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Circulation Research May 2024HIV infection and antiretroviral therapy alter mitochondrial function, which can progressively lead to mitochondrial damage and accelerated aging. The interaction... (Review)
Review
HIV infection and antiretroviral therapy alter mitochondrial function, which can progressively lead to mitochondrial damage and accelerated aging. The interaction between persistent HIV reservoirs and mitochondria may provide insight into the relatively high rates of cardiovascular disease and mortality in persons living with HIV. In this review, we explore the intricate relationship between HIV and mitochondrial function, highlighting the potential for novel therapeutic strategies in the context of cardiovascular diseases. We reflect on mitochondrial dynamics, mitochondrial DNA, and mitochondrial antiviral signaling protein in the context of HIV. Furthermore, we summarize how toxicities related to early antiretroviral therapy and current highly active antiretroviral therapy can contribute to mitochondrial dysregulation, chronic inflammation, and poor clinical outcomes. There is a need to understand the mechanisms and develop new targeted therapies. We further consider current and potential future therapies for HIV and their interplay with mitochondria. We reflect on the next-generation antiretroviral therapies and HIV cure due to the direct and indirect effects of HIV persistence, associated comorbidities, coinfections, and the advancement of interdisciplinary research fields. This includes exploring novel and creative approaches to target mitochondria for therapeutic intervention.
Topics: Humans; HIV Infections; Cardiovascular Diseases; Mitochondria; DNA, Mitochondrial; Animals; Antiretroviral Therapy, Highly Active; Mitochondrial Dynamics; Anti-HIV Agents
PubMed: 38781302
DOI: 10.1161/CIRCRESAHA.124.324296 -
Circulation Research May 2024People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people... (Review)
Review
People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8 and CD4 T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1β, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.
Topics: Humans; HIV Infections; Atherosclerosis; Inflammation; Animals; Immunity, Innate
PubMed: 38781301
DOI: 10.1161/CIRCRESAHA.124.323891 -
Ecology and Evolution May 2024Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere caused by spirochetes belonging to the sensu lato (sl) complex. spirochetes...
Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere caused by spirochetes belonging to the sensu lato (sl) complex. spirochetes circulate in obligatory transmission cycles between tick vectors and different vertebrate hosts. To successfully complete this complex transmission cycle, sl encodes for an arsenal of proteins including the PFam54 protein family with known, or proposed, influences to reservoir host and/or vector adaptation. Even so, only fragmentary information is available regarding the naturally occurring level of variation in the PFam54 gene array especially in relation to Eurasian-distributed species. Utilizing whole genome data from isolates ( = 141) originated from three major LB-causing species across Eurasia (, , and ), we aimed to characterize the diversity of the PFam54 gene array in these isolates to facilitate understanding the evolution of PFam54 paralogs on an intra- and interspecies level. We found an extraordinarily high level of variation in the PFam54 gene array with 39 PFam54 paralogs belonging to 23 orthologous groups including five novel paralogs. Even so, the gene array appears to have remained fairly stable over the evolutionary history of the studied species. Interestingly, genes outside Clade IV, which contains genes encoding for proteins associated with pathogenesis, more frequently displayed signatures of diversifying selection between clades that differ in hypothesized vector or host species. This could suggest that non-Clade IV paralogs play a more important role in host and/or vector adaptation than previously expected, which would require future lab-based studies to validate.
PubMed: 38779535
DOI: 10.1002/ece3.11397 -
Communications Medicine May 2024In 2022 the WHO recommended the discretionary expansion of the eligible age range for seasonal malaria chemoprevention (SMC) to children older than 4 years. Older...
BACKGROUND
In 2022 the WHO recommended the discretionary expansion of the eligible age range for seasonal malaria chemoprevention (SMC) to children older than 4 years. Older children are at lower risk of clinical disease and severe malaria so there has been uncertainty about the cost-benefit for national control programmes. However, emerging evidence from laboratory studies suggests protecting school-age children reduces the infectious reservoir for malaria and may significantly impact on transmission. This study aimed to assess whether these effects were detectable in the context of a routinely delivered SMC programme.
METHODS
In 2021 the Gambia extended the maximum eligible age for SMC from 4 to 9 years. We conducted a prospective population cohort study over the 2021 malaria transmission season covering 2210 inhabitants of 10 communities in the Upper River Region, and used a household-level mixed modelling approach to quantify impacts of SMC on malaria transmission.
RESULTS
We demonstrate that the hazard of clinical malaria in older participants aged 10+ years ineligible for SMC decreases by 20% for each additional SMC round per child 0-9 years in the same household. Older inhabitants also benefit from reduced risk of asymptomatic infections in high SMC coverage households. Spatial autoregression tests show impacts are highly localised, with no detectable spillover from nearby households.
CONCLUSIONS
Evidence for the transmission-reducing effects of extended-age SMC from routine programmes implemented at scale has been previously limited. Here we demonstrate benefits to the entire household, indicating such programmes may be more cost-effective than previously estimated.
PubMed: 38778226
DOI: 10.1038/s43856-024-00503-0 -
Frontiers in Veterinary Science 2024is a bacterial pathogen capable of causing serious disease in humans and abortions in goats. Infected goats can shed . through urine, feces, and parturient byproducts,...
is a bacterial pathogen capable of causing serious disease in humans and abortions in goats. Infected goats can shed . through urine, feces, and parturient byproducts, which can lead to infections in humans when the bacteria are inhaled. Goats are important . reservoirs as evidenced by goat-related outbreaks across the world. To better understand the current landscape of . infection in the domestic goat population, 4,121 vaginal swabs from 388 operations across the United States were analyzed for the presence of . by IS1111 PCR as part of the United States Department of Agriculture, Animal Plant Health Inspection Service, Veterinary Services' National Animal Health Monitoring System Goats 2019 Study. In total, 1.5% (61/4121) of swabs representing 10.3% (40/388) (weighted estimate of 7.8, 95% CI 4.4-13.5) of operations were positive for . DNA. The quantity of . on positive swabs was low with an average Ct of 37.9. Factors associated with greater odds of testing positive included suspected Q fever in the herd in the previous 3 years, the presence of wild deer or elk on the operation, and the utilization of hormones for estrus synchronization. Factors associated with reduced odds of testing positive include the presence of kittens and treatment of herds with high tannin concentrate plants, diatomaceous earth, and tetrahydropyrimidines. analysis demonstrated an inhibitory effect of the tetrahydropyrimidine, pyrantel pamoate, on the growth of . in axenic media as low as 1 μg per mL. The final multivariable logistic regression modeling identified the presence of wild predators on the operation or adjacent property (OR = 9.0, 95% CI 1.3-61.6, value = 0.0248) as a risk factor for . infection.
PubMed: 38774910
DOI: 10.3389/fvets.2024.1393296 -
Journal of Mathematical Biology May 2024Malaria is a vector-borne disease that exacts a grave toll in the Global South. The epidemiology of Plasmodium vivax, the most geographically expansive agent of human...
Malaria is a vector-borne disease that exacts a grave toll in the Global South. The epidemiology of Plasmodium vivax, the most geographically expansive agent of human malaria, is characterised by the accrual of a reservoir of dormant parasites known as hypnozoites. Relapses, arising from hypnozoite activation events, comprise the majority of the blood-stage infection burden, with implications for the acquisition of immunity and the distribution of superinfection. Here, we construct a novel model for the transmission of P. vivax that concurrently accounts for the accrual of the hypnozoite reservoir, (blood-stage) superinfection and the acquisition of immunity. We begin by using an infinite-server queueing network model to characterise the within-host dynamics as a function of mosquito-to-human transmission intensity, extending our previous model to capture a discretised immunity level. To model transmission-blocking and antidisease immunity, we allow for geometric decay in the respective probabilities of successful human-to-mosquito transmission and symptomatic blood-stage infection as a function of this immunity level. Under a hybrid approximation-whereby probabilistic within-host distributions are cast as expected population-level proportions-we couple host and vector dynamics to recover a deterministic compartmental model in line with Ross-Macdonald theory. We then perform a steady-state analysis for this compartmental model, informed by the (analytic) distributions derived at the within-host level. To characterise transient dynamics, we derive a reduced system of integrodifferential equations, likewise informed by our within-host queueing network, allowing us to recover population-level distributions for various quantities of epidemiological interest. In capturing the interplay between hypnozoite accrual, superinfection and acquired immunity-and providing, to the best of our knowledge, the most complete population-level distributions for a range of epidemiological values-our model provides insights into important, but poorly understood, epidemiological features of P. vivax.
Topics: Humans; Plasmodium vivax; Superinfection; Malaria, Vivax; Animals; Mathematical Concepts; Mosquito Vectors; Disease Reservoirs; Models, Biological; Computer Simulation; Anopheles
PubMed: 38772937
DOI: 10.1007/s00285-024-02088-7 -
Clinical Parkinsonism & Related... 2024Parkinson's disease (PD) is associated with increased mortality risk (MR), reflecting progression of motor and nonmotor symptoms. PD psychosis (PDP), a common nonmotor... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is associated with increased mortality risk (MR), reflecting progression of motor and nonmotor symptoms. PD psychosis (PDP), a common nonmotor symptom, increases with prolonged disease and elevates the MR of PD even further. Pimavanserin is the only FDA-approved treatment for PDP. This review summarizes real-world evidence around the MR of patients with PDP treated with pimavanserin versus off-label atypical antipsychotics.
METHODS
A PubMed search was conducted using the following search terms: AND AND AND AND . Inclusion criteria specified the entry of retrospective, observational, and open-label studies comparing pimavanserin to atypical antipsychotics or untreated controls.
RESULTS
A total of 10 of the 32 articles met inclusion criteria. Among five comparisons of pimavanserin with atypical antipsychotics, two were large (n = 21,719; n = 21,975), representative, Medicare-database studies, which demonstrated comparable or lower all-cause pimavanserin MR. Among three pimavanserin versus control studies, two reported lower or comparable pimavanserin MR and one, long-term care study reported higher MR for pimavanserin versus non-pimavanserin treated patients with unknown PDP status. Two open-label extensions reported pimavanserin mortality rates of 6.45 and 18.8 deaths per 100 patient-years, which are comparable to, or lower than, mortality rates for PD, PDP, and other atypical antipsychotics. Most studies (70 %; 7 of 10) demonstrated pimavanserin's MR was lower than or similar to other atypical antipsychotics or untreated controls.
CONCLUSIONS
Pimavanserin did not increase the MR in PDP. Pimavanserin's MR appears to be comparable to or lower than other atypical antipsychotics prescribed for PDP, including quetiapine.
PubMed: 38770047
DOI: 10.1016/j.prdoa.2024.100256 -
Gut Microbes 2024Inflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA)... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship. Specifically, the diversity of the gut microbiota influences BA composition, whereas altered BA profiles can disrupt the microbiota. IBD patients often exhibit increased primary bile acid and reduced secondary bile acid concentrations due to a diminished bacteria population essential for BA metabolism. This imbalance activates BA receptors, undermining intestinal integrity and immune function. Consequently, targeting the microbiota-BA axis may rectify these disturbances, offering symptomatic relief in IBD. Here, the interplay between gut microbiota and bile acids (BAs) is reviewed, with a particular focus on the role of gut microbiota in mediating bile acid biotransformation, and contributions of the gut microbiota-BA axis to IBD pathology to unveil potential novel therapeutic avenues for IBD.
Topics: Gastrointestinal Microbiome; Inflammatory Bowel Diseases; Humans; Bile Acids and Salts; Animals; Bacteria; Dysbiosis; Gastrointestinal Tract
PubMed: 38769683
DOI: 10.1080/19490976.2024.2356284 -
PloS One 2024Streptococcus pneumoniae is a leading cause of morbidity and mortality globally, causing bacteremic pneumonia, meningitis, sepsis, and other invasive pneumococcal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Streptococcus pneumoniae is a leading cause of morbidity and mortality globally, causing bacteremic pneumonia, meningitis, sepsis, and other invasive pneumococcal diseases. Evidence supports nasopharyngeal pneumococcal carriage as a reservoir for transmission and precursor of pneumococcal disease.
OBJECTIVES
To estimate the pneumococcal nasopharyngeal burden in all age groups in Latin America and the Caribbean (LAC) before, during, and after the introduction of pneumococcal vaccine conjugate (PVC).
METHODS
Systematic literature review of international, regional, and country-published and unpublished data, together with reports including data from serotype distribution in nasopharyngeal carriage in children and adults from LAC countries following Cochrane methods. The protocol was registered in PROSPERO database (ID: CRD42023392097).
RESULTS
We included 54 studies with data on nasopharyngeal pneumococcal carriage and serotypes from 31,803 patients. In children under five years old, carriage was found in 41% and in adults over 65, it was 26%. During the study period, children under five showed a colonization proportion of 34% with PCV10 serotypes and 45% with PCV13 serotypes. When we analyze the carriage prevalence of PCV serotypes in all age groups between 1995 and 2019, serotypes included in PCV10 and those included in PCV13, both showed a decreasing trend along analysis by lustrum.
CONCLUSION
The data presented in this study highlights the need to establish national surveillance programs to monitor pneumococcal nasopharyngeal carriage to monitor serotype prevalence and replacement before and after including new pneumococcal vaccines in the region. In addition, to analyze differences in the prevalence of serotypes between countries, emphasize the importance of approaches to local realities to reduce IPD effectively.
Topics: Humans; Streptococcus pneumoniae; Latin America; Caribbean Region; Nasopharynx; Pneumococcal Infections; Carrier State; Pneumococcal Vaccines; Serogroup; Child, Preschool; Adult; Child; Prevalence
PubMed: 38768099
DOI: 10.1371/journal.pone.0297767 -
Emerging Microbes & Infections Dec 2024Improved sanitation, increased access to health care, and advances in preventive and clinical medicine have reduced the mortality and morbidity rates of several... (Review)
Review
Improved sanitation, increased access to health care, and advances in preventive and clinical medicine have reduced the mortality and morbidity rates of several infectious diseases. However, recent outbreaks of several emerging infectious diseases (EIDs) have caused substantial mortality and morbidity, and the frequency of these outbreaks is likely to increase due to pathogen, environmental, and population effects driven by climate change. Extreme or persistent changes in temperature, precipitation, humidity, and air pollution associated with climate change can, for example, expand the size of EID reservoirs, increase host-pathogen and cross-species host contacts to promote transmission or spillover events, and degrade the overall health of susceptible host populations leading to new EID outbreaks. It is therefore vital to establish global strategies to track and model potential responses of candidate EIDs to project their future behaviour and guide research efforts on early detection and diagnosis technologies and vaccine development efforts for these targets. Multi-disciplinary collaborations are demanding to develop effective inter-continental surveillance and modelling platforms that employ artificial intelligence to mitigate climate change effects on EID outbreaks. In this review, we discuss how climate change has increased the risk of EIDs and describe novel approaches to improve surveillance of emerging pathogens that pose the risk for EID outbreaks, new and existing measures that could be used to contain or reduce the risk of future EID outbreaks, and new methods to improve EID tracking during further outbreaks to limit disease transmission.
Topics: Humans; Climate Change; Communicable Diseases, Emerging; Animals; Disease Outbreaks
PubMed: 38767202
DOI: 10.1080/22221751.2024.2356143