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Item A common parasite could one day deliver drugs to the brain − how scientists are turning Toxoplasma gondii from foe into friend(The Conversation US, Inc., 2024-08-07) Sullivan, BillItem Adverse events following administration of COVID-19 vaccines in Saudi Arabia(Springer Nature, 2022-11-15) Alqahtani, Saleh; Jokhdar, Hani; Al‑Tawfiq, Jaffar A.; Al‑Otaibi, Salah; Assiri, Abdullah; Almudarra, Sami; Alabdulkareem, Khaled; Haji, Alhan; Medicine, School of MedicinePrevious studies investigated the frequency of different adverse events of COVID-19 vaccines. However, this study compares these adverse events between the two main COVID-19 vaccines used in Saudi Arabia (Pfizer-BioNTech and Oxford-AstraZeneca) using telemedicine technology. A cross-sectional study was conducted among 958 individuals, 7 days after receiving either Pfizer-BioNTech or Oxford-AstraZeneca vaccines during June 2021. Immediate adverse events were reported by 1.04% and 2.09% for Pfizer-BioNTech and Oxford-AstraZeneca vaccines, respectively, with no serious events. Recipients of Pfizer-BioNTech vaccine had a higher percentage of local adverse events (24.8% versus 9.8% in AstraZeneca vaccine). The most common reported systemic adverse events in both vaccines respectively were general fatigue (23.1% and 25.1%), fever (18.5% and 27.2%), myalgia (20.6% and 20.3%), and headache (15.2% and 17.2%). No significant difference was recorded between both vaccines regarding overall systemic adverse events; however, they were more frequent following the first dose of AstraZeneca vaccine compared to Pfizer-BioNTech vaccine, while the reverse was observed for the second dose. Adverse events were more frequent in females and younger age groups for both vaccines. Most of systemic and local adverse events were mild in nature. Further cohort studies are recommended to investigate the long-term adverse events of COVID-19 vaccines.Item Barriers to and facilitators of effective management of fever episodes in hospitalised Kenyan children with cancer: protocol for convergent mixed methods study(BMJ Publishing, 2023-11-02) Nessle, Charles Nathaniel; Njuguna, Festus; Dettinger, Julia; Koima, Raphael; Nyamusi, Lenah; Kisembe, Evelynn; Kinja, Sarah; Ndung’u, Mercy; Njenga, Dennis; Langat, Sandra; Olbara, Gilbert; Moyer, Cheryl; Vik, Terry; Pediatrics, School of MedicineIntroduction: Febrile neutropenia is an oncological emergency in children with cancer, associated with serious infections and complications. In low-resourced settings, death from infections in children with cancer is 20 times higher than in high-resourced treatment settings, thought to be related to delays in antibiotic administration and management. The barriers to effective management of fever episodes in children with cancer have not previously been described. This convergent mixed-methods study will provide the evidence to develop fever treatment guidelines and to inform their effective implementation in children with cancer at Moi Teaching and Referral Hospital (MTRH), a level 6 referral hospital in western Kenya. Methods and analysis: Prospective data collection of paediatric patients with cancer with new fever episodes admitted to MTRH will be performed during routine treatment. Clinical variables will be collected from 50 fever episodes, including cancer diagnosis and infectious characteristics of the fever episode, and elapsed time from fever onset to various milestones in the management workflow. Semistructured qualitative interviews with healthcare providers (estimated 20 to reach saturation) will explore the barriers to and facilitators of appropriate management of fever episodes in children with cancer. The interview guide was informed by a theoretical framework and Consolidated Framework for Implementation Research. A mixed-methods analysis use of joint display tables and process mapping will link and integrate the two types of data with meta-inferences. Ethics and dissemination: Institutional review board approval was obtained from the MTRH (0004273) and the University of Michigan (HUM0225674), and the study was registered with National Commission for Science Technology and Innovation (P/23/22885). Written consent will be obtained from all participants. Results will be formally shared with local and national policy leadership and local end users, presented at relevant national academic conferences and submitted for publication in a peer-reviewed journal.Item Characterization of a novel RNAi yeast insecticide that silences mosquito 5-HT1 receptor genes(Springer Nature, 2023-12-15) Mysore, Keshava; Njoroge, Teresia M.; Stewart, Akilah T. M.; Winter, Nikhella; Hamid‑Adiamoh, Majidah; Sun, Longhua; Shui Feng, Rachel; James, Lester D.; Mohammed, Azad; Severson, David W.; Duman‑Scheel, Molly; Medical and Molecular Genetics, School of MedicineG protein-coupled receptors (GPCRs), which regulate numerous intracellular signaling cascades that mediate many essential physiological processes, are attractive yet underexploited insecticide targets. RNA interference (RNAi) technology could facilitate the custom design of environmentally safe pesticides that target GPCRs in select target pests yet are not toxic to non-target species. This study investigates the hypothesis that an RNAi yeast insecticide designed to silence mosquito serotonin receptor 1 (5-HTR1) genes can kill mosquitoes without harming non-target arthropods. 5-HTR.426, a Saccharomyces cerevisiae strain that expresses an shRNA targeting a site specifically conserved in mosquito 5-HTR1 genes, was generated. The yeast can be heat-inactivated and delivered to mosquito larvae as ready-to-use tablets or to adult mosquitoes using attractive targeted sugar baits (ATSBs). The results of laboratory and outdoor semi-field trials demonstrated that consumption of 5-HTR.426 yeast results in highly significant mortality rates in Aedes, Anopheles, and Culex mosquito larvae and adults. Yeast consumption resulted in significant 5-HTR1 silencing and severe neural defects in the mosquito brain but was not found to be toxic to non-target arthropods. These results indicate that RNAi insecticide technology can facilitate selective targeting of GPCRs in intended pests without impacting GPCR activity in non-targeted organisms. In future studies, scaled production of yeast expressing the 5-HTR.426 RNAi insecticide could facilitate field trials to further evaluate this promising new mosquito control intervention.Item Development of a controlled-release mosquito RNAi yeast larvicide suitable for the sustained control of large water storage containers(Springer Nature, 2024-12-04) Mysore, Keshava; Oxley, James D.; Duckham, Craig; Castilla-Gutierrez, Clarissa; Stewart, Akilah T. M.; Winter, Nikhella; Shui Feng, Rachel; Singh, Satish; James, Lester D.; Mohammed, Azad; Severson, David W.; Duman-Scheel, Molly; Medical and Molecular Genetics, School of MedicineLarge household water storage containers are among the most productive habitats for Aedes aegypti (Linnaeus, 1762), the primary mosquito vector for dengue and other arboviral pathogens. Increasing concerns for insecticide resistance and larvicide safety are limiting the successful treatment of large household water storage containers, which are among the most productive habitats for Aedes juveniles. The recent development of species-specific RNAi-based yeast larvicides could help overcome these problems, particularly if shelf stable ready-to-use formulations with significant residual activity in water can be developed. Here we examine the hypothesis that development of a shelf-stable controlled-release RNAi yeast formulation can facilitate lasting control of A. aegypti juveniles in large water storage containers. In this study, a dried inactivated yeast was incorporated into a biodegradable matrix containing a mixture of polylactic acid, a preservative, and UV protectants. The formulation was prepared using food-grade level components to prevent toxicity to humans or other organisms. Both floating and sinking versions of the tablets were prepared for treatment of various sized water containers, including household water storage tank-sized containers. The tablets passed accelerated storage tests of shelf life stability and demonstrated up to six months residual activity in water. The yeast performed well in both small and large containers, including water barrels containing 20-1000 larvae each, and in outdoor barrel trials. Future studies will include the evaluation of the yeast larvicide in larger operational field trials that will further assess the potential for incorporating this new technology into integrated mosquito control programs worldwide.Item Distal Consequences of Mucosal Infections in Intestinal and Lung Inflammation(Frontiers Media, 2022-04-28) Melo-González, Felipe; Sepúlveda-Alfaro, Javiera; Schultz, Bárbara M.; Suazo, Isidora D.; Boone, David L.; Kalergis, Alexis M.; Bueno, Susan M.; Microbiology and Immunology, School of MedicineInfectious diseases are one of the leading causes of morbidity and mortality worldwide, affecting high-risk populations such as children and the elderly. Pathogens usually activate local immune responses at the site of infection, resulting in both protective and inflammatory responses, which may lead to local changes in the microbiota, metabolites, and the cytokine environment. Although some pathogens can disseminate and cause systemic disease, increasing evidence suggests that local infections can affect tissues not directly invaded. In particular, diseases occurring at distal mucosal barriers such as the lung and the intestine seem to be linked, as shown by epidemiological studies in humans. These mucosal barriers have bidirectional interactions based mainly on multiple signals derived from the microbiota, which has been termed as the gut-lung axis. However, the effects observed in such distal places are still incompletely understood. Most of the current research focuses on the systemic impact of changes in microbiota and bacterial metabolites during infection, which could further modulate immune responses at distal tissue sites. Here, we describe how the gut microbiota and associated metabolites play key roles in maintaining local homeostasis and preventing enteric infection by direct and indirect mechanisms. Subsequently, we discuss recent murine and human studies linking infectious diseases with changes occurring at distal mucosal barriers, with particular emphasis on bacterial and viral infections affecting the lung and the gastrointestinal tract. Further, we discuss the potential mechanisms by which pathogens may cause such effects, promoting either protection or susceptibility to secondary infection.Item Flesh-eating bacteria infections are on the rise in the US − a microbiologist explains how to protect yourself(The Conversation US, Inc., 2023-09-25) Sullivan, BillItem Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial(BMJ Publishing Group, 2010-07-20) The FUTURE I/II Study Group; Dillner, Joakim; Kjaer, Susanne K.; Wheeler, Cosette M.; Sigurdsson, Kristján; Iversen, Ole-Erik; Hernandez-Avila, Mauricio; Perez, Gonzalo; Brown, Darron R.; Koutsky, Laura A.; Tay, Eng Hseon; García, Patricia; Ault, Kevin A.; Garland, Suzanne M.; Leodolter, Sepp; Olsson, Sven-Eric; Tang, Grace W.K.; Ferris, Daron G.; Paavonen, Jorma; Lehtinen, Matti; Steben, Marc; Bosch, Xavier; Joura, Elmar A.; Majewski, Slawomir; Muñoz, Nubia; Myers, Evan R.; Villa, Luisa L; Taddeo, Frank J.; Roberts, Christine; Tadesse, Amha; Bryan, Janine T.; Maansson, Roger; Lu, Shuang; Vuocolo, Scott; Hesley, Teresa M.; Barr, Eliav; Haupt, Richard; Medicine, School of MedicineObjectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up.Item A functional requirement for sex-determination M/m locus region lncRNA genes in Aedes aegypti female larvae(Springer Nature, 2021-05-20) Mysore, Keshava; Hapairai, Limb K.; Li, Ping; Roethele, Joseph B.; Sun, Longhua; Igiede, Jessica; Misenti, Joi K.; Duman‑Scheel, Molly; Medical and Molecular Genetics, School of MedicineAlthough many putative long non-coding RNA (lncRNA) genes have been identified in insect genomes, few of these genes have been functionally validated. A screen for female-specific larvicides that facilitate Aedes aegypti male sex separation uncovered multiple interfering RNAs with target sites in lncRNA genes located in the M/m locus region, including loci within or tightly linked to the sex determination locus. Larval consumption of a Saccharomyces cerevisiae (yeast) strain engineered to express interfering RNA corresponding to lncRNA transcripts resulted in significant female death, yet had no impact on male survival or fitness. Incorporation of the yeast larvicides into mass culturing protocols facilitated scaled production and separation of fit adult males, indicating that yeast larvicides could benefit mosquito population control strategies that rely on mass releases of male mosquitoes. These studies functionally verified a female-specific developmental requirement for M/m locus region lncRNA genes, suggesting that sexually antagonistic lncRNA genes found within this highly repetitive pericentromeric DNA sequence may be contributing to the evolution of A. aegypti sex chromosomes.Item International epidemiology databases to evaluate AIDS (IeDEA) in sub-Saharan Africa, 2012–2019(BMJ Publishing Group, 2020-05-15) Chammartin, Frédérique; Dao Ostinelli, Cam Ha; Anastos, Kathryn; Jaquet, Antoine; Brazier, Ellen; Brown, Steven; Dabis, Francois; Davies, Mary-Ann; Duda, Stephany N.; Malateste, Karen; Nash, Denis; Wools-Kaloustian, Kara; von Groote, Per M.; Egger, Matthias; Biostatistics, School of Public HealthPurpose: The objectives of the International epidemiology databases to evaluate AIDS (IeDEA) are to (i) evaluate the delivery of combination antiretroviral therapy (ART) in children, adolescents and adults in sub-Saharan Africa, (ii) to describe ART regimen effectiveness, durability and tolerability, (iii) to examine HIV-related comorbidities and coinfections and (iv) to examine the pregnancy-related and HIV-related outcomes of women on ART and their infants exposed to HIV or ART in utero or via breast milk. Participants: IeDEA is organised in four regions (Central, East, Southern and West Africa), with 240 treatment and care sites, six data centres at African, European and US universities, and almost 1.4 million children, adolescents and adult people living with HIV (PLWHIV) enrolled. Findings to date: The data include socio-demographic characteristics, clinical outcomes, opportunistic events, treatment regimens, clinic visits and laboratory measurements. They have been used to analyse outcomes in PLWHIV-1 or PLWHIV-2 who initiate ART, including determinants of mortality, of switching to second-line and third-line ART, drug resistance, loss to follow-up and the immunological and virological response to different ART regimens. Programme-level estimates of mortality have been corrected for loss to follow-up. We examined the impact of coinfection with hepatitis B and C, and the epidemiology of different cancers and of (multidrug resistant) tuberculosis, renal disease and of mental illness. The adoption of 'Treat All', making ART available to all PLWHIV regardless of CD4+ cell count or clinical stage was another important research topic. Future plans: IeDEA has formulated several research priorities for the 'Treat All' era in sub-Saharan Africa. It recently obtained funding to set up sentinel sites where additional data are prospectively collected on cardiometabolic risks factors as well as mental health and liver diseases, and is planning to create a drug resistance database.