnT or GalNAc-LNnT) were used to define how HepI glycan extensions affect i) mouse vaginal colonization and ii) efficacy in vitro and in vivo of a human IgG1 chimeric derivative of mAb 2C7 (2C7-Ximab) with a ‘complement-enhancing’ E-to-G Fc mutation at position 430 (2C7-Ximab-E430G). About 10-fold lower 2C7-Ximab-E430G concentrations achieved similar complement-dependent killing of three gonococcal mutants with glycan extensions beyond lactose substituted HepI (the lactose alone, LNnT or GalNAc-LNnT) as 2C7-Ximab (unmodified Fc). The fourth mutant (Gal-lactose) resisted direct complement-dependent killing, but was killed approximately 70% by 2C7-Ximab-E430G in the presence of polymorphonuclear leukocytes and complement. Only mutants with (sialylatable) LNnT from HepI colonized mice for >3 days, reiterating the importance of LNnT sialylation for infection. 2C7-Ximab-E430G significantly attenuated colonization caused by the ‘virulent’ mutants.
Seman, B. G., Vance, J. K., Rawson, T. W., Witt, M. R., Huckaby, A. B., Povroznik, J. M., Bradford, S. D., Barbier, M., Robinson, C. M.
Neonates are at increased risk for bacterial sepsis. We established that the immune suppressive cytokine interleukin (IL)-27 is elevated in neonatal mice. Similarly, human cord blood-derived macrophages express IL-27 genes and secrete more cytokine than macrophages from adults. In the present work, we hypothesized that increased levels of IL-27 predispose neonatal mice to more severe infection during Gram-negative sepsis. Serum IL-27 levels continued to rise during infection. Peripheral tissue analysis revealed systemic IL-27 expression, while myeloid cell profiling identified Gr-1 and F4/80-expressing cells as the most abundant producers of IL-27 during infection. Increased IL-27 levels were consistent with increased mortality that was improved in IL-27-receptor α (Rα)-/- mice that lack a functional IL-27 receptor. Infected IL-27Rα-/- pups also exhibited improved weight gain and reduced morbidity. This was consistent with reduced bacterial burdens and more efficient bacterial killing by Ly6B.2+ myeloid cells and macrophages compared to WT neonates. Live animal imaging further supported a more severe and disseminated infection in WT neonates. This is the first report to describe the impact of elevated early life IL-27 on the host response in a neonatal infection model while also defining the cell and tissue sources of cytokine. IL-27 is frequently associated with suppressed inflammation. In contrast, our findings demonstrate that IL-27 indirectly promotes an inflammatory cytokine response during neonatal sepsis by directly compromising control of bacteria that drive the inflammatory response. Collectively, our results suggest that IL-27 represents a therapeutic target to limit susceptibility and improve infectious outcomes in neonatal sepsis.
Koprivsek, J. J., He, Y., Song, C., Zhang, N., Tumanov, A., Zhong, G.
Revealing the mechanisms by which bacteria establish long-lasting colonization in the gastrointestinal tract is an area of intensive investigation. The obligate intracellular bacterium Chlamydia is known to colonize mouse colon for long periods of time. A colonization-deficient mutant strain of this intracellular bacterium is able to regain long-lasting colonization in IFN knockout mice following an intracolon inoculation. We now report that mice deficient in conventional T lymphocytes or recombination activating gene (Rag) failed to rescue the mutant colonization. Nevertheless, antibody depletion of IFN or genetic deletion of IL-2 receptor common gamma chain in Rag deficient mice did rescue mutant colonization. These observations suggest that colonic IFN responsible for inhibiting the intracellular bacterium mutant is produced by innate lymphoid cells (ILCs). Consistently, depletion of NK1.1+ cells in Rag deficient mice both prevented IFN production and rescued the bacterium mutant colonization. Furthermore, mice deficient in transcriptional factor RORt, but not chemokine receptor CCR6, fully rescued the long-lasting colonization of the mutant, indicating that the role of group 3-like ILCs. However, the inhibitory function of the responsible group 3-like ILCs was not dependent on the natural killer cell receptor (NCR1) since NCR1-deficient mice still inhibited the mutant colonization. Consistently, mice deficient in the transcriptional factor T-bet only delayed the clearance of the bacterial mutant without fully rescuing the long-lasting colonization of the mutant. Thus, we have demonstrated that the obligate intracellular bacterium Chlamydia maintains its long-lasting colonization in the colon by evading IFN from group 3-like ILCs.
Navas, A., Fernandez, O., Gallego-Marin, C., del Mar Castro, M., Rosales-Chilama, M., Murillo, J., Cossio, A., McMahon-Pratt, D., Gore Saravia, N., Gomez, M. A.
The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by Leishmania Viannia sp. during standard of care treatment with pentavalent antimonials. We conducted a comparative expression profiling of immune response genes in peripheral blood mononuclear cells (PBMCs) and lesion biopsies obtained from CL patients before and at the end of treatment (EoT) with meglumine antimoniate. The ex vivo response of PBMCs to L. (V.) panamensis partially reflected that of lesion micro-environments. Significant down regulation of gene expression profiles consistent with local innate immune responses (monocyte and neutrophil activation and chemoattractant molecules) was observed at EoT in biopsies of patients who cured (n=8), compared to those from patients with treatment failure (n=8). Among differentially expressed genes, pre-treatment expression of CCL2 was significantly predictive of the therapeutic response (ROC curve AUC = 0.82, p=0.02). Polymorphisms in regulatory regions of the CCL2 promoter were analyzed in a pilot cohort of DNA samples from CL patients (cures n=20 and treatment failure n=20), showing putative association of rs13900(C/T) and rs2857656(G/C) with treatment outcome. Our data indicate that dampening gene expression profiles of monocyte and neutrophil activation characterize clinical cure after treatment of CL, supporting participation of parasite-sustained inflammation or deregulated innate immune responses in treatment failure.
Mangas, K. M., Buultjens, A. H., Porter, J. L., Baines, S. L., Marion, E., Marsollier, L., Tobias, N. J., Pidot, S. J., Quinn, K. M., Price, D. J., Kedzierska, K., Zeng, W., Jackson, D. C., Chua, B. Y., Stinear, T. P.
The neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl-reductase (ER) domain of the M. ulcerans mycolactone polyketide synthases electrostatically coupled with a previously described TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of a bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis Bacille Calmette-Guérin (BCG) were equally protected, with both groups faring significantly better than non-vaccinated animals (p
Padmanabhan, B., Fielden, L. F., Hachani, A., Newton, P., Thomas, D. R., Cho, H.-J., Khoo, C. A., Stojanovski, D., Roy, C. R., Scott, N. E., Newton, H. J.
Coxiella burnetii is an obligate intracellular bacterial pathogen that replicates inside the lysosome-derived Coxiella-containing vacuole (CCV). To establish this unique niche, C. burnetii requires the Dot/Icm type IV secretion system (T4SS) to translocate a cohort of effector proteins into the host cell that modulate multiple cellular processes. To characterize the host-pathogen interactions that occur during C. burnetii infection, SILAC based proteomics was used to identify changes in the host proteome during infection of a human-derived macrophage cell line. These data revealed that the abundance of many proteins involved in host cell autophagy and lysosome biogenesis were increased in infected cells. Thus, the role of host transcription factors TFEB and TFE3, which regulate the expression of a network of genes involved in autophagy and lysosomal biogenesis, were examined in the context of C. burnetii infection. During infection with C. burnetii, both TFEB and TFE3 were activated as demonstrated by transport of these proteins from the cytoplasm into the nucleus. Nuclear translocation of these transcription factors was shown to be dependent on the T4SS as a Dot/Icm mutant showed reduced nuclear translocation of TFEB and TFE3. This was supported by the observation that blocking bacterial translation with chloramphenicol resulted in the movement of TFEB and TFE3 back into the cytoplasm. Silencing of tfeb and tfe3, alone or in combination, significantly reduced the size of the CCV, which indicates that these host transcription factors facilitate expansion and maintenance of the organelle that supports C. burnetii intracellular replication.
Demontès M, Eymard Duvernay S, Allavena C, et al.
AbstractObjectiveWe assessed prevalence of multimorbidity (MM) according to year of HIV diagnosis in people living with HIV (PLHIV) of geriatric age.DesignCross-sectional study of MM in PLHIV over 70 years old from the Dat’AIDS French multicentric cohort. MM was defined as at least three co-existent morbidities of either high blood pressure (HBP), diabetes mellitus, osteoporosis, non-AIDS cancer, chronic renal failure, cardio and cerebrovascular disease, obesity, cachexia or hypercholesterolemia. Logistic regression models evaluated the association between MM and calendar periods of HIV-diagnosis (1983-1996, 1997-2006 and 2007-2018). The secondary analysis evaluated MM as a continuous outcome and a sensitivity analysis excluded PLHIV with nadir TCD4 cells < 200 cells/mm3.ResultsBetween January 2017 and September 2018, 2476 PLHIV were included. Median age was 73 years old, 75% were men, median CD4 was 578 cells/mL, and 94% had controlled viremia. MM prevalence was 71%. HBP and hypercholesterolemia were the most prevalent comorbidities. After adjustment for age, gender, smoking status, HCV, HBV co-infection, group of exposure, nadir CD4, and CD4:CD8 ratio and last CD4 levels, calendar periods of diagnosis was not associated with MM (p=0.169). MM was associated with older age, CD4/CD8 ratio < 0.8 and nadir CD4 cells < 200 cells/mL. Similar results were found with secondary and sensitivity analyses.ConclusionMM prevalence was high and increased with age, low CD4/CD8 ratio and nadir CD4 cells < 200mm3 but was not associated with calendar periods of HIV-diagnosis. Known duration of HIV-diagnosis does not seem a criterion for selecting elderly PLHIV at risk of MM.
Peragine C, Walker S, Simor A, et al.
AbstractBackgroundAntimicrobial Resistance (AMR) constitutes an international public health threat widely believed to result from excessive antimicrobial use (AMU). Numerous authorities have recommended Antimicrobial Stewardship Programs (ASP) to curb the selection of AMR but, there is a lack of data confirming this benefit.MethodsA controlled interrupted time series study spanning 14-years was performed to assess impact of a comprehensive hospital-based ASP that included pharmacist-led audit-and-feedback on institutional AMR. Patient-level microbiologic and AMU data were obtained from October 2002 to September 2016. Poisson regression models were used to identify changes in the incidence and trend of hospital-acquired (HA-) Antibiotic Resistant Organisms (ARO) and Multidrug-Resistant Organisms (MDRO). Changes in community-acquired (CA-) ARO, CA-MDRO, and inpatient AMU were assessed as controls and process outcomes.ResultsStatistically significant shifts in AMU, HA-ARO, and HA-MDRO trends coinciding with ASP implementation were observed, corresponding with a 9% reduction in HA-ARO burden (IRR 0.91, 95%CI 0.83–0.99; p=0.03) and 13% reduction in HA-MDRO burden (IRR 0.87, 95% CI 0.73–1.04; p=0.13) in the intervention period. In contrast, CA-ARO and CA-MDRO incidence continued to rise with 40% (CA-ARO IRR 1.40, 95%CI 1.28–1.54; p
Bottichio L, Keaton A, Thomas D, et al.
AbstractBackgroundProduce-associated outbreaks of Shiga toxin-producing Escherichia coli (STEC) were first identified in 1991. In April 2018, New Jersey and Pennsylvania officials reported a cluster of STEC O157 infections associated with multiple locations of a restaurant chain. CDC queried PulseNet, the national laboratory network for foodborne disease surveillance, for additional cases and began a national investigation.MethodsA case was defined as an infection between March 13 and August 22, 2018 with one of the 22 identified outbreak-associated E. coli O157:H7 or E. coli O61 pulsed-field gel electrophoresis pattern combinations, or with a strain STEC O157 that was closely related to the main outbreak strain by whole genome sequencing. We conducted epidemiologic and traceback investigations to identify illness sub-clusters and common sources. An FDA-led environmental assessment, which tested water, soil, manure, compost, and scat samples, was conducted to evaluate potential sources of STEC contamination.ResultsWe identified 240 case-patients from 37 states; 104 were hospitalized, 28 developed hemolytic uremic syndrome, and five died. Of 179 people who were interviewed, 152 (85%) reported consuming romaine lettuce in the week before illness onset. Twenty sub-clusters were identified. Product traceback from sub-cluster restaurants identified numerous romaine lettuce distributors and growers; all lettuce originated from the Yuma growing region. Water samples collected from an irrigation canal in the region yielded the outbreak strain of STEC O157.ConclusionWe report on the largest multistate leafy green-linked STEC O157 outbreak in several decades. The investigation highlights the complexities associated with investigating outbreaks involving widespread environmental contamination.
Merchante N, Saroli Palumbo C, Mazzola G, et al.
AbstractBackgroundHuman immunodeficiency virus (HIV)-infected individuals are at increased risk of cirrhosis and esophageal varices. Baveno VI criteria, based on liver stiffness measurement (LSM) and platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for esophageal varices needing treatment (EVNT). This approach has not been validated in HIV-infected patients.MethodsHIV-infected patients from eight prospective cohorts were included if they fulfilled the following criteria: 1) compensated advanced chronic liver disease (LSM >10 kPa); 2) availability of EGD within 6 months of reliable LSM. Baveno VI (LSM 150,000), expanded Baveno VI (LSM 110,000) and HEPAVIR criteria (LSM 110,000 and LSM
Buehrle D, Shively N, Wagener M, et al.
AbstractBackgroundMost antibiotic prescribing is in outpatient settings. However, antibiotic stewardship has focused overwhelmingly on hospitalized patients. In a few studies, behavioral interventions decreased unnecessary outpatient prescribing against acute respiratory infections, but data are conflicting on sustained benefits after intervention discontinuation.MethodsWe conducted a prospective, observational study in 7 primary care clinics, in which an intervention comprised of clinician education, peer comparisons and computer decision support order sets was directed against all antibiotic prescribing. After 6 months, peer comparisons were discontinued. Antibiotic prescribing was compared in baseline (January-June 2016), intervention (January-June 2017), and post-intervention (January-June 2018) periods.ResultsMean antibiotic prescriptions significantly decreased from 76.9 (baseline) to 49.5 (intervention) and 56.3 (post-intervention) per 1,000 visits (35.6% and 26.8% reductions, respectively; p-values
Kendall E, Malhotra S, Cook-Scalise S, et al.
AbstractBackgroundMany candidate regimens for universal treatment of tuberculosis combine novel and existing, widely-used drugs. Appropriate implementation requires evidence-based, context-specific drug-susceptibility testing (DST) strategies.MethodsWe created a Markov state-transition model of 100,000 adults with TB receiving a novel, fluoroquinolone (FQ)-containing regimen. We estimated clinical outcomes and resource utilization with no FQ-DST, universal use of FQ-DST, or FQ-DST only in patients with rifampin-resistant TB (‘targeted FQ-DST’). We considered scenarios of stronger (South Africa) and weaker (Southeast Asia) correlation of fluoroquinolone resistance with rifampin resistance.ResultsRelative to no FQ-DST, targeted FQ-DST increased cure of FQ-resistant TB by 7.5% (interquartile range 6.7-9.2%) in South Africa and 1.7% (0.7 -2.5%) in Southeast Asia. However, rare FQ resistance among the more-prevalent rifampin-susceptible TB accounted for 50% of FQ-resistant TB in South Africa and 83% in Southeast Asia. As a result, universal FQ-DST further increased cure of FQ-resistant TB by 3.4% (2.3-5.4%) in South Africa and 5.8% (5.1-6.3%) in Southeast Asia. With targeted FQ-DST, one additional patient was cured per 50 (42-70) tests in South Africa and 44 (37-51) in Southeast Asia. When expanding from targeted to universal FQ-DST, one additional cure required 3500 (2300-5500) tests in South Africa and 410 (370-450) in Southeast Asia. The impact of FQ-DST was sensitive to overall treatment effectiveness, regimen robustness to loss of fluoroquinolone activity, and prevalence of both moxifloxacin and pyrazinamide resistance.ConclusionsFQ-DST improved patient outcomes and was particularly important for high-risk patient groups and less-robust regimens. A universal strategy was favored in generalized epidemics of fluoroquinolone resistance.
Robertson M, Braunstein S, Hoover D, et al.
AbstractBackgroundWe estimated the time from HIV seroconversion to ART initiation in a population-based sample of people diagnosed with HIV during an era of expanding HIV testing and treatment efforts.MethodsApplying CD4 depletion model parameters from seroconverter cohort data to our population-based sample, we related the square root of the first pre-treatment CD4 count to time of serconversion though a linear mixed model and estimated the time from seroconversion to diagnosis and ART initiation.ResultsAmong 28,162 people diagnosed with HIV during 2006-2015, 89% initiated ART by June 2017. The median CD4 count at diagnosis increased from 326 (Interquartile range (IQR):132-504) to 390 (IQR:216-571) cells/µL from 2006-2015. The median time from estimated seroconversion to ART initiation decreased by 42% from 6.4 years (IQR:3.3-11.4) in 2006 to 3.7 years (IQR:0.5-8.3) in 2015. Contributing to the reduction in time to ART initiation, the time from estimated seroconversion to diagnosis decreased by 28%, from a median of 4.6 years (IQR:0.5-10.5) to 3.3 years (IQR:0-8.1) from 2006-2015, and the time from diagnosis to ART initiation reduced by 60%, from a median of 0.5 years (IQR:0.2-2.1) to 0.2 years (IQR:0.1-0.3) from 2006-2015.ConclusionsThe estimated time from seroconversion to ART initiation was reduced in tandem with expanded HIV testing and treatment efforts. While the time from diagnosis to ART initiation decreased to a median of 0.2 years, the time from seroconversion to diagnosis was 3.3 years among people diagnosed in 2015, highlighting the need for more effective strategies for earlier HIV diagnosis.
The cytokine gene polymorphism is important for the genetic susceptibility of infectious diseases. The aim of the present study was to investigate the relationship between TNF-α, IL-12, and IL-13 gene polymorphisms and predisposition to brucellosis.
In this study, 107 patients with brucellosis and 107 healthy individuals were evaluated. The SNPs of TNF-α)- 238 G/A) and IL-12 (+ 1188 A/C) were done by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and IL-13 genotyping at positions − 1512 (A/C) and − 1112 (C/T) were analysis by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. IL-12, IL-13 and TNF-α serum levels were measured by a sandwich enzyme-linked immunosorbent assay (ELISA).
IL-13 (−1512A/C) was associated with Brucellosis risk in dominant model (OR (95% CI) = 2.17 (1.02–4.62)), P-value = 0.041. However, there was no difference in allele and genotype frequencies of TNF-α)- 238 G/A), IL-12 (+ 1188 A/C) and IL-13 [− 1512 (A/C) and − 1112 (C/T)] between patients and controls. Serum levels of IL-12 and TNF-α were significantly more frequent in the patients than in the control groups.
The IL-13 gene polymorphism can be used as a biomarker for detecting susceptibility to Brucella disease.
Shigella spp. and entero-invasive E. coli (EIEC) use the same invasive mechanism to cause diarrheal diseases. Public health regulations apply only to Shigella spp. infections, but are hampered by the lack of simple methods to distinguish them from EIEC. In the last decades, molecular methods for detecting Shigella spp. and EIEC were implemented in medical microbiological laboratories (MMLs). However, shigellosis cases identified with molecular techniques alone are not notifiable in most countries. Our study investigates the impact of EIEC versus Shigella spp. infections and molecular diagnosed shigellosis versus culture confirmed shigellosis for re-examination of the rationale for the current public health regulations.
In this multicenter cross-sectional study, fecal samples of patients suspected for gastro-enteritis, referred to 15 MMLs in the Netherlands, were screened by PCR for Shigella spp. or EIEC. Samples were cultured to discriminate between the two pathogens. We compared risk factors, symptoms, severity of disease, secondary infections and socio-economic consequences for (i) culture-confirmed Shigella spp. versus culture-confirmed EIEC cases (ii) culture positive versus PCR positive only shigellosis cases.
In 2016–2017, 777 PCR positive fecal samples with patient data were included, 254 of these were culture-confirmed shigellosis cases and 32 were culture-confirmed EIEC cases. EIEC cases were more likely to report ingestion of contaminated food and were less likely to be men who have sex with men (MSM). Both pathogens were shown to cause serious disease although differences in specific symptoms were observed. Culture-negative but PCR positive cases were more likely report travel or ingestion of contaminated food and were less likely to be MSM than culture-positive cases. Culture-negative cases were more likely to suffer from multiple symptoms. No differences in degree of secondary infections were observed between Shigella spp. and EIEC, and culture-negative and culture-positive cases.
No convincing evidence was found to support the current guidelines that employs different measures based on species or detection method. Therefore, culture and molecular detection methods for Shigella spp. and EIEC should be considered equivalent for case definition and public health regulations regarding shigellosis. Differences were found regarding risks factors, indicating that different prevention strategies may be required.
Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated.
We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC).
Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to TB at 2nd month and 6th month of anti-TB treatment (ATT). RAGE ligands were increased in TB-DM individuals with bilateral and cavitary disease. sRAGE and S100A12 correlated with glycated hemoglobin levels. Within the TB-DM group, those with known diabetes (KDM) revealed significantly increased levels of AGE and sRAGE compared to newly diagnosed DM (NDM). KDM participants on metformin treatment exhibited significantly diminished levels of AGE and sRAGE in comparison to those on non-metformin regimens.
Our data demonstrate that RAGE ligand levels reflect disease severity and extent in TB-DM, distinguish KDM from NDM and are modulated by metformin therapy.
To investigate the risk factors for brucellosis in suspected cases of the disease.
A self-designed questionnaire was developed to collect data from 3557 people whose initial visit site was the Songyuan Center for Disease Control and Prevention (CDC) from January 1st, 2009 to December 31st, 2012. After collecting blood samples, a plate agglutination test (PAT) and serum agglutination test (SAT) were used to distinguish the patients with brucellosis from the suspected cases.
Sex, occupation (farmers and herdsmen), contact with abortion products, and contact with feces were the main risk factors for brucellosis in the suspected cases (all P
Rhoden, E., Ng, T. F. F., Campagnoli, R., Nix, W. A., Konopka-Anstadt, J., Selvarangan, R., Briesach, L., Oberste, M. S., Weldon, W. C.
Viruses in species Parechovirus A (Picornaviridae) are associated with a wide variety of clinical manifestations. Parechovirus A3 (PeV-A3) is known to cause sepsis-like illness, meningitis, and encephalitis in infants and young children. To date, no specific therapies are available to treat PeV-A3-infected children. We had previously identified two FDA-cleared antifungal drugs, itraconazole (ITC) and posaconazole (POS) with potent and specific antiviral activity against PeV-A3. Time-of-addition and synchronized infection assays revealed that POS targets an early stage of the PeV-A3 life cycle. POS exerts an antiviral effect, evidenced by a reduction in viral titer following the addition of POS to Vero-P cells before infection, coaddition of POS and PeV-A3 to Vero-P cells, incubation of POS and PeV-A3 prior to Vero-P infection, and at attachment. POS exerts less of an effect on virus entry. A PeV-A3 ELISA inhibition experiment, using an anti-PeV-A3 monoclonal antibody (mAb), suggested that POS binds directly to the PeV-A3 capsid. POS-resistant PeV-A3 strains developed by serial passage in the presence of POS, acquired substitutions in multiple regions of the genome, including the capsid. Reverse genetics confirmed substitutions in capsid proteins VP0, VP3, VP1 and nonstructural proteins 2A and 3A. Single mutants VP0_K66R, VP0_A124T, VP3_N88S, VP1_Y224C, 2A_S788L and 3A_T1I were respectively 4-, 9-, 12-, 34-, 51-, and 119-fold more resistant to POS than its susceptible prototype strain. Our studies demonstrate that POS may be a valuable tool in developing an antiviral therapy for PeV-A3.
Tsolaki, V., Mantzarlis, K., Mpakalis, A., Malli, E., Tsimpoukas, F., Tsirogianni, A., Papagiannitsis, K., Zygoulis, P., Papadonta, M.-E., Petinaki, E., Makris, D., Zakynthinos, E.
Data on the effectiveness of ceftazidime-avibactam (CAZ-AVI) in critically ill, mechanically ventilated patients are limited. The present retrospective observational cohort study, which was conducted in two general Intensive Care Units (ICUs) in central Greece, compared critically-ill, mechanically ventilated patients suffering from carbapenem-resistant enterobacteriaceae (CRE) infections receiving CAZ-AVI to patients who received appropriate available antibiotic therapy. Clinical, microbiological outcomes and safety issues were evaluated. A secondary analysis in patients with blood stream infections (BSI) was conducted. Forty-one patients that received CAZ-AVI (CAZ-AVI group) were compared to thirty-six patients receiving antibiotics other than CAZ-AVI (control group). There was significant improvement in the SOFA score on Day 4 and 10 in the CAZ-AVI compared to the control group (p=0.006, and p=0.003 respectively). Microbiological eradication was accomplished in 33/35 (94.3%) in CAZ-AVI group vs 21/31 (67.7%) patients in control group (p=0.021) and clinical cure was observed in 33/41 (80.5%) vs 19/36 (52.8%) patients (p=0.010), respectively. The results were similar in BSI subgroups for both outcomes (p=0.038 and p=0.014, respectively). 28-day survival was 85.4% in the CAZ-AVI and 61.1% in the control group (log Rank=0.035), while there were 2 and 12 relapses in each group (p=0.042). A CAZ-AVI containing regime was independent predictor of survival and clinical cure (OR 5.575, p=0.012 and OR 5.125, p=0.004, respectively) along with illness severity. In conclusion, no significant side effects were reported. A CAZ-AVI containing regime is more effective than other available antibiotic agents for the treatment of CRE infections in the high-risk, mechanically-ventilated, ICU population.
Asempa, T. E., Abdelraouf, K., Carabeo, T., Schuch, R., Nicolau, D. P.
We evaluated the efficacy of escalating doses of exebacase administered with sub-therapeutic daptomycin exposures against 8 Staphylococcus aureus isolates in a neutropenic murine thigh infection model. Daptomycin alone resulted in mean growth of 0.39 ± 1.19 log10CFU/thigh. Administered in addition to daptomycin, exebacase resulted in a mean log10 CFU/thigh reduction of -1.03 ± 0.72 (range: -0.77 ± 0.98 to -1.20 ± 0.59) across evaluated doses (15 to 90 mg/kg), indicative of potential in vivo synergy.
Lai, J. C. Y., Svedin, P., Ek, C. J., Mottahedin, A., Wang, X., Levy, O., Currie, A., Strunk, T., Mallard, C.
Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis, we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult. Currently, there is no neuroprotective treatment for the preterm population. Hence, we tested the neuroprotective effects of vancomycin, with and without adjunct therapy using the anti-inflammatory agent pentoxifylline. We characterized the effects of S. epidermidis infection on the inflammatory response in the periphery and the brain, as well as the physiological changes in the central nervous system that might affect neurodevelopmental outcomes. Intraperitoneal injection of postnatal day 4 mice with a live clinical isolate of S. epidermidis led to bacteremia, induction of pro-inflammatory cytokines in the blood, as well as transient elevations of neutrophil and monocyte chemotactic cytokines and caspase-3 activity in the brain. When hypoxia-ischemia was induced post infection, more severe brain damage was observed in infected animals compared to saline injected controls. This infection-induced inflammation and potentiated brain injury was inoculum dose-dependent and alleviated with the antibiotic vancomycin. Pentoxifylline did not provide any additional neuroprotective effect. Thus, we show for the first time that live S. epidermidis, potentiates hypoxic-ischemic preterm brain injury and that peripheral inhibition of inflammation with antibiotics, such as vancomycin, reduces the extent of brain injury.
Darcis, G., Maes, N., Pasternak, A. O., Sauvage, A.-S., Frippiat, F., Meuris, C., Uurlings, F., Lecomte, M., Leonard, P., Elmoussaoui, M., Fombellida, K., Vaira, D., Moutschen, M.
Background: HIV persistence despite therapy contributes to chronic immune activation and inflammation, increasing the risk of aging-associated events in HIV-infected individuals.Objectives: To better understand the complex link between clinical and treatment features and HIV persistence despite therapy.Methods: 11045 samples from 1160 individuals under combination antiretroviral therapy (cART) with unquantifiable viral load (VL, limit of quantification: 20 copies/ml) were categorized as detectable or undetectable depending on the detection of a PCR signal using a commercially available assay. Generalized estimating equations regression was used to model viral load detectability and to assess determinants of residual viremia (RV: VL detected below 20 copies/ml) despite therapy.Results: High VL zenith was associated with a higher probability to have a detectable viremia under cART. Conversely, the probability to have a detectable viral load below 20 copies/ml decreased with time under therapy. Of therapy regimens, protease inhibitor (PI)-based cART was associated with a significantly higher probability of detectable RV compared to non-nucleoside transcriptase inhibitor- or integrase inhibitor-based cART.Conclusions: PI-based treatment regimen is highly associated with an increased frequency of RV, supporting the previous evidence suggesting that PI-based cART regimens could favor ongoing viral replication in some individuals.
Ramirez, S., Fernandez-Antunez, C., Mikkelsen, L. S., Pedersen, J., Li, Y.-P., Bukh, J.
Introduction of highly efficient therapies with direct-acting antivirals (DAA) for patients with chronic hepatitis C virus (HCV) infection offers exceptional opportunities to globally control this deadly disease. For achieving this ambitious goal, it is essential to prevent antiviral resistance against the most optimal first-line and retreatment DAA choices. We performed independent comparisons of the efficacy and barrier to resistance of pangenotypic DAA regimens for HCV genotype 2 infections, using previously, and newly developed efficient cell culture adapted strains of subtypes 2a, 2b and 2c. With applied experimental cell culture conditions, combination treatment with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir DAA-regimens was efficient in eradicating HCV infections, in contrast to single drug treatments frequently leading to viral escape. Sequence analysis of drug targets from recovered viruses revealed known resistance associated substitutions (RAS) emerging in the NS3 protease or NS5A after treatment failure, which were genetically stable after viral passage and exhibited significant phenotypic resistance. After sofosbuvir treatment failure, only a genotype 2a virus harbored NS5B-RAS S282T and thus had decreased susceptibility to nucleotide analogs (nucs). However, in most cases viral escape from sofosbuvir led to other NS5B substitutions with maintained drug susceptibility, and in one case no changes in NS5B were detected. For a genotype 2b virus, after treatment failure with sofosbuvir/velpatasvir, retreatment with glecaprevir/pibrentasvir maintained efficacy due to the high barrier to resistance and low cross-resistance of pibrentasvir. Our findings suggest slight superiority of glecaprevir/pibrentasvir for genotype 2b in culture, which could have potential therapeutic interest meriting more definitive investigations in the clinic.
Hamdi, A. M., Fida, M., Deml, S. M., Abu Saleh, O. M., Wengenack, N. L.
Nocardia species are found worldwide and are opportunistic pathogens of both immunocompromised and immunocompetent hosts. Recent updates to the taxonomy of this genus have indicated that there are more than 90 recognized species of Nocardia with 54 species reported to be clinically relevant. In this paper, we report the species distribution, specimen source distribution, and antimicrobial susceptibility profiles of 2,091 clinical isolates recovered for the years 2011 to 2017 using the updated taxonomy. The most commonly isolated species included Nocardia nova complex, Nocardia cyriacigeorgica, and Nocardia farcinica complex, with an additional 25 species or species complexes recovered from clinical specimens. The antimicrobial susceptibility profile was highly variable between the species but in general, amikacin, linezolid, and trimethoprim-sulfamethoxazole demonstrated good in vitro activity against most species.
Sonnabend, M. S., Klein, K., Beier, S., Angelov, A., Kluj, R., Mayer, C., Gross, C., Hofmeister, K., Beuttner, A., Willmann, M., Peter, S., Oberhettinger, P., Schmidt, A., Autenrieth, I. B., Schütz, M., Bohn, E.
With the aim to identify potential new targets to restore antimicrobial susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa (Pa), we generated a high-density transposon (Tn) insertion mutant library in a MDR Pa bloodstream isolate (ID40). The depletion of Tn insertion mutants upon exposure to cefepime or meropenem was measured in order to determine the common resistome for these clinically important antipseudomonal β-lactam antibiotics. The approach was validated by clean deletions of genes involved in peptidoglycan synthesis/recycling such as the lytic transglycosylase MltG, the murein endopeptidase MepM1, the MurNAc/GlcNAc-kinase AmgK and the uncharacterized protein YgfB that all were identified in our screen as playing a decisive role for survival of treatment with cefepime or meropenem. We found that the antibiotic resistance of Pa can be overcome by targeting usually non-essential genes that turn essential in the presence of therapeutic concentrations of antibiotics. For all validated genes, we demonstrated that their deletion leads to the reduction of ampC expression, resulting in a significant decrease of β-lactamase activity and consequently these mutants partly or completely lost resistance against cephalosporins, carbapenems and acylaminopenicillins. In summary, the determined resistome may comprise promising targets for developing drugs that could be used to restore the sensitivity towards existing antibiotics specifically in MDR strains of Pa.
Alkhazraji, S., Gebremariam, T., Alqarihi, A., Gu, Y., Mamouei, Z., Singh, S., Wiederhold, N. P., Shaw, K. J., Ibrahim, A. S.
There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium. Manogepix (MGX, APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 μg/ml, and 0.015 - 0.03 μg/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 and 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-live of MGX, significantly increased median survival time vs. placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in a ~2 log10 reduction in lung, kidney or brain conidial equivalents/gram (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg of fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2-3 log10 reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data with target organs showing reduced or no abscesses in fosmanogepix treated mice. The survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B dose (10-15 mg/kg). Our data support the continued development of fosmanogepix as a first in class treatment for infections caused by these rare molds.
Wong, F. H.-S., Cai, Y., Leck, H., Lim, T.-P., Teo, J. Q.-M., Lee, W., Koh, T. H., Tan, T. T., Tan, K. W., Kwa, A. L.-H.
Polymyxin B-based combinations are increasingly prescribed as a last-line option against extensively-drug resistant Acinetobacter baumannii (XDRAB). It is unknown if such combinations can result in the development of non-dividing persister cells in XDRAB. We investigated persister development upon exposure of XDRAB to polymyxin B-based antibiotic combinations using flow cytometry. Time-kill studies (TKS) were conducted in three non-clonal XDRAB strains with 5log10 CFU/ml bacteria against polymyxin B alone and in polymyxin-B based two-drug combinations over 24h. At different time-points, samples were obtained and enumerated by viable plating and flow cytometry. Propidium iodide and carboxyfluorescein succinimidyl ester dyes were used to differentiate between live/dead cells and dividing/non-dividing cells respectively at the single-cell level, and non-dividing live cells were resuscitated and characterized phenotypically. Our results in viable plating showed that polymyxin B + meropenem and polymyxin B + rifampicin were each bactericidal (>99.9% kill compared to initial inoculum) against 2/3 XDRAB strains in viable plating at 24h. In flow cytometry, however, none of the combinations were bactericidal against the XDRAB at 24h. Further analysis using cellular dyes in flow cytometry revealed that upon exposure to polymyxin B-based combinations, the XDRAB entered a viable but non-dividing persister state. These bacterial cells re-initiated division upon removal of antibiotic pressure, and did not have growth deficit compared to the parent strain. We conclude that persister cells develops in XDRAB upon exposure to polymyxin-B based combinations, and that non-plating methods appear to complement viable plating methods in describing the killing activity of polymyxin-B based combinations against XDRAB.
Torres, S. R., Pichowicz, A., Torres-Velez, F., Song, R., Singh, N., Lasek-Nesselquist, E., De Jesus, M.
Candida auris has become a global public health threat due to its multidrug resistance and persistence. Currently, there are limited murine models to study C. auris infection. These models use a combination of cyclophosphamide and cortisone acetate that suppress both innate and adaptive immunity. Here we compare C. auris infection in two neutrophil depleted (ND) murine models, where innate immunity is targeted using the monoclonal antibodies 1A8 and RB6-8C5.
Scangarella-Oman, N. E., Ingraham, K. A., Tiffany, C. A., Tomsho, L., Van Horn, S. F., Mayhew, D. N., Perry, C. R., Ashton, T. C., Dumont, E. F., Huang, J., Brown, J. R., Miller, L. A.
A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12h [q12h], 1,000 mg q12h, and 1,000 mg every 8h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA) and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the 750-mg q12h group, 89% for the gepotidacin 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 μg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N,both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial.
Onyamboko, M. A., Hoglund, R. M., Lee, S. J., Kabedi, C., Kayembe, D., Badjanga, B. B., Turner, G. D. H., Jackson, N. V., Tarning, J., McGready, R., Nosten, F., White, N. J., Day, N. P. J., Fanello, C.
Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 non-pregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth, 1, 3, 6 and 12 months. Nonlinear mixed-effects modelling was used to characterise the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range]: 3.30 [1.39-7.83] hours) compared to non-pregnant women (2.43 [1.05-6.00] hours), p=0.005. Pregnant women had lower exposures to artemether and dihydroartemisinin compared to non-pregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to non-pregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and non-pregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure, and so could be a promising treatment option in pregnancy in areas with lower malaria transmission and/or emerging drug resistance (http://www.clinicalTrials.gov/;NCT 01916954).
Specialespecifikt kursus om immundefekt og feber af ukendt årsag
28.01.2020 - 29.01.2020
International Congress on Infectious Diseases (ICID) 2020
Kuala Lumpur, Malaysia
20.02.2020 - 23.02.2020
Dansk Selskab for Intern Medicin (DSIM) årsmøde og overrækkelse af Hagedorn prisen 2020
Novo Nordisk Fonden, Tuborg Havnevej 19, 2900 Hellerup
Conference on Retroviruses and Opportunistic Infections (CROI) 2020
Boston, Massachusetts, USA
8.03.2020 - 11.03.2020
Når CROI går i fisk - med transmissioner fra CROI 2020
10.03.2020 - 11.03.2020
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
Single dose of Doxycycline for the prevention of TBRF
19.01.2020Clinical Infectious Diseases Advance Access
Characteristics of invasive pneumococcal disease (IPD) caused by emerging serotypes after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in England; prospective observational cohort study, 2014-18
19.01.2020Clinical Infectious Diseases Advance Access
The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial
17.01.2020Latest Results for BMC Infectious Diseases
Fatal hemorrhagic varicella in a patient with abdominal pain: a case report
17.01.2020Latest Results for BMC Infectious Diseases
Antifungal resistance in patients with Candidaemia: a retrospective cohort study
17.01.2020Latest Results for BMC Infectious Diseases
Hvad synes Professor Jens Lundgren om"Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV."?
Hvad synes Professor Troels Lillebæk om"The global prevalence of latent tuberculosis: a systematic review and meta-analysis."?
Hvorfor anbefaler Professor Lars Østergaard artiklen"Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial."?
Hvad mener Professor Thomas Benfield om artiklen"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvad tænker Professor Niels Obel om"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
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