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Thompson, G. R., Lewis, P., Mudge, S., Patterson, T. F., Burnett, B. P.
SUBA™-itraconazole (S-ITZ) which releases drug in the duodenum compared to conventional ITZ (C-ITZ) in the stomach were compared in two PK studies: a 3-day loading dose and a 15-day steady-state. These were crossover, oral bioequivalence studies under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (2x100 mg) and S-ITZ (2x65 mg) were administered TID for 3 days and once on day 4 (N=15). For the steady-state study, C-ITZ (2x100 mg) and S-ITZ (2x65 mg) were administered BID for 14 days and a last dose 30min after a meal on day 15 (N=16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares-geometric means were used to compare Cmax,ss, Ctrough and AUCtau of each formulation. Ratios of ITZ and OH-ITZ for S-ITZ to C-ITZ were between 107% to 118% in both studies for Cmax,ss, Ctrough and AUCtau, within the FDA-required bioequivalence range of 80-125%. At the end of the steady-state study, 13 of 16 volunteers obtained higher mean Ctrough ITZ blood levels >1000ng/mL when administered S-ITZ (81%) vs C-ITZ (44%). The study drugs were well-tolerated in both studies with similar AEs. All treatment emergent AEs resolved after study completion. One C-ITZ volunteer discontinued due to an treatment unrelated AE in the steady-state study. No SAEs were reported. Total, trough and peak ITZ and OH-ITZ exposure were similar between formulations. Therefore, SUBA™-ITZ was bioequivalent to C-ITZ in healthy adult volunteers with 35% less drug and exhibited a similar safety profile.
Poirel, L., Vuillemin, X., Juhas, M., Masseron, A., Bechtel-Grosch, U., Tiziani, S., Mancini, S., Nordmann, P.
KPC-50 is a KPC-3 variant identified from a Klebsiella pneumoniae clinical isolate recovered in Switzerland in 2019. As compared to KPC-3, KPC-50 shows i) a three amino-acid insertion (Glu-Ala-Val) between amino acids 276 and 277 amino acid sequence, (ii) an increased affinity to ceftazidime, (iii) a decreased sensitivity to avibactam, explaining the ceftazidime-avibactam resistance, and (iv) associated to a sharp reduction of its carbapenemase activity.
Ma, J., Guo, F., Jin, Z., Geng, M., Ju, M., Ravichandran, A., Orugunty, R., Smith, L., Zhu, G., Zhang, H.
Novel antiparasitic activity was observed for the antifungal occidiofungin. It efficaciously and irreversibly inhibited the zoonotic enteric parasite Cryptosporidium parvum in vitro with limited cytotoxicity (EC50 = 120 nM vs. TC50 = 988 nM), and its treatment disrupted the parasite morphology. Besides expanded activity spectrum, occidiofungin as a glycolipopeptide is characterized by poor absorbability and its ability to retain in gastrointestinal tract, making it worth to also investigate its potential activities on other enteric parasites.
Tanusree Sharma, Masooda Bashir
Nature Medicine, Published online: 26 May 2020; doi:10.1038/s41591-020-0928-yMobile apps provide a convenient source of tracking and data collection to fight against the spread of COVID-19. We report our analysis of 50 COVID-19-related apps, including their use and their access to personally identifiable information, to ensure that the right to privacy and civil liberties are protected.
Moran Amit, Heli Kimhi, Tarif Bader, Jacob Chen, Elon Glassberg, Avi Benov
Nature Medicine, Published online: 26 May 2020; doi:10.1038/s41591-020-0927-zAs the COVID-19 pandemic escalates, teams around the world are now advocating for a new approach to monitoring transmission: tapping into cellphone location data to track infection spread and warn people who may have been exposed. Here we present data collected in Israel through this approach so far and discuss the privacy concerns, alternatives and different ‘flavors’ of cellphone surveillance. We also propose safeguards needed to minimize the risk for civil rights.
Anup P. Challa, Robert R. Lavieri, Ethan S. Lippmann, Jeffery A. Goldstein, Lisa Bastarache, Jill M. Pulley, David M. Aronoff
Nature Medicine, Published online: 26 May 2020; doi:10.1038/s41591-020-0925-1Testing drug safety in people who are pregnant remains a wicked problem, but in the transition toward big data and machine learning, target trials could afford a viable alternative to randomized, controlled trials.
Venu M. Konala,
Pavani Reddy Garlapati,
Mohamed A. Merghani,
Journal of Medical Virology, EarlyView.
Van Thuan Hoang,
Thi Loi Dao,
Journal of Medical Virology, Accepted Article.
Fernanda M. Malta,
Luiz Augusto M. Fonseca,
Ana Paula R. Veiga,
Marcello M.C. Magri,
Alberto J.S Duarte,
ADEE 3002 Group
Kristoffer Skaalum Hansen, Bo Langhoff Hønge, Hans Beier Ommen, Charles Marinus Pedersen, Merete Storgaard
Sukbin Jang, Ji-Young Rhee
Since the COVID-19 outbreak started in China, most deaths occur in the elderly or people with underlying diseases. The pathogenesis of COVID-19 is still not well understood why the viral infections lead to respiratory failure with a high mortality rate(Gao et al., 2020). An excessive immune response contributes to COVID-19 pathogenesis and lethality(Gao et al., 2020, Jin et al., 2020). Recently, complement suppression may represent a therapeutic approach to treat COVID-19(Gao et al., 2020).
Yi-Chun Lin, Chien-Yu Cheng, Chen Cheng-Pin, Shu-Hsing Cheng, Sui-Yuan Chang, Po-Ren Hsueh
Di Wu, Jianyun Lu, Lan Cao, Xiaowei Ma, Qun Liu, Yanhui Liu, Zhoubin Zhang
The pandemic of Corona Virus Disease 2019 (COVID-19) is becoming a worldwide disaster. According to the WHO, more than 4 248 389 cases were reported and 294 046 deaths were conformed globally as of 14 May, 2020(WHO, 2020). It has been reported that humans may be more likely to be infected with different types of viruses through respiratory transmission. Here we report the protective effect to pneumonia while fighting against COVID-19.
Simin Ma, Xiaoquan Lai, Zhe Chen, Shenghao Tu, Kai Qin
The World Health Organization (WHO) named the coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as 2019 novel coronavirus disease (COVID-19) and declared it as a pandemic. Similar to the influenza virus, SARS-CoV-2 is commonly transmitted through respiratory droplets and contact. The world’s population is generally susceptible to SARS-CoV-2 infection. Most COVID-19 patients show mild influenza-like symptoms, such as fever, cough, and fatigue. However, approximately 5% of patients rapidly progress to acute respiratory distress syndrome (ARDS), septic shock, and multiple organ failure and are admitted to intensive care units.
Annamaria Tavernese, Maria Stelitano, Agnese Mauceri, Rocco Mollace, Giuseppe Uccello, Francesco Romeo, Valeria Cammalleri
Endocarditis due to Lactobacillus species is extremely rare. We introduce an uncommon case of Lactobacillus Plantarum bioprosthetic aortic valve endocarditis, presenting with severe aortic steno-regurgitation, which responded to conventional medical and surgical treatment. This case provides a better understanding of the disease process of Lactobacillus Plantarum and highlights the role of the transesophageal echocardiogram to follow the entire endocarditis course.
Rutger A. Middelburg, Frits R. Rosendaal
Since the start of the outbreak of SARS-CoV-2 in December 2019, in the Hubei province in China, the virus has quickly spread across the world (Ahn et al., 2020; Bar-On et al., 2020; Dyer, 2020). As the virus spread, so did the COVID-19 disease that it causes. To curb the surge in COVID-19 related mortality, different governments enforced different measures for the containment of the epidemic (Yan et al., 2020; Pike and Saini, 2020). Comparing numbers of cases between countries is difficult, due to vast differences in testing policies.
Ariel L. Rivas, José L. Febles, Stephen D. Smith, Almira L. Hoogesteijn, George P. Tegos, Folorunso O. Fasina, James B. Hittner
The challenges associated with the COVID-19 pandemic may require novel approaches. Given the numerous asymptomatic infections reported in this disease, actions that focus on symptomatic individuals are prone to fail.(Nishiura and Linton, in press) Some classic concepts –e.g., ‘recovered’ and ‘contact tracing’−may not apply: patients regarded as recovered may be test-positive and people without a travel history may be infected.(Lan et al., 2020; CDC, 2020) To avoid these ambiguities, here an unambiguous metric was explored: mortality.
E. R. Osen
S. Zayet et al.
Anke Huss, Laura A.N. Derks, Dick J.J. Heederik, Inge M. Wouters
Legionella is a bacterial species able to cause influenza-like illness (Pontiac fever) or severe pneumonia (Legionnaires Disease, LD). We assessed Legionella presence and concentration in composting facilities in the Netherlands.
Chaturaka Rodrigo, Sumadhya Deepika Fernando, Senaka Rajapakse
Repurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with new viral epidemics.
Pedro María Martínez Pérez-Crespo, Luis Eduardo López-Cortés, Pilar Retamar-Gentil, Joaquín Felipe Lanz García, David Vinuesa García, Eva León Jiménez, Juan Manuel Sánchez Calvo, Fátima Galán-Sánchez, Clara Natera Kindelan, Alfonso del Arco Jiménez, Antonio Sánchez-Porto, Carmen Herrero Rodríguez, Berta Becerril Carral, Isabel María Reche Molina, Jose María Reguera Iglesias, Inés Pérez Camacho, Marcos Guzman García, Inmaculada López-Hernández, Jesús Rodríguez-Baño, PROBAC REIPI/GEIH-SEIMC/SAEI Group
During the last decade, some changes in the epidemiology of invasive infections have been reported; however, specific studies with patient-level data are scarce. The aim of this study is to describe and evaluate the epidemiologic changes in bloodstream infections (BSI) during the last decade in Andalucía, Spain.
Berta Isabel Fidalgo, Jordi Bosch, Teresa Cobo, Laura Ribera, Manel Almela, Climent Casals
Burkholderia cenocepacea is a member of the Burkholderia cepacea complex (BCC) currently formed by 22 species. It is a Gram negative bacillus, mobile, non-spore-forming, aerobic, non fermenter of glucose and positive catalase and oxidase. It is considered an opportunistic pathogen for humans and is one of the main infectious agents in patients with cystic fibrosis. A case of choriamnionitis due to Burkholderia pseudomallei infection in pregnancy was reported in Australia1, however the first case of bacteremia with intraamniotic infection (IIA) by B.cenocepacea in a pregnant woman is described below.
In 2017, inhabitants along the border between French Guiana and Brazil were affected by a malaria outbreak primarily due to Plasmodium vivax (Pv). While malaria cases have steadily declined between 2005 and 2016 in this Amazonian region, a resurgence was observed in 2017.
Two investigations were performed according to different spatial scales and information details: (1) a local study on the French Guiana border, which enabled a thorough investigation of malaria cases treated at a local village health center and the entomological circumstances in the most affected neighborhood, and (2) a regional and cross-border study, which enabled exploration of the regional spatiotemporal epidemic dynamic. Number and location of malaria cases were estimated using French and Brazilian surveillance systems.
On the French Guianese side of the border in Saint-Georges de l’Oyapock, the attack rate was 5.5% (n = 4000), reaching 51.4% (n = 175) in one Indigenous neighborhood. Entomological findings suggest a peak of Anopheles darlingi density in August and September. Two female An. darlingi (n = 1104, 0.18%) were found to be Pv-positive during this peak. During the same period, aggregated data from passive surveillance conducted by Brazilian and French Guianese border health centers identified 1566 cases of Pv infection. Temporal distribution during the 2007–2018 period displayed seasonal patterns with a peak in November 2017. Four clusters were identified among epidemic profiles of cross-border area localities. All localities of the first two clusters were Brazilian. The localization of the first cluster suggests an onset of the outbreak in an Indigenous reservation, subsequently expanding to French Indigenous neighborhoods and non-Native communities.
The current findings demonstrate a potential increase in malaria cases in an area with otherwise declining numbers. This is a transborder region where human mobility and remote populations challenge malaria control programs. This investigation illustrates the importance of international border surveillance and collaboration for malaria control, particularly in Indigenous villages and mobile populations.
Marion Mathelié-Guinlet, Abir T. Asmar, Jean-François Collet, Yves F. Dufrêne
The bacterial cell envelope plays essential roles in controlling cell shape, division, pathogenicity, and resistance against external stresses. In Escherichia coli, peptidoglycan (PG) has long been thought to be the primary component that conveys mechanical strength to the envelope. But a recent publication demonstrates the key contribution of the lipoprotein Lpp in defining the stiffness of the cell envelope and its sensitivity to drugs.
Maria Paula Roberti, Satoru Yonekura, Connie P. M. Duong, Marion Picard, Gladys Ferrere, Maryam Tidjani Alou, Conrad Rauber, Valerio Iebba, Christian H. K. Lehmann, Lukas Amon, Diana Dudziak, Lisa Derosa, Bertrand Routy, Caroline Flament, Corentin Richard, Romain Daillère, Aurélie Fluckiger, Isabelle Van Seuningen, Mathias Chamaillard, Audrey Vincent, Stephanie Kourula, Paule Opolon, Pierre Ly, Eugénie Pizzato, Sonia Becharef, Juliette Paillet, Christophe Klein, Florence Marliot, Filippo Pietrantonio, Stéph
Nature Medicine, Published online: 25 May 2020; doi:10.1038/s41591-020-0882-8Local microbiome composition influences treatment efficacy of chemotherapy in colon cancer via modulation of tolerogenic versus immunogenic ileal intestinal epithelial cell death, which in turn influences follicular helper T cell priming.
Gregory P. Donaldson, Daniel Mucida
Nature Medicine, Published online: 25 May 2020; doi:10.1038/s41591-020-0902-8Therapeutic interventions in colorectal cancer are dependent on immune responses to dying epithelial cells that are modulated by specific members of the gut microbiota.
Breanna M. Allen, Kamir J. Hiam, Cassandra E. Burnett, Anthony Venida, Rachel DeBarge, Iliana Tenvooren, Diana M. Marquez, Nam Woo Cho, Yaron Carmi, Matthew H. Spitzer
Nature Medicine, Published online: 25 May 2020; doi:10.1038/s41591-020-0892-6Primary tumor presence and progression shape the systemic immune landscape and immune responses to pathogens in multiple murine tumor models.
Benjamin N. Ostendorf, Jana Bilanovic, Nneoma Adaku, Kimia N. Tafreshian, Bernardo Tavora, Roger D. Vaughan, Sohail F. Tavazoie
Nature Medicine, Published online: 25 May 2020; doi:10.1038/s41591-020-0879-3Heritable APOE variants in patients with melanoma influence anti-tumor immunity and modulate metastatic progression and response to immunotherapy.
Rajagopal Murugan, Stephen W. Scally, Giulia Costa, Ghulam Mustafa, Elaine Thai, Tizian Decker, Alexandre Bosch, Katherine Prieto, Elena A. Levashina, Jean-Philippe Julien, Hedda Wardemann
Nature Medicine, Published online: 25 May 2020; doi:10.1038/s41591-020-0881-9Characterization of 200 antibodies that bind a malaria parasite protein provides insights that could enable better vaccine design.
Bruno Bockorny, Valerya Semenisty, Teresa Macarulla, Erkut Borazanci, Brian M. Wolpin, Salomon M. Stemmer, Talia Golan, Ravit Geva, Mitesh J. Borad, Katrina S. Pedersen, Joon Oh Park, Robert A. Ramirez, David G. Abad, Jaime Feliu, Andres Muñoz, Mariano Ponz-Sarvise, Amnon Peled, Tzipora M. Lustig, Osnat Bohana-Kashtan, Stephen M. Shaw, Ella Sorani, Marya Chaney, Shaul Kadosh, Abi Vainstein Haras, Daniel D. Von Hoff, Manuel Hidalgo
Nature Medicine, Published online: 25 May 2020; doi:10.1038/s41591-020-0880-xResults from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation.
Plasmodium falciparum zygotes develop in the mosquito midgut after an infectious blood meal containing mature male and female gametocytes. Studies of mosquito-produced P. falciparum zygotes to elucidate their biology and development have been hampered by high levels of contaminating mosquito proteins and macromolecules present in zygote preparations. Thus, no zygote-specific surface markers have been identified to date. Here, a methodology is developed to obtain large quantities of highly purified zygotes using in vitro culture, including purification methods that include magnetic column cell separation (MACS) followed by Percoll density gradient centrifugation. This straightforward and effective approach provides ample material for studies to enhance understanding of zygote biology and identify novel zygote surface marker candidates that can be tested as transmission blocking vaccine (TBV) candidates.
Plasmodium falciparum gametocyte cultures were established and maintained from asexual cultures. Gametocytes were matured for 14 days, then transferred into zygote media for 6 h at 27 ± 2 °C to promote gamete formation and fertilization. Zygotes were then purified using a combination of MACS column separation and Percoll density gradient centrifugation. Purity of the zygotes was determined through morphological studies: the parasite body and nuclear diameter were measured, and zygotes were further transformed into ookinetes. Immunofluorescence assays (IFA) were also performed using the ookinete surface marker, Pfs28.
After stimulation, the culture consisted of transformed zygotes and a large number of uninfected red blood cells (RBCs), as well as infected RBCs with parasites at earlier developmental stages, including gametes, gametocytes, and asexual stages. The use of two MACS columns removed the vast majority of the RBCs and gametocytes. Subsequent use of two Percoll density gradients enabled isolation of a pure population of zygotes. These zygotes transformed into viable ookinetes that expressed Pfs28.
The combined approach of using two MACS columns and two Percoll density gradients yielded zygotes with very high purity (45-fold enrichment and a pure population of zygotes [approximately 100%]) that was devoid of contamination by other parasite stages and uninfected RBCs. These enriched zygotes, free from earlier parasites stages and mosquito-derived macromolecules, can be used to further elucidate the biology and developmental processes of Plasmodium.
Ronald Olum, Felix Bongomin
Coronavirus disease -2019 (COVID-19) continues to hit-hard on many countries across the world. Uganda reported its first case of COVID-19 on the March 21, 2020 (Coronavirus Disease, 2020). A 36-year-old businessman from Kampala, Uganda’s capital, who had travelled to Dubai, United Arab Emirates (UAE) in a healthy condition four days prior to his return. He presented with fever and flu-like symptoms at Entebbe International Airport (EIA) and his sample tested positive for SARS-CoV-2, the causative agent of COVID-19 (Coronavirus Disease, 2020).
Muthukrishnan Eaaswarkhanth, Ashraf Al Madhoun, Fahd Al-Mulla
Increasing number of deaths due to COVID-19 pandemic has raised serious global concerns. Higher testing capacity and ample intensive care availability could explain lower mortality in some countries compared to others. Nevertheless, it is also plausible that the SARS-CoV-2 mutations giving rise to different phylogenetic clades are responsible for the obvious death disparities around the world. Current research literature linking the genetic make-up of SARS-CoV-2 with fatality is lacking. Here, we suggest that this disparity in fatality rates may be attributed to SARS-CoV-2 evolving mutations and urge the international community to begin addressing the phylogenetic clade classification of SARS-CoV-2 in relation to clinical outcomes.
Chetna Soni, Oriana A. Perez, William N. Voss, Joseph N. Pucella, Lee Serpas, Justin Mehl, Krystal L. Ching, Jule Goike, George Georgiou, Gregory C. Ippolito, Vanja Sisirak, Boris Reizis
Autoantibodies to self-DNA are a defining feature of systemic lupus erythematosus (SLE), yet the mechanisms of their development remain poorly understood. Soni et al. show that anti-DNA autoreactivity is driven by extrafollicular B cell differentiation into short-lived plasmablasts, which is facilitated by plasmacytoid dendritic cells, type I interferon, and endosomal Toll-like receptors 7 and 9.
Amir Nutman, Yehuda Carmeli
We thank the author for his constructive comments.
After successful of antiretroviral therapy, highly effective direct acting antiviral (DAA) make HCV elimination reasonable in HIV/HCV co-infected patients. However, in achieving this target, there are still barriers to start DAA treatment, particularly in the area of liver fibrosis assessment that determine the duration of therapy. We aimed to assess the diagnostic performance of APRI and FIB-4 for diagnosing cirrhosis in HIV/HCV co-infected patients using hepatic transient elastography (TE) as gold standard.
This is a retrospective study on HIV/HCV co-infected patients who concomitantly performed hepatic TE measurement, APRI, and FIB-4 evaluation before HCV treatment initiation at a tertiary hospital in Jakarta from 2014 to 2019. Sensitivity, specificity and diagnostic accuracy of indirect biomarkers for liver stiffness measurement (LSM) ≥ 12.5 kPa was determined by receiver operator characteristics curves.
223 HIV/HCV co-infected patients on stable antiretroviral therapy were included, of whom 91.5% were male with mean age of 37 (SD 5) years. Only 28.7% of patients were classified as cirrhosis (F4). Using TE as gold standard (≥12.5 kPa), the low threshold of APRI (1) had specificity 95%, sensitivity 48.4%, correctly classified 81.6% of patients, with moderate performance, AUC at 0.72 (95% CI 0.63–0.80). The optimal cut-off of FIB-4 was 1.66 [specificity 92.5%, sensitivity 53.1%, AUC at 0.73 (95% CI 0.65–0.81)] and correctly classified 81.1% of the patients.
APRI score ≥ 1 and FIB-4 score ≥ 1.66 had moderate performance with high specificity in diagnosing cirrhosis. These biochemical markers could be used while TE is not available.
Grebely J, Tran L, Degenhardt L, et al.
AbstractBackgroundPeople who inject drugs (PWID) experience barriers to accessing testing and treatment for hepatitis C virus (HCV) infection. Opioid agonist therapy (OAT) may provide an opportunity to improve access to HCV care. This systematic review assessed the association of OAT and HCV testing, treatment, and treatment outcomes among PWID.MethodsBibliographic databases and conference presentations were searched for studies assessing the association between OAT and HCV testing, treatment, and treatment outcomes [direct-acting antiviral (DAA) therapy only] among people who inject drugs (in the past year). Meta-analysis was used to pool estimates.ResultsAmong 9,877 articles identified, 22 studies conducted in Australia, Europe, North America, and Thailand were eligible and included. Risk of bias was serious in 21 studies and moderate in one study. Current/recent OAT was associated with an increased odds of recent HCV antibody testing [4 studies; odds ratio (OR), 1.80; 95% CI:1.36, 2.39), HCV RNA testing among those who were HCV antibody positive (2 studies; OR, 1.83; 95% CI:1.27, 2.62), and DAA treatment uptake among those who were HCV RNA positive (7 studies; OR 1.53; 95% CI: 1.07, 2.20). There was insufficient evidence of an association between OAT and treatment completion (9 studies) or sustained virologic response following DAA therapy (9 studies).ConclusionsOpioid agonist therapy can increase linkage to HCV care, including uptake of HCV testing and treatment among PWID. This supports the scale-up of OAT as part of strategies to enhance HCV treatment to further HCV elimination efforts.
Glick H, Miyazaki T, Hirano K, et al.
AbstractBACKGROUNDPneumonia is a common and serious illness in the elderly with poorly characterized long-term impact on health-related quality of life (HRQoL). The Japanese Goto Epidemiology Study is a prospective, active, population-based surveillance study of adults with X-ray/CT-scan–confirmed community-onset pneumonia, assessing the HRQoL outcome quality-adjusted life years (QALYs). Here we report QALY scores and losses among a subset of participants in the Goto Study.METHODSQALYs were derived from responses to the Japanese version of the EuroQol-5D-5L health-state classification instrument at days 0, 7, 15, 30, 90, 180 and 365 after pneumonia diagnosis from participants enrolled from June 2017 to May 2018. We used patients as their own controls, calculating comparison QALYs by extrapolating EuroQol-5D-5L scores for Day −30 accounting for mortality and changes in scores with age.RESULTSOf 405 participants, 85% were aged ≥65 years, 58% were male, and 69% were hospitalized for clinical and radiological confirmed pneumonia. Compliance with interviews by either patients or proxies was 100%. Adjusted EuroQol-5D-5L scores were 0.759 at day −30, 0.561 at diagnosis, 0.702 by day 180 and .689 by day 365. Average scores at all time points remained below the average day −30 scores (P ≤ .001). Pneumonia resulted in a mean adjusted loss of 0.13 QALYs (~47.5 quality-adjusted days lost) at 365 days (P
Chiang S, Brooks M, Jenkins H, et al.
AbstractBackgroundHousehold contacts of patients with drug-resistant tuberculosis are at high risk for being infected with Mycobacterium tuberculosis and for developing tuberculosis disease. To guide regimen composition for the empirical treatment of tuberculosis infection and disease in these household contacts, we estimated drug resistance profile concordance between index patients with drug-resistant tuberculosis and their household contacts.MethodsWe performed a systematic review and meta-analysis of studies published through July 24, 2018 and reported resistance profiles of drug-resistant tuberculosis index and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only.ResultsWe identified 33 eligible studies, which evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI]: 40.7-67.6, I2=85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI: 72.3-90.9; I2=73%). Concordance estimates were similar in a sub-analysis of 16 studies from high tuberculosis-burden countries. There were insufficient data to perform a sub-analysis among pediatric secondary cases.ConclusionHousehold contacts of drug-resistant TB patients should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.
Over the last decade, artemisinin-based combination therapy (ACT) has contributed substantially to the decrease in malaria-related morbidity and mortality. The emergence of Plasmodium falciparum parasites resistant to artemisinin derivatives in Southeast Asia and the risk of their spread or of local emergence in sub-Saharan Africa are a major threat to public health. This study thus set out to estimate the proportion of P. falciparum isolates, with Pfkelch13 gene mutations associated with artemisinin resistance previously detected in Southeast Asia.
Blood samples were collected in two sites of Bangui, the capital of the Central African Republic (CAR) from 2017 to 2019. DNA was extracted and nested PCR were carried out to detect Plasmodium species and mutations in the propeller domain of the Pfkelch13 gene for P. falciparum samples.
A total of 255 P. falciparum samples were analysed. Plasmodium ovale DNA was found in four samples (1.57%, 4/255). Among the 187 samples with interpretable Pfkelch13 sequences, four samples presented a mutation (2.1%, 4/187), including one non-synonymous mutation (Y653N) (0.5%, 1/187). This mutation has never been described as associated with artemisinin resistance in Southeast Asia and its in vitro phenotype is unknown.
This preliminary study indicates the absence of Pfkelch13 mutant associated with artemisinin resistance in Bangui. However, this limited study needs to be extended by collecting samples across the whole country along with the evaluation of in vitro and in vivo phenotype profiles of Pfkelch13 mutant parasites to estimate the risk of artemisinin resistance in the CAR.
Anecdotal reports from DRC suggest that long-lasting insecticidal nets (LLIN) distributed through mass campaigns in DRC may not last the expected average three years. To provide the National Malaria Control Programme with evidence on physical and insecticidal durability of nets distributed during the 2016 mass campaign, two brands of LLIN, DawaPlus® 2.0 and DuraNet©, were monitored in neighbouring and similar health zones in Sud Ubangi and Mongala Provinces.
This was a prospective cohort study of representative samples of households from two health zones recruited at baseline, 2 months after the mass campaign. All campaign nets in these households were labelled, and followed up over a period of 31 months. Primary outcome was the “proportion of nets surviving in serviceable condition” based on attrition and integrity measures and the median survival in years. The outcome for insecticidal durability was determined by bio-assay from subsamples of campaign nets.
A total of 754 campaign nets (109% of target) from 240 households were included in the study. Definite outcomes could be determined for 67% of the cohort nets in Sud Ubangi and 74% in Mongala. After 31 months all-cause attrition was 57% in Sud Ubangi and 76% in Mongala (p = 0.005) and attrition due to wear and tear was 26% in Sud Ubangi and 48% in Mongala (p = 0.0009). Survival in serviceable condition at the last survey was 37% in Sud Ubangi and 17% in Mongala (p = 0.003). Estimated median survival was 1.6 years for the DawaPlus® 2.0 in Mongala (95% CI 1.3–1.9) and 2.2 years for the DuraNet in Sud Ubangi (95% CI 2.0–2.4). Multivariable Cox proportionate hazard models suggest that the difference between sites was mainly attributable to the LLIN brand. Insecticidal effectiveness was optimal for DuraNet©, but significantly dropped after 24 months for DawaPlus® 2.0.
In the environment of northwest DRC the polyethylene LLIN DuraNet© performed significantly better than the polyester LLIN DawaPlus® 2.0, but both were below a three-year median survival. Improvement of net care behaviours should be able to improve physical durability.
Malaria transmission in Zanzibar has dramatically reduced in recent years but vector control interventions such as long-lasting insecticidal nets (LLIN) must continue to reach malaria elimination. To achieve this, the Zanzibar Malaria Elimination Programme needs actionable evidence of the durability of the LLIN brands distributed. This study compared physical and insecticidal durability of two LLIN brands: Olyset® and PermaNet© 2.0 in two similar districts on the islands of Unguja and Pemba.
This was a prospective cohort study of representative samples of households from two districts, recruited at baseline 4 months after the mass campaign. All campaign nets in these households were labelled and followed up over a period of 33 months. Primary outcome was the “proportion of nets surviving in serviceable condition” based on attrition and integrity measures and the median survival in years. The outcome for insecticidal durability was determined by bio-assay from sub-samples of campaign nets.
A total of 834 campaign nets (121% of target) from 299 households were included in the study. Definite outcomes could be determined for 86% of the cohort nets in Unguja (PermaNet® 2.0) and 89% in Pemba (Olyset®). After 33 months, physical survival in serviceable condition was 55% in Unguja and 51% in Pemba. Estimated median survival was lower in Pemba at all time points with 2.3–2.7 years compared to 3.1–3.3 yeas in Unguja. Multivariable Cox proportionate hazard models confirmed the difference between brands (p
Long-lasting insecticidal nets (LLINs) are the most favoured vector control tools worldwide. Timely monitoring and evaluation of LLINs is important to sustain the impact of this promising vector control method and for replacement of worn-out and those rendered ineffective. During the mid-2017, LLINs were distributed by the National Vector Borne Disease Control Programme (NVBDCP) in high malaria endemic districts of the eastern coastal state of Odisha. The study was carried out to assess the field performance of the LLINs post 30 months of distribution in Koraput district of Odisha state.
A total of 130 households were randomly selected from three villages of Laxmipur CHC in Koraput district, Odisha, India; one each from hilltop, foothill and plain terrain. The net users were interviewed to elicit information on usage, washing practices, physical integrity, bio-efficacy and survivorship of LLINs to confirm the claimed three-year life of the LLINs.
74.8% of the LLINs were physically present after 30 months of distribution. The numbers (%) of LLINs used previous night varied from 30 to 61% between study villages. 74% respondents were using the LLINs throughout the year and 26% only seasonally. Of the total, 85% of the nets were reported to be washed and 95% nets were dried under shade as recommended. Altogether, 58% of the surveyed nets were found torn with holes. Of these, 74 (57%) nets were in good condition, 10 (8%) nets were in serviceable and 45 (35%) nets were badly torn and needed replacement. A total of 45 (93.75%), 68 (80%) and 71 (63.8%) LLINs were physically present in hilltop, foothill and plain villages, respectively. The LLINs did meet the efficacy criteria, given the 100% mortality to the exposed Anopheles jeyporiensis mosquitoes post 30 months distribution.
The findings of this study were communicated to the programme officials of the state and LLINs were replenished soon after 31st month post-distribution of LLINs.
Prevention and treatment of malaria during pregnancy is crucial in dealing with maternal mortality and adverse fetal outcomes. The World Health Organization recommendation to treat all pregnant women with sulfadoxine-pyrimethamine (SP) through antenatal care structures was implemented in Kenya in the year 1998, but concerns about its effectiveness in preventing malaria in pregnancy has arisen due to the spread of SP resistant parasites. This study aimed to determine the prevalence of SP resistance markers in Plasmodium falciparum parasites isolated from pregnant women seeking antenatal care at Msambweni County Referral Hospital, located in coastal Kenya, between the year 2013 and 2015.
This hospital-based study included 106 malaria positive whole blood samples for analysis of SP resistance markers within the Pfdhfr gene (codons 51, 59 and 108) and Pfdhps gene (codons 437 and 540). The venous blood collected from all pregnant women was tested for malaria via light microscopy, then the malaria positive samples were separated into plasma and red cells and stored in a − 86° freezer for further studies. Archived red blood cells were processed for molecular characterization of SP resistance markers within the Pfdhfr and Pfdhps genes using real time PCR platform and Sanger sequencing.
All samples had at least one mutation in the genes associated with drug resistance; polymorphism prevalence of Pfdhfr51I, 59R and 108N was at 88.7%, 78.3% and 93.4%, respectively, while Pfdhps polymorphism accounted for 94.3% and 91.5% at 437G and 540E, respectively. Quintuple mutations (at all the five codons) conferring total SP resistance had the highest prevalence of 85.8%. Quadruple mutations were observed at a frequency of 10.4%, and 24.5% had a mixed outcome of both wildtype and mutant genotypes in the genes of interest.
The data suggest a high prevalence of P. falciparum genetic variations conferring resistance to SP among pregnant women, which may explain reduced efficacy of IPTp treatment in Kenya. There is need for extensive SP resistance profiling in Kenya to inform IPTp drug choices for successful malaria prevention during pregnancy.
While sub-microscopic malarial infections are frequent and potentially deleterious during pregnancy, routine molecular detection is still not feasible. This study aimed to assess the performance of a Histidine Rich Protein 2 (HRP2)-based ultrasensitive rapid diagnostic test (uRDT, Alere Malaria Ag Pf) for the detection of infections of low parasite density in pregnant women.
This was a retrospective study based on samples collected in Benin from 2014 to 2017. A total of 942 whole blood samples collected in 327 women in the 1st and 3rd trimesters and at delivery were tested by uRDT, conventional RDT (cRDT, SD BIOLINE Malaria Ag Pf), microscopy, quantitative polymerase chain-reaction (qPCR) and Luminex-based suspension array technology targeting P. falciparum HRP2. The performance of each RDT was evaluated using qPCR as reference standard. The association between infections detected by uRDT, but not by cRDT, with poor maternal and birth outcomes was assessed using multivariate regression models.
The overall positivity rate detected by cRDT, uRDT, and qPCR was 11.6% (109/942), 16.2% (153/942) and 18.3% (172/942), respectively. Out of 172 qPCR-positive samples, 68 were uRDT-negative. uRDT had a significantly better sensitivity (60.5% [52.7–67.8]) than cRDT (44.2% [36.6–51.9]) and a marginally decreased specificity (93.6% [91.7–95.3] versus 95.7% [94.0–97.0]). The gain in sensitivity was particularly high (33%) and statistically significant in the 1st trimester. Only 28 (41%) out of the 68 samples which were qPCR-positive, but uRDT-negative had detectable but very low levels of HRP2 (191 ng/mL). Infections that were detected by uRDT but not by cRDT were associated with a 3.4-times (95%CI 1.29–9.19) increased risk of anaemia during pregnancy.
This study demonstrates the higher performance of uRDT, as compared to cRDTs, to detect low parasite density P. falciparum infections during pregnancy, particularly in the 1st trimester. uRDT allowed the detection of infections associated with maternal anaemia.
Zika virus (ZIKV, genus Flavivirus, family Flaviviridae) is transmitted mainly by Aedes mosquitoes. This virus has become an emerging concern of global public health with recent epidemics associated to neurological complications in the pacific and America. ZIKV is the most frequently amplified arbovirus in southeastern Senegal. However, this virus and its adult vectors are undetectable during the dry season. The aim of this study was to investigate how ZIKV and its vectors are maintained locally during the dry season.
Soil, sand, and detritus contained in 1339 potential breeding sites (tree holes, rock holes, fruit husks, discarded containers, used tires) were collected in forest, savannah, barren and village land covers and flooded for eggs hatching. The emerging larvae were reared to adult, identified, and blood fed for F1 production. The F0 and F1 adults were identified and tested for ZIKV by Reverse Transcriptase-Real time Polymerase Chain Reaction.
A total of 1016 specimens, including 13 Aedes species, emerged in samples collected in the land covers and breeding sites investigated. Ae. aegypti was the dominant species representing 56.6% of this fauna with a high plasticity. Ae. furcifer and Ae. luteocephalus were found in forest tree holes, Ae. taylori in forest and village tree holes, Ae. vittatus in rock holes. ZIKV was detected from 4 out of the 82 mosquito pools tested. Positive pools included Ae. bromeliae (2 pools), Ae. unilineatus (1 pool), and Ae. vittatus (1 pool), indicating that the virus is maintained in these Aedes eggs during the dry season.
Our investigation identified breeding sites types and land cover classes where several ZIKV vectors are maintained, and their maintenance rates during the dry season in southeastern Senegal. The maintenance of the virus in these vectors in nature could explain its early amplification at the start of the rainy season in this area.
Brain abscesses, a severe infectious disease of the CNS, are usually caused by a variety of different pathogens, which include Streptococcus intermedius (S. intermedius). Pulmonary arteriovenous fistulas (PAVFs), characterized by abnormal direct communication between pulmonary artery and vein, are a rare underlying cause of brain abscesses.
The patient was a previous healthy 55-year-old man who presented with 5 days of headache and fever. Cerebral magnetic resonance imaging (MRI) suggested a brain abscess. Thoracic CT scan and angiography demonstrated PAVFs. Aiding by metagenomic next-generation sequencing (mNGS) of the cerebrospinal fluid (CSF) sample which identified S. intermedius as the causative pathogen, the patient was switched to the single therapy of large dose of penicillin G and was cured precisely and economically.
It is an alternative way to perform mNGS to identify causative pathogens in patients with brain abscesses especially when the results of traditional bacterial culture were negative. Further thoracic CT or pulmonary angiography should also be undertaken to rule out PAVFs as the potential cause of brain abscess if the patient without any known premorbid history.
Northern European Conference on Travel Medicine (NECTM) 2020
Mødet udskudt på grund af COVID-19
3.06.2020 - 5.06.2020
ASM Microbe 2020
Aflyst på grund af COVID-19
18.06.2020 - 22.06.2020
Ph.d. forsvar ved Kristina Langholz Kristensen
International AIDS Conference (AIDS) 2020
6.07.2020 - 10.07.2020
International Liver Congress (ILC) 2020
27.08.2020 - 29.08.2020
COVID-19 retningslinje (2020)
National handlingsplan for antibiotika til mennesker (2017)
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
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Device-Associated Menstrual Toxic Shock Syndrome [Reviews]
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