Infectious Disease Of Global Importance Research Articles

Remdesivir for the Treatment of COVID-19: A Narrative Review.

Despite the wide availability of effective vaccines, COVID-19 continues to be an infectious disease of global importance. Remdesivir is a broad-spectrum antiviral and was the first US Food and Drug Administration-approved treatment for COVID-19. In clinical guidelines, remdesivir is currently the only recommended antiviral for use in hospitalized patients with COVID-19, with or without a supplemental oxygen requirement. It is also recommended for nonhospitalized patients with COVID-19 and hospitalized patients with severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) infection who are at high risk of progression to severe disease. This narrative review explores the evidence for remdesivir across various clinical outcomes and evolution of clinical guidelines through a survey over time of randomized controlled trials, observational studies, and meta-analyses. Remdesivir, compared to standard of care, appears to improve survival and disease progression in a variety of patient populations with COVID-19 across a spectrum of disease severity and SARS-CoV-2 variant periods. Remdesivir also appears to improve time to clinical recovery, increase rate of recovery, and reduce time on supplemental oxygen and readmission rates. More recent large, real-world studies further support the early use of remdesivir in a range of patient populations, including those with immunocompromising conditions.

Middle East respiratory syndrome coronavirus and the 2022 world cup football tournament in Qatar.

No Middle East respiratory syndrome coronavirus cases were detected during the 2022 FIFA World Cup in Qatar in November–December 2022, which attracted 1.4 million visitors. Robust monitoring mechanisms instituted by Qatar before and during the FIFA WC can serve as a template for future similar events to detect infectious diseases of global importance.

Capacity and Readiness Assessment of Healthcare Facilities for Digital Health Interventions Against Tuberculosis and HIV in Addis Ababa, Ethiopia.

BackgroundThere is a high level of concern that low-income countries lack the capacity and readiness to effectively adopt, implement, and scale up digital health interventions (DHIs). We aimed to assess the infrastructure and human resource capacity and readiness of healthcare facilities to adopt and implement any new DHI for tuberculosis (TB) and HIV care and treatment in Addis Ababa, Ethiopia.MethodWe carried out a cross-sectional, mixed-methods study in 14 public healthcare facilities that provide TB and HIV care and treatment services. Providers' perceived readiness to adopt and implement digital health was assessed using a self-administered questionnaire designed based on an adapted eHealth readiness assessment model that covers six domains: core readiness, organizational cultural readiness, value proposition readiness, technological readiness, regulatory policy readiness, and operational resource readiness. The infrastructure and human resource capacity were assessed on-site using a tool adapted from the Technology Infrastructure Checklist. Internal consistency was assessed using Cronbach's alpha, and the significant relationship between the composite variables was assessed using Pearson's correlation coefficients (r).ResultWe assessed 14 facilities on-site and surveyed 60 TB and HIV healthcare providers. According to Cronbach's alpha test, all the six technology acceptance domains had a value of >0.8, suggesting a strong interrelatedness between the measuring items. The correlation between technological readiness and operational resource readiness was significant (r = 0.8). The providers perceived their work environment as good enough in electronic data protection, while more efforts are needed in planning, training, adapting, and implementing digital health. Of the 14 facilities, 64.3% lack the plan to establish a functional local area network, and 43% lack skilled staff on payroll to provide maintenance of computers and other digital technologies.ConclusionLike many developing countries, there was a modest infrastructure and human resource capacity and readiness of public healthcare facilities in Addis Ababa, Ethiopia, to nurture and strengthen DHIs across the TB and HIV cascades of care. Technological and operational resource readiness, including funding and a Well-trained workforce, are essential for successful implementation and use of digital health against the two infectious diseases of global importance in such settings.

Challenges and Prospects of Plant-Derived Oral Vaccines against Hepatitis B and C Viruses.

Hepatitis B and C viruses chronically affect approximately 3.5% of the global population, causing more than 800,000 deaths yearly due to severe liver pathogenesis. Current HBV vaccines have significantly contributed to the reduction of chronic HBV infections, supporting the notion that virus eradication is a feasible public health objective in the near future. In contrast to HBV, a prophylactic vaccine against HCV infection is not available yet; however, intense research efforts within the last decade have significantly advanced the field and several vaccine candidates are shortlisted for clinical trials. A successful vaccine against an infectious disease of global importance must not only be efficient and safe, but also easy to produce, distribute, administer, and economically affordable to ensure appropriate coverage. Some of these requirements could be fulfilled by oral vaccines that could complement traditional immunization strategies. In this review, we discuss the potential of edible plant-based oral vaccines in assisting the worldwide fight against hepatitis B and C infections. We highlight the latest research efforts to reveal the potential of oral vaccines, discuss novel antigen designs and delivery strategies, as well as the limitations and controversies of oral administration that remain to be addressed to make this approach successful.

The Use and Misuse of Mathematical Modeling for Infectious Disease Policymaking: Lessons for the COVID-19 Pandemic.

Mathematical modeling has played a prominent and necessary role in the current coronavirus disease 2019 (COVID-19) pandemic, with an increasing number of models being developed to track and project the spread of the disease, as well as major decisions being made based on the results of these studies. A proliferation of models, often diverging widely in their projections, has been accompanied by criticism of the validity of modeled analyses and uncertainty as to when and to what extent results can be trusted. Drawing on examples from COVID-19 and other infectious diseases of global importance, we review key limitations of mathematical modeling as a tool for interpreting empirical data and informing individual and public decision making. We present several approaches that have been used to strengthen the validity of inferences drawn from these analyses, approaches that will enable better decision making in the current COVID-19 crisis and beyond.

Estimating the basic reproduction number for the 2015 bubonic plague outbreak in Nyimba district of Eastern Zambia.

BackgroundPlague is a re-emerging flea-borne infectious disease of global importance and in recent years, Zambia has periodically experienced increased incidence of outbreaks of this disease. However, there are currently no studies in the country that provide a quantitative assessment of the ability of the disease to spread during these outbreaks. This limits our understanding of the epidemiology of the disease especially for planning and implementing quantifiable and cost-effective control measures. To fill this gap, the basic reproduction number, R0, for bubonic plague was estimated in this study, using data from the 2015 Nyimba district outbreak, in the Eastern province of Zambia. R0 is the average number of secondary infections arising from a single infectious individual during their infectious period in an entirely susceptible population.Methodology/Principal findingsSecondary epidemic data for the most recent 2015 Nyimba district bubonic plague outbreak in Zambia was analyzed. R0 was estimated as a function of the average epidemic doubling time based on the initial exponential growth rate of the outbreak and the average infectious period for bubonic plague. R0 was estimated to range between 1.5599 [95% CI: 1.382–1.7378] and 1.9332 [95% CI: 1.6366–2.2297], with average of 1.7465 [95% CI: 1.5093–1.9838]. Further, an SIR deterministic mathematical model was derived for this infection and this estimated R0 to be between 1.4 to 1.5, which was within the range estimated above.Conclusions/SignificanceThis estimated R0 for bubonic plague is an indication that each bubonic plague case can typically give rise to almost two new cases during these outbreaks. This R0 estimate can now be used to quantitatively analyze and plan measurable interventions against future plague outbreaks in Zambia.

The impact of ocular tuberculosis on vision after two months of intensive therapy

Tuberculosis is an infectious disease of global importance with major economic and social burden accounting for 25% of all avoidable deaths in developing countries. Extrapulmonary involvement may occur either in association with clinically apparent pulmonary tuberculosis or in isolation. This cross-sectional descriptive study aimed to evaluate the impact of ocular tuberculosis in visual acuity at baseline and after two months of intensive anti-tuberculous therapy. A sample of 133 pulmonary tuberculosis patients, seven disseminated tuberculosis, and three pleural tuberculosis patients was evaluated. All patients underwent routine ophthalmic evaluation, including assessment of visual acuity, biomicroscopy, applanation tonometry, indirect ophthalmoscopy, and fluorescent angiography as appropriate. None of the patients had impaired visual acuity due to tuberculosis. A rate of 4.2% (6/143) of ocular involvement was found. None of the patients with ocular involvement were HIV-infected. Of the six patients with ocular involvement, five met the diagnostic criteria for probable and one for possible ocular lesions. As for the type of ocular lesions, two patients had bilateral findings: one had sclerouveitis and the second had choroidal nodules. The other four patients presented with unilateral lesions: peripheral retinal artery occlusion in the right eye (one case), choroidal nodules in the left eye (one case), and choroidal nodules in the right eye (two cases). Patients progressed favorably after two month of intensive therapy, with no significant reduction in vision.

A gene expression atlas of adult Schistosoma mansoni and their gonads

RNA-Seq has proven excellence in providing information about the regulation and transcript levels of genes. We used this method for profiling genes in the flatworm Schistosoma mansoni. This parasite causes schistosomiasis, an infectious disease of global importance for human and animals. The pathology of schistosomiasis is associated with the eggs, which are synthesized as a final consequence of male and female adults pairing. The male induces processes in the female that lead to the full development of its gonads as a prerequisite for egg production. Unpaired females remain sexually immature. Based on an organ-isolation method we obtained gonad tissue for RNA extraction from paired and unpaired schistosomes, with whole adults included as controls. From a total of 23 samples, we used high-throughput cDNA sequencing (RNA-Seq) on the Illumina platform to profile gene expression between genders and tissues, with and without pairing influence. The data obtained provide a wealth of information on the reproduction biology of schistosomes and a rich resource for exploitation through basic and applied research activities.

A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis.

ABSTRACTSeveral infectious diseases of global importance—e.g., HIV infection and tuberculosis (TB)—require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of Mycobacterium tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB—defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)—exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.

Leptospira surface adhesin (Lsa21) induces Toll like receptor 2 and 4 mediated inflammatory responses in macrophages.

Leptospirosis is zoonotic and emerging infectious disease of global importance. Little is understood about Leptospira pathogenesis and host immune response. In the present work we have investigated how Leptospira modulates the host innate immune response mediated by Toll-like receptors (TLRs) via surface exposed proteins. We screened Leptospira outer membrane/surface proteins for their ability to activate/inhibit TLR2/4 signaling in HEK293 cell lines. Of these the 21 kDa Leptospira surface adhesin, Lsa21 had strong TLR2 and TLR4 activity leading to production of proinflammatory cytokines and expression of costimulatory molecules in mouse macrophages. This activity of Lsa21 on innate response was dependent on activation of mitogen activated protein kinases (MAPKs) via stimulating the rapid phosphorylation of p38, JNK and activation of transcription factor NF-κB. Additionally, neutralizing antibodies against TLR2 and TLR4 significantly inhibited cytokine secretion and attenuated Lsa21 induced phosphorylation of p38 and JNK. Furthermore, Lsa21 induced cytokine levels were significantly lower in TLR2−/− and TLR4−/− than in wild type mouse macrophage cell lines. Confocal microscopy and molecular docking confirmed that Lsa21 interacted with both TLR2 and TLR4. These results indicate that Lsa21 is a potent TLR2 and TLR4 agonist that induces strong innate response and may play important role in Leptospira pathogenesis.

Comparative genomics of closely related Salmonella enterica serovar Typhi strains reveals genome dynamics and the acquisition of novel pathogenic elements.

BackgroundTyphoid fever is an infectious disease of global importance that is caused by Salmonella enterica subsp. enterica serovar Typhi (S. Typhi). This disease causes an estimated 200,000 deaths per year and remains a serious global health threat. S. Typhi is strictly a human pathogen, and some recovered individuals become long-term carriers who continue to shed the bacteria in their faeces, thus becoming main reservoirs of infection.ResultsA comparative genomics analysis combined with a phylogenomic analysis revealed that the strains from the outbreak and carrier were closely related with microvariations and possibly derived from a common ancestor. Additionally, the comparative genomics analysis with all of the other completely sequenced S. Typhi genomes revealed that strains BL196 and CR0044 exhibit unusual genomic variations despite S. Typhi being generally regarded as highly clonal. The two genomes shared distinct chromosomal architectures and uncommon genome features; notably, the presence of a ~10 kb novel genomic island containing uncharacterised virulence-related genes, and zot in particular. Variations were also detected in the T6SS system and genes that were related to SPI-10, insertion sequences, CRISPRs and nsSNPs among the studied genomes. Interestingly, the carrier strain CR0044 harboured far more genetic polymorphisms (83% mutant nsSNPs) compared with the closely related BL196 outbreak strain. Notably, the two highly related virulence-determinant genes, rpoS and tviE, were mutated in strains BL196 and CR0044, respectively, which revealed that the mutation in rpoS is stabilising, while that in tviE is destabilising. These microvariations provide novel insight into the optimisation of genes by the pathogens. However, the sporadic strain was found to be far more conserved compared with the others.ConclusionsThe uncommon genomic variations in the two closely related BL196 and CR0044 strains suggests that S. Typhi is more diverse than previously thought. Our study has demonstrated that the pathogen is continually acquiring new genes through horizontal gene transfer in the process of host adaptation, providing novel insight into its unusual genomic dynamics. The understanding of these strains and virulence factors, and particularly the strain that is associated with the large outbreak and the less studied asymptomatic Typhi carrier in the population, will have important impact on disease control.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1007) contains supplementary material, which is available to authorized users.

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.

An In Vivo Transfection Approach Elucidates a Role for Aedes aegypti Thioester-Containing Proteins in Flaviviral Infection

Mosquitoes transmit pathogens that cause infectious diseases of global importance. Techniques to easily introduce genes into mosquitoes, however, limit investigations of the interaction between microbes and their arthropod vectors. We now show that a cationic liposome significantly enhances delivery and expression of plasmid DNA in Aedes aegypti and Anopheles gambiae mosquitoes. We then introduced the genes for Ae. aegypti thioester-containing proteins (AeTEPs), which are involved in the control of flaviviral infection, into mosquitoes using this technique. In vivo transfection of AeTEP-1 into Ae. aegypti significantly reduced dengue virus infection, suggesting that the approach can further our understanding of pathogen-mosquito interactions.

Tuberculosis: Current Treatment and New Drug Development

Mycobacterial infections, including tuberculosis (TB) and leprosy, are infectious diseases of global importance. Control of TB is complicated by difficulties in administrating the long-course chemotherapy regimens, the inability to eliminate latent organisms, and the increasing appearance of multidrug resistant strains of Mycobacterium tuberculosis . New drugs for the control of TB are urgently needed, including developments of short-term antibiotic regimens to minimize the emergence of drug resistance and new drugs to treat MDR-TB patients and to eradicate the latent bacteria. Recent years have witnessed emergence of many new structural classes of antimycobacterial agents, some of which exhibit promising activities against susceptible and resistant strains of M. tuberculosis. In particular, the newly discovered diarylquinoline with superior antituberculous activity and encouraging results from recent studies of nitroimidazopyrans and oxazolidinones have generated considerable excitement. Genetic and biochemical studies, facilitated by the availability of mycobacterial genomes, have provided much insight into the biosynthesis of mycobacterial cell wall and metabolic processes unique to the pathogen, which reveal many potential drug targets. Some progresses toward targeting novel enzymes or biochemical processes have been made. This review summarizes these developments. Efforts to make use of existing drugs for treatment of TB, but which are currently marketed for controlling of other infections, are discussed. In addition, mechanisms of antibiotic resistance including the mycobacterial cell wall permeability barrier and novel resistance mechanisms are also discussed. Keywords: TB, Mycobacterium tuberculosis, antibiotic resistance, drug development, mycobacteria, mycobacterial cell wall

The renaissance in global health

This decade is witnessing a renaissance in the research, development and control of infectious diseases of global importance. Starting with the availability of some existing tools (such as drugs for mass drug administration to treat communities for helminths) and fueled by the potential application of science to develop novel tools (such as vaccines for malaria and hookworm), the possibilities of what can be done across the research, development and implementation spectrum to achieve a global health impact is beginning to be realized.

The AIDS research model: implications for other infectious diseases of global health importance.

This article presents the implications of the AIDS Research Model for other infectious diseases of global health importance. The evolution of AIDS as a global pandemic has heightened awareness of the persistent threat posed by established emerging and re-emerging infectious diseases of global importance. Each of these global health threats requires a multifaceted response involving a variety of public health measures such as surveillance; public education and other prevention efforts; vector control; sanitation; programs to improve nutritional status; and the efficient provision of health services including available treatments and vaccines. In addition to these public health considerations critical components of any strategic approach to the control of infectious diseases are basic and clinical research efforts to improve the diagnosis prevention and treatment of the disease in question. In this regard the potential for biomedical research to provide the tools for lasting solutions to the major infectious disease killers and all diseases that afflict mankind is enormous. It remains critical that the medical and public health communities continue to argue cogently for adequate attention and sustained research support for all diseases of global health importance. The biomedical research experience with the AIDS epidemic should serve as an important paradigm in the pursuit of this goal.