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Biannual mass azithromycin administration to preschool children reduces all-cause mortality, but the mechanism for the effect is not understood. Azithromycin has activity against malaria parasites, and malaria is a leading cause of child mortality in the Sahel. The effect of biannual versus annual azithromycin distribution for trachoma control on serological response to merozoite surface protein 1 (MSP-119), a surrogate for malaria incidence, was evaluated among children in Niger.
Markers of malaria exposure were measured in two arms of a factorial randomized controlled trial designed to evaluate targeted biannual azithromycin distribution to children under 12 years of age compared to annual azithromycin to the entire community for trachoma control (N = 12 communities per arm). Communities were treated for 36 months (6 versus 3 distributions). Dried blood spots were collected at 36 months among children ages 1–5 years, and MSP-119 antibody levels were assessed using a bead-based multiplex assay to measure malaria seroprevalence.
Antibody results were available for 991 children. MSP-119 seropositivity was 62.7% in the biannual distribution arm compared to 68.7% in the annual arm (prevalence ratio 0.91, 95% CI 0.83 to 1.00). Mean semi-quantitative antibody levels were lower in the biannual distribution arm compared to the annual arm (mean difference − 0.39, 95% CI − 0.05 to − 0.72).
Targeted biannual azithromycin distribution was associated with lower malaria seroprevalence compared to that in a population that received annual distribution.
Trial Registration Clinicaltrials.gov NCT00792922
Malaria is known to contribute to reduction in productivity through absenteeism as worker-hours are lost thus impacting company productivity and performance. This paper analysed the impact of malaria on productivity in a banana plantation through absenteeism.
This study was carried out at Matanuska farm in Burma Valley, Zimbabwe. Raw data on absenteeism was obtained in retrospect from the Farm Manager. Malaria infection was detected using malaria Rapid Diagnostic Test. Measures of absence from work place were determined and included; incidence of absence (number of absentees divided by the total workforce), absence frequency (number of malaria spells), frequency rate (number of spells divided by the number of absentees), estimated duration of spells (number of days lost due to malaria), severity rate (number of days lost divided by number of spells), incapacity rate (number of days lost divided by the number of absentees), number of absent days (number of spells times the severity rate), number of scheduled working days (actual working days in 5 months multiplied by total number of employees), absenteeism rate.
A total of 143 employees were followed up over a 5-month period. Malaria positivity was 21%, 31.5%, 44.8%, 35.7% and 12.6% for January 2014 to May 2014, respectively. One spell of absence [194 (86.6%)] was common followed by 2 spells of absence [30 (13.4%)] for all employees. Duration of spells of absence due to malaria ranged from 1.5 to 4.1 working-days, with general workers being the most affected. Incidence of absence was 143/155 (93.3%), with total of spells of absence of over a 5-month period totalling 224. The frequency rate of absenteeism was 1.6 with severity rate of absence being 2.4. and incapacity rate was 3.7.
Malaria contributes significantly to worker absenteeism. Employers, therefore, ought to put measures that protect workers from malaria infections. Protecting workers can be done through malaria educative campaigns, providing mosquito nets, providing insecticide-treated work suits, providing repellents and partnering with different ministries to ensure protection of workers from mosquito bites.
Muhammad Suleman Rana,
Muhammad Masroor Alam,
Journal of Medical Virology, EarlyView.
Wang J, Ortiz C, Fontenot L, et al.
AbstractBackgroundClostridium difficile infection (CDI) causes diarrhea and colitis. We aimed at finding a common pathogenic pathway in CDI among humans and mice by comparing toxin-mediated effects in human and mouse colonic tissues.MethodWe determined the cytokine secretion of toxin A- and B-treated human and mouse colonic explants using multiplex ELISA.ResultsToxin A and toxin B exposure to fresh human and mouse colonic explants caused different patterns of cytokine secretion. Toxin A induced macrophage inflammatory protein 1 alpha (MIP-1α) secretion in both human and mouse explants. Toxin A reduced chloride anion exchanger SLC26A3 expression in mouse colonic explants and human colonic epithelial cells. C. difficile-infected patients had increased colonic MIP-1α expression and reduced colonic SLC26A3 expression compared to controls. Anti-MIP-1α neutralizing antibody prevented mortality, ameliorated colonic injury, reduced colonic IL-1beta mRNA expression, and restored colonic Slc26a3 expression in C. difficile-infected mice. The anti-MIP-1α neutralizing antibody prevented CDI recurrence. Slc26a3 inhibition augmented colonic IL-1β mRNA expression and abolished the protective effect of anti-MIP-1α neutralizing antibody in C. difficile-infected mice.ConclusionMIP-1α is a common toxin A-dependent chemokine in human and mouse colon. MIP-1α mediates detrimental effects by reducing Slc26a3 and enhancing IL-1β expression in the colon.
Markowitz L, Naleway A, Klein N, et al.
AbstractBackgroundHighly effective human papillomavirus (HPV) vaccines are used in many national programs in 3- or 2-dose schedules. We examined HPV vaccine effectiveness against HPV prevalence by number of doses.MethodsWe collected residual liquid-based cytology samples from US women aged 20–29 years who were screened for cervical cancer. Women continuously enrolled from 2006 through the specimen collection date were analyzed. Specimens were tested using the Linear Array assay. We analyzed prevalence of quadrivalent HPV vaccine (4vHPV) types (HPV 6,11,16,18) and other HPV-type categories and determined prevalence ratios (PRs) and 95% confidence intervals (CIs) for 1, 2, and 3 compared with no vaccine doses.ResultsAmong 4269 women, 1052 (24.6%) were unvaccinated, 2610 (61.1%) received 3 doses, 304 (7.1%) received 2 doses, and 303 (7.1%) received 1 dose. The 4vHPV-type prevalence was 7.4% among unvaccinated women compared with 1.7%, 1.0%, and 1.0% among 1-, 2-, and 3-dose recipients. Among women vaccinated at ≤18 years, adjusted PRs for 1, 2, and 3 doses were 0.06 (95% CI, 0.01–0.42), 0.05 (95% CI, 0.01–0.39), and 0.06 (95% CI, 0.04–0.12).ConclusionsAmong women who received their first dose at age ≤18, estimated HPV vaccine effectiveness was high regardless of number of doses.
Yinda C, Seifert S, Macmenamin P, et al.
AbstractViruses in the genus Henipavirus encompass 2 highly pathogenic emerging zoonotic pathogens, Hendra virus (HeV) and Nipah virus (NiV). Despite the impact on human health, there is currently limited full-genome sequence information available for henipaviruses. This lack of full-length genomes hampers our ability to understand the molecular drivers of henipavirus emergence. Furthermore, rapidly deployable viral genome sequencing can be an integral part of outbreak response and epidemiological investigations to study transmission chains. In this study, we describe the development of a reverse-transcription, long-range polymerase chain reaction (LRPCR) assay for efficient genome amplification of NiV, HeV, and a related non-pathogenic henipavirus, Cedar virus (CedPV). We then demonstrated the utility of our method by amplifying partial viral genomes from 6 HeV-infected tissue samples from Syrian hamsters and 4 tissue samples from a NiV-infected African green monkey with viral loads as low as 52 genome copies/mg. We subsequently sequenced the amplified genomes on the portable Oxford Nanopore MinION platform and analyzed the data using a newly developed field-deployable bioinformatic pipeline. Our LRPCR assay allows for the amplification and sequencing of 2 or 4 amplicons in seminested reactions, and coupled with an easy-to-use bioinformatic pipeline, it makes this method particularly useful in the field during outbreaks in resource-poor environments.
Tiraboschi J, Imaz A, Khoo S, et al.
AbstractWe determined total and unbound concentrations of bictegravir (BIC) in cerebrospinal fluid (CSF) in 15 asymptomatic, virologically suppressed patients. The median (IQR) plasma and CSF total BIC concentrations were 1837,1 ng/ml (1237,2-2586,7) and 6,9 (4,8-10,9) respectively. Median (IQR) unbound BIC concentration was 2,48 ng/ml (1,6-3,7). Total and unbound BIC CSF concentrations were above the EC50 value in all patients and all subjects had HIV viral suppression in plasma and CSF. BIC may contribute to inhibit viral replication in this compartment.
Murphy, E. R., Rossmanith, J., Sieg, J., Fris, M. E., Hussein, H., Kouse, A. B., Gross, K., Zeng, C., Hines, J. V., Narberhaus, F., Coschigano, P. W.
RNA thermometers are cis-acting ribo-regulators that mediate post-transcriptional regulation of gene expression in response to environmental temperature. Such regulation is conferred by temperature-responsive structural changes within the RNA thermometer that result directly in differential ribosomal binding to the regulated transcript. The significance of RNA thermometers in controlling bacterial physiology and pathogenesis is becoming increasingly clear. This study combines in silico, molecular genetics and biochemical analyses to characterize both the structure and function of a newly identified RNA thermometer within the ompA transcript of Shigella dysenteriae. First identified by in silico structural predictions, genetic analyses have demonstrated that the ompA RNA thermometer is a functional ribo-regulator sufficient to confer post-transcriptional temperature-dependent regulation, with optimal expression observed at the host-associated temperature of 37°C. Structural studies and ribosomal binding analyses have revealed both increased exposure of the ribosomal binding site and increased ribosomal binding to the ompA transcript at permissive temperatures. The introduction of site-specific mutations predicted to alter the temperature-responsiveness of the ompA RNA thermometer has predictable consequences on both the structure and function of the regulatory element. Finally, in vitro tissue culture-based analyses implicate the ompA RNA thermometer as a bona fide S. dysenteriae virulence factor in this bacterial pathogen. Given that ompA is highly conserved among Gram-negative pathogens, these studies not only provide insight into the significance of ribo-regulation in controlling Shigella virulence, but also have the potential to facilitate further understanding of the physiology and/or pathogenesis of a wide range of bacterial species.
Kennedy, J. M., Georges, A., Bassenden, A. V., Vidal, S. M., Berghuis, A. M., Taniuchi, I., Majewski, J., Lathrop, M., Behr, M. A., Langlais, D., Gros, P.
We have used a genome-wide screen in N-ethyl-N-nitrosourea (ENU) mutagenized mice to identify genes in which recessive loss of function mutations protect against pathological neuroinflammation. We identified an R367Q mutation in the ZBTB7B (ThPOK) protein which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA (PbA). Zbtb7bR367Q homozygous mice show a defect in the lymphoid compartment expressed as severe reduction in the number of single positive CD4 T cells in the thymus and in the periphery, reduced brain infiltration of pro-inflammatory leukocytes in PbA infected mice and reduced production of pro-inflammatory cytokines by primary T cells ex vivo and in vivo. Dampening of proinflammatory immune responses in Zbtb7bR367Q mice is concomitant to increased susceptibility to infection with avirulent (Mycobatcerium bovis, BCG) and virulent (M. tuberculosis, H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK, and causes a loss of base contact by R367 in the major groove of DNA which is predicted to impair DNA binding. Global immunoprecipitation of ThPOK-containing chromatin complexes coupled to DNA sequencing (ChIP-seq) identified transcriptional networks and candidate genes likely to play a key role in CD4+/CD8+ T cell development and in the expression of lineage specific functions of these cells. This study highlights ThPOK as a global regulator of immune function in which alterations may affect normal responses to infectious and inflammatory stimuli.
Ledbetter, L., Cherla, R., Chambers, C., Zhang, Y., Mitchell, W. J., Zhang, G.
To understand the role of major histocompatibility complex class I (MHC-I) and class II (MHC-II) in vaccine-mediated protection against C. burnetii, we evaluated the protective efficacy of a formalin-inactivated C. burnetii Nine Mile phase I vaccine (PIV) in beta-2-microglobulin-deficient (B2m KO) and MHC-II-deficient (MHC-II KO) mice. Vaccination reduced disease severity in wild-type (WT) and B2m KO mice, but failed to reduce bacterial burden in MHC-II KO mice. This suggests that the MHC-II antigen presentation pathway is required for PIV-mediated protection against C. burnetii infection. MHC-I and MHC-II affect antibody isotype switching, as both PIV-vaccinated B2m KO and MHC-II KO mice produced less Coxiella-specific IgG than PIV-vaccinated WT mice. Interestingly, MHC-II and CD4 deficiency were not equivalent in terms of splenomegaly and bacterial clearance. This demonstrates a partial role for CD4+ T cells while revealing MHC-II-restricted, CD4-independent mechanisms. Adoptive transfer of CD4+ T cells from PIV-vaccinated WT mice to naïve CD4-deficient (CD4 KO) mice demonstrated that antigen-experienced CD4+ T cells are sufficient to generate protection. Conversely, transfer of naïve CD4+ T cells to PIV-vaccinated CD4 KO mice exacerbates disease. Using Tbet-deficient mice (Tbet KO), we showed a partial role for Th1 subset CD4+ T cells in vaccine protection. Furthermore, Th1-independent roles for Tbet were suggested by significant differences in disease between PIV-vaccinated Tbet KO and CD4 KO mice. Interferon-gamma (IFN-) was shown to contribute to the host inflammatory response, but not bacterial clearance. Collectively, these findings suggest that vaccine-induced protective immunity against a murine model of experimental Q fever requires MHC-II-restricted, CD4+ T cell-dependent and -independent mechanisms that can be exploited for a new-generation human Q fever vaccine.
Lee, E. D., Navas, K. I., Portnoy, D. A.
Isoprenoids are an essential and diverse class of molecules present in all forms of life that are synthesized from an essential common precursor derived from either the mevalonate pathway or the nonmevalonate pathway. Most bacteria have one pathway or the other, but the Gram-positive, facultative intracellular pathogen Listeria monocytogenes is unusual because it encodes all the genes for both pathways. While the mevalonate pathway has previously been reported as essential, here we demonstrate that the nonmevalonate pathway can support growth of strains 10403S and EGD-e, but only anaerobically. L. monocytogenes lacking the gene hmgR, the rate-limiting enzyme of the mevalonate pathway, had a doubling time of four hours in anaerobic conditions in contrast to the 45-minute doubling time of WT. In contrast, deleting hmgR in two clinical isolates resulted in mutants that grew significantly faster, doubling in approximately two hours anaerobically, although they still failed to grow under aerobic conditions without mevalonate. The difference in anaerobic growth rate was traced to three amino acid changes in the nonmevalonate pathway enzyme GcpE, and these changes were sufficient to increase the growth rate of 10403S to the rate observed in the clinical isolates. Despite an increased growth rate, virulence was still dependent on the mevalonate pathway in 10403S strains expressing the more active GcpE allele.
Green, E. R., Juttukonda, L. J., Skaar, E. P.
Acinetobacter baumannii is an emerging opportunistic pathogen that primarily infects critically ill patients in nosocomial settings. Because of its rapid acquisition of antibiotic resistance, infections caused by A. baumannii have become extremely difficult to treat, underlying the importance of identifying new antimicrobial targets for this pathogen. Manganese (Mn) is an essential nutrient metal required for a number of bacterial processes, including the response to oxidative stress. Here, we show that exogenous Mn can restore A. baumannii viability in the presence of reactive oxygen species (ROS). This restoration is not dependent on the high-affinity Nramp-family Mn transporter, MumT, as a mumT mutant is no more sensitive to hydrogen peroxide (H2O2) killing than wildtype A. baumannii. However, mumR, which encodes the transcriptional regulator of mumT, is critical for growth and survival in the presence of H2O2, suggesting that MumR regulates additional genes that contribute to H2O2 resistance. RNA-sequencing revealed a role for mumR in regulating the activity of a number of metabolic pathways, including two pathways, phenylacetate and gamma-aminobutyric acid catabolism, which were found to be important for resisting killing by H2O2. Finally, mumR exhibited reduced fitness in a murine model of pneumonia, indicating that MumR-regulated gene products are crucial for protection against the host immune response. In summary, these results suggest that MumR facilitates resistance to the host immune response by activating a transcriptional program that is critical for surviving both Mn starvation and oxidative stress.
Tams, R. N., Wagner, A. S., Jackson, J. W., Gann, E. R., Sparer, T. E., Reynolds, T. B.
Candida albicans is a leading cause of systemic bloodstream infections and synthesis of the phospholipid phosphatidylethanolamine (PE) is required for virulence. The psd1/ psd2/ mutant, which cannot synthesize PE by the CDP-DAG pathway, is avirulent in the mouse model of systemic candidiasis. Similarly, an ept1/ mutant, which cannot produce PE by the Kennedy pathway, exhibits decreased kidney fungal burden in systemically infected mice. Conversely, overexpression of EPT1 results in a hypervirulent phenotype in this model. Thus, mutations that increase PE synthesis increase virulence, and mutations that decrease PE synthesis decrease virulence. However, the mechanism by which virulence is regulated by PE synthesis is only partially understood. RNA sequencing was performed on strains with deficient or excessive PE biosynthesis to elucidate the mechanism. Decreased PE synthesis from loss of EPT1 or PSD1 and PSD2 leads to down-regulation of genes that impact mitochondrial function. Losses of PSD1 and PSD2, but not EPT1, cause significant increases in transcription of glycosylation genes, which may reflect the substantial cell wall defects in the psd1/ psd2/ mutant. These accumulated defects could contribute to the decreased virulence observed for mutants with deficient PE synthesis. In contrast to mutants with decreased PE synthesis, there were no transcriptional differences between the EPT1 overexpression strain and the wild-type, indicating that the hypervirulent phenotype is a consequence of post-transcriptional changes. It was found that overexpression of EPT1 causes increased chitin content and increased hyphal length. These phenotypes may help to explain the previously observed hypervirulence in the EPT1 overexpressor.
Kamar N, Abravanel F, Behrendt P, et al.
AbstractBackgroundRibavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response.MethodsData from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29–1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25–18) months.ResultsAfter a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event.ConclusionsThis large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.
Sassen S, Mathôt R, Pieters R, et al.
AbstractBackgroundCiprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose.AimsTo determine the pharmacokinetics and -dynamics of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and anti-leukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied.MethodsA total of 615 samples from 129 children (0 – 18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio.ResultsA one-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P
Treatment for severe malaria must be prompt with effective parenteral antimalarial drugs for at least 24 h to achieve fast parasite clearance, and when the patient can tolerate oral therapy, treatment should be completed with effective artemisinin based combination therapy (ACT) for complete parasite clearance and to prevent recrudescence. We evaluated piperaquine concentration and malaria treatment outcomes among Ugandan children treated for severe malaria with intravenous artesunate (AS) or quinine (QN) plus dihydroartemisinin-piperaquine (DP), in Tororo District Hospital in Eastern Uganda.
Capillary blood piperaquine concentration data were obtained from a randomized clinical trial whose objective was to evaluate parasite clearance, 42-day parasitological treatment outcomes and safety, following treatment of severe malaria with intravenous AS or QN, plus artemether-lumefantrine or DP among children in Tororo District Hospital, in Eastern Uganda.
Piperaquine concentration data from 150 participants who received DP were analyzed. Participants with unadjusted treatment failure had lower median day 7 capillary piperaquine concentration than those with treatment success (34.7 (IQR) (17.9–49.1) vs 66.7 (IQR) (41.8–81.9), p
In 2018 in Ethiopia, magnitude of human immunodeficiency virus Acquired Immunodeficiency Syndrome treatment failure was 15.9% and currently the number of patient receiving second line antiretroviral therapy (ART) is more increasing than those taking first line ART. Little is known about the predictors of treatment failure in the study area. Therefore; more factors that can be risk for first line ART failure have to identified to make the patients stay on first line ART for long times. Consequently, the aim of this study was to identify determinants of first line ART treatment failure among patients on ART at St. Luke referral hospital and Tulubolo General Hospital, 2019.
A 1:2 un-matched case-control study was conducted among adult patients on active follow up. One new group variables was formed as group 1 for cases and group 0 for controls and then data was entered in to Epi data version 3 and exported to STATA SE version 14 for analysis. From binary logistic regression variables with p value ≤0.25 were a candidate for multiple logistic regression. At the end variables with a p-value ≤0.05 were considered as statistically significant.
A total of 350 (117 cases and 233 controls) patients were participated in the study. Starting ART after 2 years of being confirmed HIV positive (AOR = 3.82 95% CI 1.37,10.6), nevirapine (NVP) based initial ART (AOR = 2.77,95%CI 1.22,6.28) having history of lost to follow up (AOR 3.66,95%CI 1.44,9.27) and base line opportunistic infection (AOR = 1.97,95%CI 1.06,3.63), staying on first line ART for greater than 5 years (AOR = 3.42,95%CI 1.63,7.19) and CD4 less than100cell/ul (AOR = 2.72,95%CI 1.46,5.07) were independent determinants of first line ART treatment failure.
Lost to follow up, staying on first line ART for greater than 5 years, presence of opportunistic infections, NVP based NNRT, late initiation of ART are determinant factors for first line ART treatment failure. The concerned bodies have to focus and act on those identified factors to maintain the patient on first line ART.
Viral hepatitis is a global public health problem affecting millions of people worldwide, causing thousands of deaths due to acute and persistent infection, cirrhosis, and liver cancer. Providing updated serologic data can improve both surveillance and disease control programs. This study is aimed to determine the seroprevalence of markers for viral hepatitis (A, B, C, D and E) and the epidemiology of such infections in the general population of southern Iran’s Hormozgan province.
Between 2016 and 2017, a total of 562 individuals with ages ranging from 1 to 86 years, who visited governmental public laboratories for routine check-ups, were tested for the presence of serological markers to hepatitis virus types A to E using enzyme-linked immunosorbent assays.
The overall anti-hepatitis A virus (HAV) antibody seroprevalence was 93.2% (524/562). The prevalence of anti-hepatitis E virus (HEV) antibodies was 15.8% (89/562) among which 1.6% (9/562) of the seropositive individuals also had evidence of recent exposure to the virus (IgM positivity). Two and a half percent (14/562) were positive for hepatitis B surface (HBs) antigen, whereas 11.6% (65/562) tested positive for anti-hepatitis B core (HBc) antibodies. Among anti-HBc positive patients, 11% (7/65) had HBs Ag and 5% (3/65) were positive for anti-hepatitis D virus (HDV) antibodies. The prevalence of anti-hepatitis C virus (HCV) antibodies was 0.7% (4/562). The seroprevalence of anti-HAV, HEV IgG, anti-HBc antibodies, and HBs Ag increased with age.
The present study confirms a high seroprevalence of HAV infection among the examined population and reveals high levels of endemicity for HEV in the region. Planned vaccination policies against HAV should be considered in all parts of Iran. In addition, improvements on public sanitation and hygiene management of drinking water sources for the studied area are recommended.
Richard, M., Gutierrez, A. V., Kremer, L.
Macrolides are the cornerstone of Mycobacterium abscessus multidrug therapy, although most patients respond poorly to this class of antibiotics, due to the inducible resistance phenotype that occurs during drug treatment. This mechanism is driven by the macrolide inducible ribosomal methylase encoded by erm(41), whose expression is activated by the transcriptional regulator WhiB7. However, it has been debated whether clarithromycin and azithromycin differ in the extent to which they induce erm(41)-mediated macrolide resistance. Herein, we show that macrolide resistance is induced more rapidly in various M. abscessus isolates upon exposure to azithromycin than to clarithromycin, based on minimal inhibitory concentration determination. Macrolide-induced expression of erm(41) was assessed in vivo using a strain carrying tdTomato placed under the control of the erm(41) promoter. Visualization of fluorescent bacilli in infected zebrafish demonstrates that azithromycin and clarithromycin activate erm(41) expression in vivo. That azithromycin induces a more rapid expression of erm(41) was confirmed by measuring the β-galactosidase activity of a reporter strain in which lacZ was placed under the control of the erm (41) promoter. Shortening the promoter region in the lacZ reporter plasmid identified DNA elements involved in the regulation of erm(41) expression, particularly an AT-rich motif sharing partial conservation with the WhiB7-binding site. Mutation of this motif abrogated the macrolide-induced and WhiB7-dependent expression of erm(41). This study provides new mechanistic information on the adaptive response to macrolide treatment in M. abscessus.
Wu, Y., Totten, M., Memon, W., Ying, C., Zhang, S. X.
Candida auris, a globally emerging human fungal pathogen, has arisen as a public health concern worldwide because of its ability to cause nosocomial outbreaks and its resistance to multiple antifungal drugs (1, 2)....
Sun, Q., Xiong, K., Yuan, Y., Yu, J., Yang, L., Shen, C., Su, C., Lu, Y.
Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first line therapy for patients with invasive candidiasis. However, therapeutic efforts to thwart echinocandin resistance have been hampered by a lack of fungal-specific drug targets. Here, we show that deleting CDC43, the β subunit of geranylgeranyltransferase type I (GGTase I), confers hypersensitive to echinocandins, which renders GGTase I a tractable target in combatting echinocandin resistance. The membrane localization of Rho1, which is critical for (1,3)-β-D-glucan synthase Fks1 activation, is disrupted in the cdc43 mutant, resulting in decreased amounts of glucans in cell wall, thereby exacerbating the cell wall stress upon caspofungin addition. Guided by this insight, we find that selective chemical inhibition of GGTase I by L-269289 potentiates echinocandin activity and renders echinocandin-resistant Candida albicans responsive to treatment in vitro and in animal models for disseminated infection. Furthermore, L-269289 and echinocandins also act in a synergistic manner for the treatment of Candida tropicalis and Candida parapsilosis. Importantly, deletion of CDC43 is lethal in Candida glabrata. L-269289 is active on its own to kill C. glabrata and its fungicidal activity is enhanced when combined with caspofungin. Thus, targeting GGTase I has therapeutic potential to address the clinical challenge of echinocandin-resistant candidasis.
Song, H., Liu, D., Li, R., Fu, Y., Zhai, W., Liu, X., He, T., Wu, C., Bai, L., Wang, Y.
Recently, two novel plasmid-mediated tigecycline resistance genes, tet(X3) and tet(X4), have been identified in Acinetobacter baumannii and Escherichia coli, respectively, both of which can significantly compromise the efficacy of tigecycline (1-3), which is one of the few available drugs that can be used to treat infections caused by extensively drug-resistant pathogens (4)....
Lu, R.-Y., Ni, T.-J.-H., Wu, J., Yan, L., Lv, Q.-Z., Li, L.-P., Zhang, D.-Z., Jiang, Y.-Y.
In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described the leading compound NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed wide range activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata and Candida parapsilosis, with MIC values ranging from 0.002 to 1 μg/ml. Particularly, NT-a9 exhibited excellent efficacy against C. neoformans with MIC value as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in sterols content in C. neoformans, similar to fluconazole. In addition, NT-a9 possessed a relatively low cytotoxicity and high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated cryptococcosis model. Mice were infected intravenously with 1.8 ¡Á 106 CFU C. neoformans H99. In the survival study, NT-a9 significantly prolonged mice survival time compared with the control group, the isavuconazole, fluconazole or amphotericin B treated groups. Especially, 4 and 8 mg/kg of NT-a9 rescued all the mice with a survival of 100%. In the fungal burden study, NT-a9 also significantly reduced fungal burden in brains and lungs, while fluconazole and amphotericin B only reduced fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.
Dong, W., Li, S., Wen, S., Jing, W., Shi, J., Ma, Y., Huo, F., Gao, F., Pang, Y., Lu, J.
In this study, we aimed to assess in vitro susceptibility of GSK656 against multiple mycobacteria species, and investigate the correlation between sequence variations within LeuRS and in vitro susceptibility of GSK656 between mycobacteria species. A total of 187 mycobacteria isolates, comprising 105 Mycobacterium tuberculosis (MTB) and 82 nontuberculous mycobacteria (NTM), were randomly selected for the determination of in vitro susceptibility. For MTB, 102 out of 105 isolates had MICs ≤0.5 mg/L, demonstrating a MIC50 of 0.063 mg/L and a MIC90 of 0.25 mg/L, respectively. An ECOEF value of 0.5 mg/L was proposed for identifying GSK656-resistant MTB. For NTM, the MIC50s and MIC90s were both >8.0 mg/L for M. intracellulare and M. avium, respectively. In contrast, all M. abscessus isolates had MICs ≤0.25 mg/L, yielding a MIC90 of 0.063 mg/L. LeuRS from M. abscessus showed higher sequence similarity with MTB LeuRS than LeuRSs from M. avium and M. intracellulare. Sequence alignment revealed 28 different residues between LeuRSs from M. avium and M. intracellulare and LeuRSs from MTB and M. abscessus. Among them, 15 residues were in the drug binding domain. Structure modeling revealed that several different residues were close to the tRNA-LeuRS interface or the entrance of drug-tRNA binding pocket. In conclusion, our data demonstrate that GSK656 exhibits significant species diversity in in vitro susceptibility against various mycobacteria species. GSK656 has potent efficacy against MTB and M. abscessus, whereas the inherent resistance is noted in M. intracellulare and M. avium.
Fabián Segovia-Miranda, Hernán Morales-Navarrete, Michael Kücken, Vincent Moser, Sarah Seifert, Urska Repnik, Fabian Rost, Mario Brosch, Alexander Hendricks, Sebastian Hinz, Christoph Röcken, Dieter Lütjohann, Yannis Kalaidzidis, Clemens Schafmayer, Lutz Brusch, Jochen Hampe, Marino Zerial
Nature Medicine, Published online: 02 December 2019; doi:10.1038/s41591-019-0660-7A combination of high-resolution imaging and modeling approaches facilitates the study of the mechanisms and clinical progression of non-alcoholic fatty liver disease in humans.
International AIDS Conference (AIDS) 2020
6.07.2020 - 10.07.2020
International Liver Congress (ILC) 2020
27.08.2020 - 29.08.2020
World Sepsis Day
Det 8. videnskabelige nationale møde om infektiøs endokarditis
International Congress for Tropical Medicine and Malaria (ICTMM) 2020
20.09.2020 - 24.09.2020
COVID-19 retningslinje (2020)
National handlingsplan for antibiotika til mennesker (2017)
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Infections in Patients Colonized with Extended-Spectrum Beta-Lactamase-Producing Enterobacterales – a Retrospective Cohort Study
30.07.2020Clinical Infectious Diseases Advance Access
Zoonoses: beyond the human–animal–environment interface
Ambulatory management of primary spontaneous pneumothorax: when less is more
Surgery for benign prostatic obstruction
Investing in surgery: a value proposition for African leaders
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Hvorfor synes Professor Niels Obel, at du bør læse"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
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