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Current medical research suggests that latently infected cells are the primary source of the virus's resistance to elimination. Moreover, these cells can participate in cell–cell transmission. Human immunodeficiency virus type 1 (HIV-1) can transmit to CD4 + T cells by three transmission modes, cell-free, latent cell–cell and active cell–cell. Incorporating the effect of latent infection, weakened humoral and CTL responses as well as three transmission modes, we investigate two generalized HIV-1 dynamics models. Three general incidence functions are used to represent the three viral transmission modes. Our proposed models extend and generalize many viral infection models presented in the virology literature. We begin by demonstrating the solutions' boundedness and nonnegativity which guarantee the model's wellposedness. We calculate the model's basic reproduction ratio (ℜ 0). We establish that the model admits two steady-states, namely, virus-free steady-state and virus-persistence steady-state. Through application of Lyapunov's approach and LaSalle's invariance principle, we demonstrate the global stability of each state-state. For two special forms of the general incidence functions, Holling type-II incidence and Crowley–Martin incidence, we provide numerical simulations to validate our theoretical findings. We illustrate how time delay and weakened adaptive immunity affect HIV-1 dynamics. More specifically, numerical data support our theoretical conclusions on the stability of steady-states. To demonstrate the impact of the parameter values on ℜ 0 , we examine the sensitivity analysis. We have demonstrated that each of the three viral transmission modes adds to ℜ 0 , and that ℜ 0 would be underestimated if any one of them were ignored. This might lead to inadequate medication effectiveness that aims to remove the viruses from the body. The effects of weakened adaptive immunity and time delay on HIV-1 progression are examined. As per our findings, reduced adaptive immunity plays a crucial role in the proliferation of the infection. Weaken adaptive immunity can lead to the acquired immune deficiency syndrome (AIDS) and give a chance for opportunistic infections. We showed that ℜ 0 fall as a function of both medication efficacy and delay parameter. If a model with time delays is used, fewer treatment efficacies will be required to maintain the system at the virus-free steady-state and eradicate HIV-1 from the body. Our study's findings can help us better understand HIV-1 dynamics in the host and can also guide the development of new pharmacological therapies. [ABSTRACT FROM AUTHOR]

Viruses sense cellular states and environmental signals by recruiting host transcription factors to cis -regulatory elements (CREs) in viral genomes. Viral CREs act as signal integration hubs that impart specificity to viral gene regulation. Viral CREs are highly evolvable due to their high mutation rate and ability to rapidly change sensing mechanisms, affecting infection spread and patient outcomes. Latent viral infections can be treated by targeting viral CREs for reactivation or permanent silencing. To withstand a hostile cellular environment and replicate, viruses must sense, interpret, and respond to many internal and external cues. Retroviruses and DNA viruses can intercept these cues impinging on host transcription factors via cis -regulatory elements (CREs) in viral genomes, allowing them to sense and coordinate context-specific responses to varied signals. Here, we explore the characteristics of viral CREs, the classes of signals and host transcription factors that regulate them, and how this informs outcomes of viral replication, immune evasion, and latency. We propose that viral CREs constitute central hubs for signal integration from multiple pathways and that sequence variation between viral isolates can rapidly rewire sensing mechanisms, contributing to the variability observed in patient outcomes. [ABSTRACT FROM AUTHOR]

Retinal photography was performed in pregnancy and postpartum in pregnant Hispanic women with latent Toxoplasma gondii (TG) infection in order to screen for characteristic retinal lesions or the particular scars found in people with active T. gondii infection. A comparison group of TG negative women was included in the study but they did not have retinal photography. The goal of the parent study was to assess for adverse pregnancy events and evidence for parasite reactivation in TG positive (TG +) women, through examination of the eyes for characteristic lesions. Retinal photography, usually at prenatal visits 2 (17 +/- 3.35 weeks) and 3 (26.3+/-1.75) weeks, was done on TG + women. Fifty-six of these women also (43 %) had retinal photography at the postpartum visit. Health and demographic data were obtained at the first prenatal visit for all women. From the 690 recruited at the first prenatal visit, 128 TG – women and 158 TG + women were enrolled in a prospective study through pregnancy and the postpartum. All TG- women (n = 532) provided data at the first prenatal visit and throughout their pregnancy and birth through the EHR. This allowed comparison of health and outcome data for the TG + compared to a larger number of TG- Hispanic pregnant women. While there was no evidence of ocular toxoplasmosis during pregnancy, there was a surprisingly large number (42 %) of TG + women with diabetic retinopathy (DR). We also observed that TG + women had a 20 % incidence of gestational diabetes mellitus (GDM) compared to 11.3 % in the TG- women (p = 0.01). At postpartum (mean 5.6 weeks), 23 of 30 women with pregnancy DR showed no DR in the postpartum. No characteristic T. gondii lesions were discovered. Retinal photography serendipitously revealed DR in these T. gondii positive women. It was also found that latent TG infection was associated with increased incidence of GDM. Hispanic pregnant women's increased risk for latent TG infection, GDM and DR are underappreciated. Retinal photography may need to be considered an innovative approach to screening. [ABSTRACT FROM AUTHOR]

Despite antiretroviral therapy (ART), chronic forms of HIVassociated neurocognitive disorders (HAND) affect an estimated 50% of individuals living with HIV, greatly impacting their quality of life. The prevailing theory of HAND progression posits that chronic inflammation arising from the activation of latent viral reservoirs leads to progressive damage in the central nervous system (CNS). Recent evidence indicates that blood-brain barrier (BBB) pericytes are capable of active HIV-1 infection; however, their latent infection has not been defined. Given their location and function, BBB pericytes are poised to be a key viral reservoir in the development of HAND. We present the first transcriptional analysis of uninfected, active, and latent human BBB pericytes, revealing distinct transcriptional phenotypes. In addition, we demonstrate that latent infection of BBB pericytes relies on AKT signaling for reservoir survival. These findings provide insight into the state of reservoir maintenance in the CNS during HIV-1 infection and provide novel targets for reservoir clearance. [ABSTRACT FROM AUTHOR]

Adenovirus (AdV) is a common cause of mild respiratory tract and gastrointestinal tract infections in immunocompetent children and adults. Among hematopoietic stem cell (HSCT) and solid organ transplant (SOT) recipients, such infections can be severe and lead to significant morbidity and mortality. The prevalence of AdV infections in immunocompromised individuals varies according to the degree of immunosuppression and age, with such infection due to either primary infections or reactivation of latent virus. Diagnosis of AdV is frequently made using molecular test methods, mainly qualitative and quantitative polymerase chain reaction (PCR) assays. Qualitative-PCR assays provide a presumptive diagnosis of AdV infections, while serial quantitative-PCR assay results provide clinical specificity in determining the significance of AdV detection in immunocompromised patients. Since AdV can be detected in various clinical specimens obtained from asymptomatic individuals, clinical correlation of positive AdV DNA test results is essential for clinical management of HSCT and SOT recipients. [ABSTRACT FROM AUTHOR]

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug–drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients. [ABSTRACT FROM AUTHOR]

At the core entry process of human herpesviruses (HHVs), the glycoprotein H and L (gHgL)-based entry complex (EC) induces conformational change (pre- to post-fusion) of the fusogen glycoprotein B (gB). Vaccines and neutralizing antibodies (nAbs) against EC and gB are tested in clinical trials to prevent HHV infection. New structures of pre-gB are shorter with different arrangements of domains compared to post-gB. From pre-gB to post-gB transition, domain I, II, and V flip around the center, while buried domian IV is exposed to form a crown. Vaccines comprising pre-gB are predicted to be more effective. The structures of ECs and their receptors continue to be determined, further uncovering new neutralizing epitopes and mechanisms while characterizing the molecular processes of HHV entry. Structure-based approaches in vaccine design include stabilizing pre-gB, refining the fusion signal transmission model, and identifying more potent nAbs. Herpesviruses are among the most successful viruses found in human populations. They establish lifelong latent infections, which are punctuated by recurrent reactivations. The entry process of herpesviruses into specific target cells requires a well-orchestrated teamwork involving multiple envelope glycoproteins. The conserved glycoprotein B (gB) is the membrane fusogen, of which conformational changes are induced by an entry complex (EC) consisting of at least gH and gL. Despite the high prevalence and heavy disease burdens associated with human herpesviruses (HHVs), vaccines against these pathogens are still lacking, except for varicella zoster virus (VZV). Recent advances in understanding the coordinated mechanisms of action of the key EC glycoproteins and fusogen will help to improve approaches for effective vaccine development and neutralizing antibody (nAb) screening. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) latency in CD34+ progenitor cells is the outcome of a complex and continued interaction of virus and host that is initiated during very early stages of infection and reflects pro- and anti-viral activity. We hypothesized that a key event during early infection could involve changes to host miRNAs, allowing for rapid modulation of the host proteome. Here, we identify 72 significantly upregulated miRNAs and three that were downregulated by 6hpi of infection of CD34+ cells which were then subject to multiple in silico analyses to identify potential genes and pathways important for viral infection. The analyses focused on the upregulated miRNAs and were used to predict potential gene hubs or common mRNA targets of multiple miRNAs. Constitutive deletion of one target, the transcriptional regulator JDP2, resulted in a defect in latent infection of myeloid cells; interestingly, transient knockdown in differentiated dendritic cells resulted in increased viral lytic IE gene expression, arguing for subtle differences in the role of JDP2 during latency establishment and reactivation of HCMV. Finally, in silico predictions identified clusters of genes with related functions (such as calcium signaling, ubiquitination, and chromatin modification), suggesting potential importance in latency and reactivation. Consistent with this hypothesis, we demonstrate that viral IE gene expression is sensitive to calcium channel inhibition in reactivating dendritic cells. In conclusion, we demonstrate HCMV alters the miRNAome rapidly upon infection and that in silico interrogation of these changes reveals new insight into mechanisms controlling viral gene expression during HCMV latency and, intriguingly, reactivation. [ABSTRACT FROM AUTHOR]

• Pulmonary nodules before intestinal transplant are common, however, associated pulmonary infections are rare. • Appearance of new or worsening pulmonary nodules does not appear to directly correlate with pulmonary infections after intestinal transplant. • Routine computed tomography chest scans are not recommended in the pretransplant period. Pulmonary nodules in asymptomatic patients could represent latent pulmonary infections. Intestinal transplant (ITx) recipients with preexisting lung nodules might be at higher risk for pulmonary infections. However, data is scarce. This retrospective study included adult patients who underwent ITx from May 2016 to May 2020. Chest computed tomography scans performed within 12 months before ITx were obtained to evaluate for preexisting pulmonary nodules. Screening for endemic mycoses, Aspergillus, Cryptococcus, and latent tuberculosis infection performed within 12 months before ITx was obtained. We assessed for worsening pulmonary nodules, and fungal and mycobacterial infections during the first year post-transplant. Survival and graft loss at 1-year post-transplant was also assessed. Forty-four patients underwent ITx. Thirty-one had preexisting lung nodules. No invasive fungi were recorded in the pretransplant period and one individual had latent tuberculosis infection. In the post-transplant period, one individual developed probable invasive aspergillosis and had worsening nodular opacities, whereas one had disseminated histoplasmosis with stable lung nodules in chest computed tomography. No mycobacterial infections were documented. The cohort survival was 84% at 12 months after transplant. Preexisting pulmonary nodules were common in the cohort (71%), yet latent and active pulmonary infections were rare. Appearance of new or worsening pulmonary nodules does not appear to directly correlate with pulmonary infections in the post-transplant period. Routine chest computed tomography is not recommended in the pretransplant period, but follow-up is favored in patients with confirmed nodular opacities. Clinical monitoring is essential. [ABSTRACT FROM AUTHOR]

• We assessed the differential expression of biomarkers in symptomatic presumptive participants later confirmed with tuberculosis, latent pulmonary TB infection (LTBI) or no-LTBI. • We identified candidate biomarkers that were differentially expressed among the three patient groups. • A bio-signature comprising IFNγ, IL1ra, and eotaxin predicted LTBI among symptomatic presumptive pulmonary tuberculosis (PTB) participants without active TB. • A bio-signature comprising IL6, IL1ra, TNF-α, IL-1β, IP10, and IL12p70 identified participants with active PTB. • The identified biomarkers may be considered as additional candidates for future TB point-of-care tests. There is a need for new tools for the diagnosis of tuberculosis (TB) amongst patients who present at primary health care centers with symptoms suggestive of TB. To assess the abilities of selected blood-based host biomarkers to discriminate between patients who self-presented with symptoms suggestive of TB and were subsequently diagnosed with pulmonary tuberculosis (PTB), other respiratory diseases (ORD) with latent Mycobacterium tuberculosis infection (ORD_LTBI) or ORD without latent infection (ORD_NoLTBI). Presumptive TB patients (n = 161) were enrolled at a TB Clinic in Kampala, Uganda, and blood was collected. Participants were later classified as having PTB or ORD using standard microbiological confirmatory tests. Patients with ORD were subsequently classified as having LTBI or no LTBI using the QuantiFERON Gold-plus test. The concentrations of 27 host biomarkers were evaluated in patient sera using the Luminex platform, followed by an evaluation of their abilities to discriminate between PTB, ORD_LTBI, and ORD_NoLTBI. Multiple host biomarkers including IP10, IL6, IL2, IL1β, TNFα, IFNγ, and IL12p70, were significantly different between patients with PTB (n = 55), ORDs (n = 106), and between PTB and the two ORD sub-groups. A bio-signature comprising IP10, IL6, TNFα IL1β, IL1ra, and IL12p70 best diagnosed PTB disease, with an area under the ROC curve of 90. We identified host biomarkers that discriminated between different M.tb infection states amongst patients who presented with symptoms requiring investigation for TB. The biomarkers that showed diagnostic potential in our study may be considered as additional candidate markers for future active PTB rapid screening tests. [ABSTRACT FROM AUTHOR]

• Propose a Group-Disentangled Representation Learning framework (GDRL). • Introduce an implicit group-swap structure. • Extract linking relationship between semantical concepts of pathology and visual features. • Demonstrate that GDRL can significantly improve classification accuracy. Deep learning methods have shown significant performance in medical image analysis tasks. However, they generally act like "black box" without explanations in both feature extraction and decision processes, leading to lack of clinical insights and high risk assessments. To aid deep learning in envisioning diseases with visual clues, we propose a novel Group-Disentangled Representation Learning framework (GDRL). The key contribution is that GDRL completely disentangles latent space into disease concepts with abundant and non-overlapping feature related explanations, thus enhancing interpretability in feature extraction and decision processes. Furthermore, we introduce an implicit group-swap structure by emphasizing the linking relationship between semantical concepts of disease and low-level visual features, other than explicit explanations on general objects and their attributes. We demonstrate our framework on predicting four categories of diseases from chest X-ray images. The AUROC of GDRL on ChestX-ray14 for thoracic pathologic prediction are 0.8630, 0.8980, 0.9269 and 0.8653 respectively, and we showcase the potential of our framework in enhancing interpretability of the factors contributing to different diseases. [ABSTRACT FROM AUTHOR]

Mathematical models have been considered as a robust tool to support biological and medical studies of the coronavirus disease 2019 (COVID-19). This new disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This paper develop a within-host SARS-CoV-2 dynamics model with logistic growth for healthy epithelial cells, humoral (antibody) immune response and general SARS-CoV-2-target incidence rate. The model is incorporated with four mixed (distributed/discrete) time delays, delay in the formation of latent infected epithelial cells, delay in the formation of active infected epithelial cells, delay in the activation of latent infected epithelial cells, and maturation delay of new SARS-CoV-2 particles. The model is formulated as a system of delay differential equations (DDEs). We establish that the model's solutions are non-negative and ultimately bounded. We deduce that the model has three equilibria and their existence and stability are perfectly determined by two threshold parameters. We prove the global stability of the model's equilibria by utilizing the Lyapunov method and applying the LaSalle's invariance principle. To support and illustrate our theoretical findings we present numerical simulations for the model with a special form of the general incidence rate function. The effect of time delays on the SARS-CoV-2 dynamics is addressed. We observe that increasing time delays values can have the same impact as drug therapies in suppressing viral progression. [ABSTRACT FROM AUTHOR]

Cyprinid herpesvirus 1 (CyHV-1) disease induced by CyHV-1 (Cyvirus cyprinidallo1) causes mortality in common carp (Cyprinus carpio) and formation of tumors on the skin of infection-tolerant fish. Similar to other viruses in the Orthoherpesviridae family, CyHV-1 appears to establish latent infections. However, information regarding the mechanisms of genetic conservation for a prolonged period and tumorigenesis by CyHV-1 is limited. Here, we aimed to reveal i) potential tissues where the virus establishes persistent infection, and ii) the transcriptome characteristics of tumors formed in common carp infected with CyHV-1. In fish experimentally infected with the virus, the presence of the viral genome was observed in kidney, spleen, and gill tissue at 300 days post injection, a long time after the injection. This result suggests that CyHV-1 may utilize one or more of these tissues for its persistency. In fish naturally infected with CyHV-1 at a fish farm, transcriptome analysis showed substantial quantities of viral transcripts in tumor tissue. Of the 5 most abundant viral transcripts expressed in the tumor tissue, 4 transcripts (ORF81, ORF78, ORF31, and ORF72) are believed to encode virion proteins. This indicates the virus was active in the tumor tissue. Pathways altered in tumor tissue included those related to viral infection or cancer cells, suggesting that viral infection and tumor formation affect the metabolism of the host. This study is the first to report the likely persistent tissues of CyHV-1 and molecular mechanisms involved in tumor formation caused by an oncogenic virus in fish. These findings contribute to the development of quarantine measures for CyHV-1 and provide insights into the oncogenic mechanism of fish viruses. • CyHV-1 DNA was detected in immune tissue of carp at least 300 days post infection. • The virus was propagated actively in tumor tissue of virus-infected fish. • Metabolic pathways were disturbed in the tumor tissue. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nineteen compounds were identified that possessed IC 50 values from 10 µM to 340 nM. • The most potent inhibitor was MMV 1580488 (17), which was observed to have an IC 50 of 340 nM. • Docking experiments show that the inhibitors are predicted to bind in the S1 pocket and S1′ pockets of the Rp MetAp1 enzyme. • The most potent inhibitors are also interacting with the Mn2+ in the active site. Methionine aminopeptidase (MetAp) enzymes catalyze the post-translational removal of the initiator methionine residue in newly synthesized proteins, a process that is often essential in the maturation of proteins. Consequently, these enzymes serve as important targets for drug development. Rickettsia prowazekii (Rp) is an obligate coccobacillus and the causative agent of the louse-borne epidemic typhus and despite adequate treatment causes a latent infection. This research aimed to identify potential anti-rickettsial agents by screening 400 compounds from the MMV Pandemic Response Box against Rp MetAp1. Overall, 19 compounds were identified that possessed IC 50 values from 10 µM to 340 nM. The most potent inhibitor was MMV 1580488 (17), which was observed to have an IC 50 of 340 nM. The selected hits serve as chemical leads that can be used for the development of potent inhibitors of the Rp MetAp1 enzyme. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is one of the leading causes of death from infectious diseases, killing approximately 1.3 million people worldwide in 2022 alone. The current vaccine for TB contains a live attenuated bacterium, Mycobacterium bovis BCG (Bacille Calmette-Guérin). The BCG vaccine is highly effective in preventing severe forms of childhood TB but does not protect against latent infection or disease in older age groups. A new or improved BCG vaccine for prevention of pulmonary TB is urgently needed. In this study, we infected murine bone marrow derived dendritic cells from C57BL/6 mice with M. bovis BCG followed by elution and identification of BCG-derived MHC class I and class II-bound peptides using tandem mass spectrometry. We identified 1436 MHC-bound peptides of which 94 were derived from BCG. Fifty-five peptides were derived from MHC class I molecules and 39 from class II molecules. We tested the 94 peptides for their immunogenicity using IFN- γ ELISPOT assay with splenocytes purified from BCG immunized mice and 10 showed positive responses. Seven peptides were derived from MHC II and three from MHC class I. In particular, MHC class II binding peptides derived from the mycobacterial surface lipoprotein Mpt83 were highly antigenic. Further evaluations of these immunogenic BCG peptides may identify proteins useful as new TB vaccine candidates. [ABSTRACT FROM AUTHOR]

Herpesviruses-encoded microRNAs (miRNAs) have been discovered to be essential regulators in viral life cycle, participating in viral replication, latent or lytic infection, and immunological escape. However, the roles of miRNAs encoded by duck plague virus (DPV) are still unknown. Dev-miR-D28-3p is a miRNA uniquely encoded by DPV CHv strain. The aim of this study was to explore the effect of dev-miR-D28-3p on DPV replication and explore the potential mechanisms involved. Our findings demonstrated that transfection of dev-miR-D28-3p mimic into duck embryo fibroblasts (DEFs) effectively suppressed viral copies, viral titers and viral protein expressions during DPV infection, while the results above were reversed after transfection with dev-miR-D28-3p inhibitor. Subsequently, we further discovered that dev-miR-D28-3p specifically bound to DPV-encoded UL27 and inhibited its expression, suggesting that UL27 was the target gene of dev-miR-D28-3p. Finally, we investigated the role of UL27 in DPV replication and found the overexpression of UL27 increased viral copies, viral titers, and viral protein expressions; whereas the opposite results appear when knockdown of UL27. Our findings illustrated a novel mechanism that DPV regulated itself replication via dev-miR-D28-3p, paving the way for exploring the role of DPV-encoded miRNAs. ● DPV-encoded dev-miR-D28-3p inhibits DPV replication. ● Dev-miR-D28-3p targets and inhibits DPV UL27. ● DPV UL27 regulates DPV replication. [ABSTRACT FROM AUTHOR]

This paper is concerned with the dual influences of climate change and distributed delay on dynamics of a vector-borne disease model. Compared to the previous works, the effect of climate change in a latent infection model is first considered since it increases the viral transmission probability of cross species. To deal with the non-monotonicity and heterogeneity of the model, we use some new ideas to investigate the spatio-temporal dynamics. The theoretical analyses suggest that three scenarios will occur as follows (i) If the disease persistence ahead of the climate change, the disease will die out by limiting the propagation speed of susceptible or infected individuals. (ii) The emergence of pulse type epidemic wave is obtained, which means the disease switches rapidly between persistence and disappearance. (iii) If susceptible individuals track the speed of climate change while infected individuals do not, the disease cannot evolve to the endemic disease. [ABSTRACT FROM AUTHOR]

• A recombinant protein subunit vaccine A986 expressing three latency antigens and one early secreted antigen Ag85A was constructed. • A986 adjuvanted with MPL/QS21 induced robust cellular and humoral immune responses in mice. • A986 adjuvanted with MPL/QS21 induced immune protection against Mtb infection in naïve and BCG-primed mice. The eradication of tuberculosis remains a global challenge. Despite being the only licensed vaccine, Bacillus Calmette-Guérin (BCG) confers limited protective efficacy in adults and individuals with latent tuberculosis infections (LTBI). There is an urgent need to develop novel vaccines that can enhance the protective effect of BCG. Protein subunit vaccines have garnered significant research interest due to their safety and plasticity. Based on previous studies, we selected three antigens associated with LTBI (Rv2028c, Rv2029c, Rv3126c) and fused them with an immunodominant antigen Ag85A, resulting in the construction of a multistage protein subunit vaccine named A986. We evaluated the protective effect of recombinant protein A986 adjuvanted with MPL/QS21 as a booster vaccine for BCG against Mycobacterium tuberculosis (Mtb) infection in mice. The A986 + MPL/QS21 induced the secretion of antigen-specific Th1 (IL-2+, IFN-γ+ and TNF-α+) and Th17 (IL-17A+) cytokines in CD4+ and CD8+ T cells within the lung and spleen of mice, while also increased the frequency of central memory and effector memory T cells. Additionally, it also induced the enhanced production of IgG antibodies. Compared to BCG alone, A986 + MPL/QS21 boosting significantly augmented the proliferation of antigen-specific multifunctional T cells and effectively reduced bacterial load in infected mice. Taken together, A986 + MPL/QS21 formulation induced robust antigen-specific immune responses and provided enhanced protection against Mtb infection as a booster of BCG vaccine. [ABSTRACT FROM AUTHOR]

The Beijing genotype of Mycobacterium tuberculosis (Mtb) has sparked debate regarding its virulence and transmissibility. This study contributes to this discussion by assessing its effect on the risk of latent tuberculosis infection (LTBI), active tuberculosis (TB) disease among contacts, and clustering of known TB cases. We conducted a retrospective cohort study using the records of 4457 culture-confirmed TB patients and their contacts (20,448) reported to the Florida Department of Health between 2009 and 2023. Univariate and multivariate analyses were used to evaluate the effect of the Beijing strain on LTBI, active TB risk among contacts, and case clustering. Our study revealed no significant difference in transmissibility between the Beijing and non-Beijing genotypes among contacts. LTBI prevalence was 19.9%, slightly higher in non-Beijing than Beijing genotypes (20.2% vs. 15.5%, p < 0.001). The prevalence of active TB was 1.8%, with no significant difference between the Beijing and non-Beijing genotypes (1.4% vs. 1.8%, p = 0.296). Increased LTBI risk was associated with older age, male sex, Hispanic ethnicity, multidrug-resistant TB exposure, household exposure, and a longer exposure duration. Active TB risk was higher for males, HIV-positive individuals, and contacts with more prolonged exposure to index cases. The Beijing genotype was associated with increased TB case clustering (aOR = 1.98, 95%CI: 1.53, 2.55, p < 0.001) as compared to the non-Beijing genotypes. US birthplace (aOR = 2.75, 95%CI: 2.37, 3.19, p < 0.001), pulmonary disease (aOR = 1.27, 95%CI: 1.04, 1.56, p < 0.020), cavitary TB (aOR = 1.25, 95% CI: 1.08, 1.44, p < 0.003), previous year alcohol use (aOR = 1.68, 95%CI: 1.38, 2.04, p < 0.001), and recreational drug use (aOR = 1.32, 95%CI: 1.04, 1.67, p < 0.024) were also associated with an increased risk of TB case clustering. While the Beijing genotype did not increase the risk of LTBI or active TB among contacts, it showed a higher tendency for case clustering. Hence, interventions should prioritize populations where this genotype is prevalent. • Large study of TB cases (4457) categorized into Beijing (337) and non-Beijing (4120) genotypes, with their contacts (20,448) • No significant difference in the rate of transmission between the Beijing and non-Beijing genotypes among contacts • Beijing Mtb lineage is associated with increased clustering of TB cases • Findings provide insights into strain heterogeneity effects on TB epidemiology and transmission [ABSTRACT FROM AUTHOR]

Adenovirus infection in transplant recipients may present from asymptomatic viremia to multisystemic involvement. Most frequently, it occurs in the first year after a kidney transplant, and it is secondary to the reactivation of latent disease. However, primary infection may occur, and disseminated disease is more common when related to primary infection. Kidney involvement may be confirmed by biopsy, although diagnosis may be presumptive. Reduction of immunosuppression and supportive care are important components of therapy. A 41-year-old female renal–pancreatic recipient 12 years before with chronic renal graft dysfunction and a functional pancreatic graft had a history of cytomegalovirus and polyoma virus infection 2 years after transplantation. She was taking tacrolimus, mycophenolate mofetil, and prednisolone. The patient was admitted after persistent uncharacteristic diarrhea 3 weeks before hospitalization without any relevant epidemiologic context. She was dehydrated, and the lab results showed worsened kidney function and leucocytosis. The viral culture revealed adenovirus. Vigorous hydration was implemented, and the mycophenolate mofetil dose was reduced. The patient was discharged, and renal function returned to previous values. Adenovirus infection has a wide clinical presentation, and multisystemic involvement may occur in transplant recipients. Supportive care is paramount. The clinical features and viral culture confirm the diagnosis, although tissue samples and quantitative polymerase chain reaction may be required in more severe cases. [ABSTRACT FROM AUTHOR]

• 'Blue skies research' refers to basic science or fundamental research • 'Blue skies research' is essential new TB tools development for eradicating TB • Investments into fundamental TB research in LMICs is long overdue • COVID-19 advances bring hope for more holistic care for all RTIs Investments into 'Blue Skies' fundamental TB research in low- and middle-income countries (LMICs) have not been forthcoming. We highlight why blue skies research will be essential for achieving global TB control and eradicating TB. We review the historical background to early TB discovery research and give examples of where investments into basic science and fundamental 'blue skies research' are delivering novel data and approaches to advance diagnosis, management and holistic care for patients with active and latent TB infection. The COVID-19 pandemic has shown that making available adequate funding for priority investments into 'Blue skies research' to delineate scientific understanding of a new infectious diseases threat to global health security can lead to rapid development and rollout of new diagnostic platforms, treatments, and vaccines. Several advances in new TB diagnostics, new treatments and vaccine development are underpinned by basic science research. Blue Skies research is required to pave the way for a personalized medicine approach for management of TB and other Respiratory Tract Infections and preventing long-term functional disability. Transfer of skills and resources by wealthier nations is required to empower researchers in LMICs countries to engage in and lead Blue Skies research. [ABSTRACT FROM AUTHOR]

• Tuberculosis (TB) incidence was very high among socially marginalized citizens with latent TB • No TB cases were seen in the first 2 years after preventive treatment completion • No reduction in overall TB incidence by preventive treatment was found • TB was associated with concurrent use of alcohol and cannabis Tuberculosis (TB) prevalence is high among socially marginalized citizens in Denmark, and management of latent TB infection (LTBI) may be part of preventing new cases. Patients with LTBI are offered either preventive treatment (TPT) or follow-up chest x-rays, but knowledge about the long-term outcome in terms of active TB is sparse. We performed a retrospective cohort study investigating the long-term outcomes for socially marginalized citizens who were diagnosed with LTBI or who had a positive interferon-gamma release assay (IGRA) but were lost to follow-up. Information on TB examinations, diagnostics, and treatment along with data on death were gathered from medical records from the date of positive IGRA to February 1, 2021. We identified 119 patients with LTBI, 18 of which (15.1%) were diagnosed with TB during the follow-up period (mean, 4.5 years). TPT was completed by 36.1% and the TB incidence rate ratio of those completing TPT to those who did not was 0.78 (confidence interval, 0.25-2.17; P =.6). Of the patients with TB, 16 of 18 achieved treatment success. High rates of TB development are found among socially marginalized citizens with LTBI. Overall incidence of TB was not significantly reduced by administration of TPT, although TB did not develop in the first 2 years following TPT. [ABSTRACT FROM AUTHOR]

• Overall, 6% more female close contacts developed latent tuberculosis infection than men. • Modeling resulted in limited attenuation of observed sex-specific effect sizes. • Subtle differences in quantitative assay measurements may reveal a biological basis. • Findings should be confirmed in other study populations to increase precision. • Yet, this provides some evidence for an unconfounded sex difference. More men than women develop and die of tuberculosis (TB). Fewer data exist on sex differences in latent TB infection (LTBI). We assessed for potential sex differences in LTBI acquisition among close TB contacts. Regional Prospective Observational Research for TB-Brazil is an observational multi-center cohort of individuals with culture-confirmed pulmonary TB and their close contacts. Participants were enrolled from five sites in Brazil from June 2015 - June 2019. Close contacts were followed for 24 months after enrollment, with LTBI defined as a positive interferon-γ release assay (IGRA; QuantiFERON 3rd or 4th generation) at baseline or 6 months. We performed univariate, bivariate, and multivariable logistic regression and propensity-score weighted models to assess odds ratios (OR) and 95% confidence intervals (CI) for LTBI acquisition by birth sex among close contacts. Of 1093, 504 (46%) female close contacts were IGRA positive compared to 295 of 745 (40%) men. The unadjusted OR for IGRA positivity among women vs men was 1.31 (95% CI: 1.08-1.58). Bivariate adjustments yielded ORs in women vs men ranging from 1.19 to 1.33 (P -value range: <0.01-0.07). Multivariable regression and weighted models yielded similar ORs in women vs men, of 1.14 (95% CI: 0.92-1.41) and 1.15 (95% CI: 0.94-1.40), respectively. The point estimate for LTBI among close TB contacts in Brazil was higher in women, though less pronounced in multivariable models. If the sex difference in LTBI is confirmed in additional settings, studies of possible underlying differences in socio-behavioral factors or TB pathogenesis are warranted. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), the world's deadliest bacterial infection, afflicts more human males than females, with a male/female (M/F) ratio of 1.7. Sex disparities in TB prevalence, pathophysiology, and clinical manifestations are widely reported, but the underlying biological mechanisms remain largely undefined. This review assesses epidemiological data on sex disparity in TB, as well as possible underlying hormonal and genetic mechanisms that might differentially modulate innate and adaptive immune responses in males and females, leading to sex differences in disease susceptibility. We consider whether this sex disparity can be extended to the efficacy of vaccines and discuss novel animal models which may offer mechanistic insights. A better understanding of the biological factors underpinning sex-related immune responses in TB may enable sex-specific personalized therapies for TB. Tuberculosis (TB) continues to remain one of the world's most important medical challenges with a significant male bias. Elucidating the underlying mechanisms that mediate differences in immune responses to Mycobacterium tuberculosis in males and females will not only enlighten our understanding of TB pathogenesis but also aid in developing novel sex-specific vaccines and therapies. Human adult males are 1.7-fold more likely than females to develop active tuberculosis (TB) disease. Recent studies indicate that reporting biases and differential healthcare access do not fully explain the higher TB incidence in males worldwide. Sex steroid hormones, sex chromosome-encoded genes, and miRNAs differentially modulate innate and adaptive immune responses to TB in males and females, both in humans and in animal models of TB. Research addressing the biological bases for the male bias is likely to provide novel insights into the pathogenesis of active TB disease and latent TB infection. Understanding the immunological basis for the male bias might enable the development of precision medicine interventions for TB, including host-directed therapies that are sex-specific. Dissecting the molecular and immunological mechanisms of the male bias in TB will benefit from improved animal models and sex-linked biomarkers that can predict the risk of developing active disease. [ABSTRACT FROM AUTHOR]

• Psychotherapy is limited by the latent disease model. • Psychotherapy should be studied idiographically. • Psychotherapy can be viewed as process toward adaptation to context. • Psychotherapy is applied evolutionary science. • Process-based therapy combines evolutionary science and network approaches. Cognitive behavioral therapy (CBT) has been one of the most influential developments in psychiatry ever. Since it was developed and introduced, a vast number of treatment protocols focused on specific psychiatric syndromes have been developed. Although this has benefitted many patients and advanced the field, CBT as a treatment with its focus on alleviating psychiatric syndromes seemed to have reached a plateau and a process-focus approach is now emerging within the family of CBT models. This represents a new form of idiographic functional analysis guided by models that integrate a coherent set of change processes. Here, I describe the foundations of this new approach to mental health, called process-based therapy (PBT) and discuss its scientific and clinical implications. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection of immunocompetent hosts is usually inapparent, but typically results in a non-silent chronic latency which is considerably more active than previously considered. In adults with schizophrenia spectrum disorders, CMV latent infection has been associated with cognitive disturbance including lower intelligent quotient (IQ). We hypothesized that the same pattern will be present in adolescent patients with schizophrenia spectrum disorders (early-onset non-affective psychosis). We included 17 adolescents with schizophrenia spectrum disorders (10 patients with schizophrenia, one patient with schizoaffective disorder and six patients with psychosis not otherwise specified), mean age 16.7 years, females 71% and CMV seropositivity 35%. Current IQ was estimated with the Wechsler Abbreviated Scale of Intelligence. CMV immunoglobulin G (IgG) concentrations were measured by solid-phase immunoassays and expressed as dichotomous measures (seropositive/CMV + vs. seronegative/CMV-). CMV + patients (mean IQ 91) had significantly lower full-scale IQ than CMV- patients (mean IQ 110) (20 units difference; p < 0.001). Post-hoc analyses showed that CMV + patients had both lower performance and lower verbal IQ relative to CMV- patients (p = 0.001 and 0.049, respectively). In this preliminary report, we found that CMV IgG seropositivity, reflecting previous CMV infection and current latency, was associated with lower IQ. This may be indicative of an unfavorable impact of CMV infection on general intelligence in early-onset non-affective psychosis. • Adolescent patients with non-affective psychosis were included. • CMV+ and CMV- patients were compared in terms of IQ. • CMV + patients had significantly lower IQ than CMV- patients. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) efficiently protects the central nervous system (CNS) from infectious insults. Yet, the apicomplexan parasite Toxoplasma gondii has a remarkable capability to establish latent cerebral infection in humans and other vertebrates. In addition to the proposed mechanisms for access to the brain parenchyma, recent findings highlight a paramount role played by the BBB in restricting parasite passage and minimizing parasite loads in the brain. Consistent with clinically asymptomatic primary infections in humans, mounting evidence indicates that the original colonization of the brain by T. gondii encompasses previously unappreciated, nondisruptive translocation processes that precede the onset of parasite-limiting immune responses. Within the extensive cerebral vascular network, passage of Toxoplasma gondii to the brain parenchyma takes place principally across cortical capillaries. Early passage of T. gondii occurs in the absence of a generalized increase in BBB permeability, perivascular leukocyte cuffs or hemorrhage, albeit with focal BBB permeability elevations. Inflammatory responses and transient dysregulation of the BBB during T. gondii infection facilitate parasite translocation to the brain parenchyma. Mechanisms proposed for T. gondii passage to the brain parenchyma include growth across endothelium (transcellular traversal), direct transmigration (paracellular traversal), and trafficking within parasitized leukocytes (Trojan horse). [ABSTRACT FROM AUTHOR]

This study aimed to investigate the management of Alternaria rot in citrus by evaluating the efficacy of late-season fungicide programs in reducing latent infections and fruit drop. Furthermore, the occurrence of mutations conferring resistance to QoI and SDHI fungicides within an Alternaria population isolated from citrus was investigated. In field trials, high frequencies of Alternaria infections were observed on the stem end and stylar end of Satsuma and Shiranui mandarins, with a higher prevalence of stem-end infections. Fungicide treatments applied towards the end of the season effectively reduced the frequency of latent infections on the stem end, indicating that such infections occur during this period under specific conditions. While some fungicide treatments demonstrated efficacy in reducing fruit drop caused by Alternaria rot, the results varied across different orchards and years. Latent infections on fruits persisted at high frequencies in the majority of trials, highlighting the complex nature of disease management. Mutations associated with resistance against QoI and SDHI fungicides were identified within the Alternaria population affecting California citrus. Our study suggests the potential need for fungicide sprays at the onset of the season to reduce the frequency of Alternaria infections on the stem end and stylar end of fruits. However, the observed non-correlation or low correlation between latent infections and fruit drop indicates that latent infections alone cannot reliably predict fruit drop. Our findings indicate that pre-harvest fungicide treatments have inconsistent efficacy and are cost-effective only during unpredictable disease outbreaks. • Late-season fungicide programs reduced latent Alternaria infections on stems. • Resistance mutations to QoI and SDHI fungicides were identified in the Alternaria population. • Fungicide treatments had inconsistent effects on fruit drop across different orchards and years. • Targeting fungicide applications earlier in the season might improve overall disease control. [ABSTRACT FROM AUTHOR]

The cultivation of 'Shine-Muscat' grape variety is rapidly expanding in East Asia due to its exceptional qualities favored by consumers. However, studies on the disease pathogens affecting this variety and how to control them remain limited. This study focuses on investigating postharvest diseases that impact 'Shine-Muscat' grapes and explores potential prevention methods, with regional emphasis on Shanghai metropolitan area, a key market for edible grapes in China. Common market diseases such as Alternaria spot, grey mold, and Aspergillus rot are frequently found in 'Shine-Muscat' grapes, accounting for 29.2%, 20.4%, and 16.7% of diagnostic cases, respectively. The study revealed that Alternaria spp., Cladosporium spp., and Botrytis cinerea could attach to or invade grape fruits during the flowering, young fruit, and veraison stages of 'Shine-Muscat'. In contrast to conventional open field cultivation methods, the rain-shelter and root restriction cultivation can aid in reducing fruit disease incidence during production, and thus alleviate the postharvest disease risks. Moreover, the application of calcium propionate during fruit development stages could efficiently manage both in-field and post-harvest diseases, and extend storage life of harvested fruit. • The occurrence rule of disease in 'Shine-Muscat' grapes was investigated. • tenuissimas was identified as the key pathogen in 'Shine-Muscat' grapes. • CP spray reduced the incidence of grape disease and maintained the quality. • Prevent post-harvest diseases by controlling grape development diseases. [ABSTRACT FROM AUTHOR]

Rhodococcus equi has recently been identified in various animals, including ruminants. Several studies have highlighted the emergence of pVAPN-harboring strains, isolated from multiple abscesses, in the liver and lungs of ruminants. Epidemiological evidence strongly suggests that pVAPN-harboring strains are pathogenic in ruminants. This study aims to replicate the disease in goats through experimental infection. Intravenous administration of the pVAPN-harboring strain (Yokkaichi), pVAPA-harboring strain (ATCC33701), and pVAPN-cured strain (Yokkaichi_P−), each at 1.0 × 107 CFU/head, was conducted in 24-month-old goats (n = 1 per group). During the observation period, goats treated with Yokkaichi or ATCC33701 exhibited transient increases in body temperature and white blood cell count, alongside a decrease in body weight from the administration day. Conversely, goats treated with Yokkaichi_P− displayed no significant changes in these values. The Yokkaichi-treated goat demonstrated a >10-fold increase in anti-VapN antibody titers from 11 to 14 days postadministration, whereas the other two goats exhibited no variation in anti-VapA and VapN antibody titers. Pathological autopsy analysis of organs harvested 28 days postadministration revealed no characteristic lesions on gross examination. However, the inoculated strain (vapN -positive R. equi) was exclusively recovered from the tracheobronchial lymph node in the Yokkaichi-treated goat. Immunohistochemistry detected a VapN-positive reaction in the tracheobronchial lymph node, confirming latent infection despite the absence of dramatic suppurative lesions seen in ruminants. Overall, this study highlights the latent infection in lymph nodes induced by the pVAPN-harboring strain, despite the absence of overt pathological manifestations. • In goats, the latent infection in lymph nodes induced by the pVAPN-harboring R.equi. • The pVAPN strain-treated goat showed a >10-fold increase in anti-VapN titers. • The pVAPN strain could be recovered from the tracheobronchial lymph node (TLN). • Immunohistochemistry detected a VapN-positive reaction in the TLN. • Ruminants raised on farms with pVAPN strains could be exposed to latent infections. [ABSTRACT FROM AUTHOR]

Combinational antiretroviral therapy (cART) suppresses human immunodeficiency virus type 1 (HIV-1) viral replication and pathogenesis in acquired immunodeficiency syndrome (AIDS) patients. However, HIV-1 remains in the latent stage of infection by suppressing viral transcription, which hinders an HIV-1 cure. One approach for an HIV-1 cure is the "shock and kill" strategy. The strategy focuses on reactivating latent HIV-1, inducing the viral cytopathic effect and facilitating the immune clearance for the elimination of latent HIV-1 reservoirs. Here, we reported that the H3K4 trimethylation (H3K4me3)-specific demethylase KDM5A/B play a role in suppressing HIV-1 Tat/LTR-mediated viral transcription in HIV-1 latent cells. Furthermore, we evaluated the potential of KDM5-specific inhibitor JQKD82 as an HIV-1 "shock and kill" agent. Our results showed that JQKD82 increases the H3K4me3 level at HIV-1 5' LTR promoter regions, HIV-1 reactivation, and the cytopathic effects in an HIV-1-latent T cell model. In addition, we identified that the combination of JQKD82 and AZD5582, a non-canonical NF-κB activator, generates a synergistic impact on inducing HIV-1 lytic reactivation and cell death in the T cell. The latency-reversing potency of the JQKD82 and AZD5582 pair was also confirmed in peripheral blood mononuclear cells (PBMCs) isolated from HIV-1 aviremic patients and in an HIV-1 latent monocyte. In latently infected microglia (HC69) of the brain, either deletion or inhibition of KDM5A/B results in a reversal of the HIV-1 latency. Overall, we concluded that KDM5A/B function as a host repressor of the HIV-1 lytic reactivation and thus promote the latency and the survival of HIV-1 infected reservoirs. • KDM5A/B function as host repressors of the HIV-1 lytic reactivation. • KDM5A/B suppress HIV-1 Tat/LTR-driven transcription. • KDM5 inhibitors have the potential to eliminate HIV-1 latent reservoir cells. • JQKD82 synergizes with AZD5582 to promote HIV-1 reactivation and cell death. [ABSTRACT FROM AUTHOR]

• CMV infection status can be difficult to discriminate. • The first study of CMV specific multi-cytokine immune responses in RD patients. • CMV antigen-specific IFN-γ, TNF-α had higher AUCs. • Combined noninvasive biomarkers may effectively differentiate infection status. To explore Cytomegalovirus (CMV) antigen-specific multi-cytokine immune responses in patients with rheumatic disease (RD) under different CMV infection status. A total of 60 RD patients in our center from March 2023 to August 2023 were enrolled. The patients were divided into latent CMV infection and active CMV infection, the latter was classified as subclinical CMV infection or CMV disease based on presence or absence of symptoms related to CMV. Whole blood was collected and stimulated with QuantiFERON-CMV antigen. The levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17 and CXCL-2 in supernatant were measured by Luminex Assays. The receiver operating characteristic curve was used to evaluate the diagnostic accuracy of cytokine for distinguishing different CMV infection status. The proportion of patients with severe lymphopenia was lowest in the latent CMV infection group, while there were no significant differences in medication usage in different CMV infection status. After stimulation with QF-CMV antigens, the levels of IFN-γ, TNF-α and IL-2 in the CMV disease group were significantly lower than those in the latent CMV infection group. CMV antigen-specific IFN-γ, TNF-α levels and severe lymphopenia together provided the best discriminatory performance for distinguishing between latent and either active CMV infection patients (AUC = 0.854) or CMV disease patients (AUC = 0.935). Noninvasive peripheral blood biomarkers (the combination of CMV antigen-specific IFN-γ, TNF-α levels and severe lymphopenia) may have the potential to diferentiate different status of CMV infection in RD population. [ABSTRACT FROM AUTHOR]

The fig Bionectria canker, caused by Stilbocrea banihashemiana , is rapidly spreading in fruit trees, posing a significant threat to the horticultural industry. Early and specific detection of this pathogen is crucial for effective management. We developed a PCR-based assay using species-specific primers designed by exploiting sequence differences in the translation elongation factor 1-alpha (tef1) gene for early, rapid, and reliable diagnostics of this pathogen. The primers successfully amplified the target pathogen and did not react with other non-target fig canker-causing agents in direct and nested PCR. The designated primer pair, TEF-Sb3, with a 577 bp amplicon, demonstrated its efficacy by successfully detecting the pathogen with the lowest detectable concentration of 1 × 10−15 and 1 × 10−17 g.L−1 in direct and nested PCR, respectively. Furthermore, the selected primer pair had high performance in detecting the target pathogen in naturally infected samples with evident canker symptoms in nested PCR. Moreover, our molecular tool has effectively identified latent infection of S. banihashemiana in asymptomatic samples from fig and walnut trees from three different regions of Fars Province. This is a notable advancement, as traditional culture-based methods have failed to detect these infections. Our results suggested that the designed species-specific PCR assays were sufficiently sensitive, specific, and reliable for identifying S. banihashemiana from pure cultures and detecting the pathogen in symptomatic and asymptomatic trees. This assay can be a rapid and cost-effective tool for monitoring and managing Bionectria canker caused by S. banihashemiana in natural and potential host trees. [Display omitted] • A PCR-basedassay was developed for canker pathogen S tilbocrea banihashemiana detection. • The tool's specificity and efficiency were validated for detection and identification. • The assay identified latent infection in asymptomatic fruit trees. • The primers detected the pathogen at low concentrations in both direct and nested PCR. • It is a rapid, cost-effective tool for monitoring and managing Bionectria canker. [ABSTRACT FROM AUTHOR]

• Tuberculosis is an infectious disease with a risk of reactivation in Multiple Sclerosis by immunosuppressant therapy. • Patients with Multiple Sclerosis should be screened for Latent Tuberculosis Infection and treated before or during the immunosuppressive therapy. • IGRA (Interferon Gamma Release Assay) is test of choice for the diagnosis of Latent Tuberculosis Infection. In case IGRA is unavailable, the Tuberculin Skin Test (TST) is acceptable for latent tuberculosis screening. • High prevalence of Latent tuberculosis in patients with multiple sclerosis in Brazil. • The treatment of latent tuberculosis with Isoniazid or Isoniazid associated with Rifapentine, monitored by an infectious disease specialist, has been shown to be safe. Tuberculosis is an infectious disease with a risk of reactivation in Multiple Sclerosis patients on immunosuppressant therapy. Diagnosis and treatment of Latent Tuberculosis Infection (LTBI) prevents the infection. To diagnose and treat LTBI in Multiple Sclerosis (MS). Cross-sectional study of the prevalence and treatment of LTBI in MS, between February 2021 and June 2023. LTBI was defined as an absence of symptoms, positive PPD or IGRA and normal chest X-ray. Of the 58 patients with MS, 17 (29.3 %) were diagnosed with LTBI, 15 with PPD > 5 mm and 2 with positive IGRA, 10 (58.8 %) female and 7 (41.1 %) male, mean age of 41.3 (SD ±13.4) years. All patients with LTBI were treated with immunomodulators or immunosuppressants: Fingolimod 5 (29.4 %), Natalizumab 5 (29.4 %), Cladribine 2 (11.8 %), Glatiramer 2 (11.8 %), Ocrelizumab 2 (11.8 %), and Interferon beta 1 (5.9 %). Steroids therapy for relapses, were used in 5/17 (93.8 %) with LTBI and 30/37 (81.1 %) without LTBI. To treat LTBI, 11 (64.7 %) received Isoniazid and 6 (35.3 %) Isoniazid plus Rifapentine. Hepatotoxicity occurred in 3 (17.6 %) with INH. There were no interruptions of ILTB treatment during the study. The prevalence of LTBI was found to be high and treatment proved safe. [ABSTRACT FROM AUTHOR]

Human herpesvirus 6 (HHV-6) causes primary infection in early childhood and establishes lifelong latency in its host. Reactivation of HHV-6, especially in immunosuppressed patients, has been associated with a variety of clinical complications. Diagnosis of acute HHV-6 infection has been a major challenge due to high prevalence of the virus and the difficulty in distinguishing latent infections from acute. Chromosomal integration of HHV-6 also occurs further complicating the management and diagnostics of HHV-6 disease. PCR-based methods have become the mainstay of HHV-6 diagnostics, however, interpretation of results in the context of clinical disease is of utmost importance. [ABSTRACT FROM AUTHOR]

• This study explored tuberculosis (TB): management of contact patients with kidney disease or transplant. • TB treatment was given to contacts of circle 1 or with positive IGRA. • No case of TB disease occurred in this cohort of immunocompromised patients. • Systematic TB prophylaxis on highly vulnerable contact is questionable. To describe the investigation, follow-up, management, and outcomes in a cohort of chronic kidney disease (CKD) and kidney transplant recipients (KTR) exposed to a case of pulmonary tuberculosis (TB). Contacts were investigated following a concentric circles approach and followed-up according to their level of priority. In those with evidence of latent TB infection, treatment decision was based on the level of exposure, individual vulnerability, as well as the results of an interferon-gamma release assay. A total of 130 patients with CKD and 180 KTR were identified as contacts and followed-up over a 2-year period. Few vulnerable high-priority contacts received anti-TB treatment, including the two (100%) highly exposed patients in circle 1, 11/78 (14.1%) CKD patients and 4/142 (2.8%) KTR in circle 2, and 10/52 (19.2%) CKD patients and 2/36 (5.6%) KTR in circle 3; all had a positive interferon-gamma release assay result. No incident cases of TB disease occurred. These findings suggest that latent TB treatment, as recommended in European guidelines, might be reasonably avoided in vulnerable high-priority contacts of circle 2, with a negative interferon-gamma release assay and in countries with low prevalence of TB. [ABSTRACT FROM AUTHOR]

Active tuberculosis (TB) in solid organ transplant (SOT) recipients most commonly occurs due to reactivation of latent infection and is associated with poor clinical outcomes, including allograft loss and death. National transplant societies, including the American Society of Transplantation, recommend screening for latent TB prior to transplant, with treatment in the peritransplant setting to reduce the subsequent risk of TB reactivation. Though screening is traditionally conducted using laboratory-based assays, such as the QuantiFERON-TB Gold, false negatives may occur in SOT candidates due to anergy from end-stage organ dysfunction, highlighting the need for a multimodal diagnostic approach. In this case series, we describe the clinical characteristics and outcomes of 3 SOT recipients at the University of Pennsylvania with negative pretransplant QuantiFERON-TB Gold testing who subsequently developed active TB in the posttransplant setting, contributing to a growing body of knowledge regarding this challenging population. Each patient experienced a complicated clinical course that arose in part from the lack of diagnosis of TB prior to transplant. Because all had epidemiologic risk factors for TB, the findings of our study highlight the need for more individualized approaches to pretransplant TB screening. [ABSTRACT FROM AUTHOR]

• A biopsy that shows narrow-based budding yeast confirms the diagnosis of Histoplasmosis capsulatum. • Latent infections may trigger a strong immune response after starting combined antiretroviral therapy. • Immune reconstitution inflammatory syndrome is possible with latent H. capsulatum. • Altered mental status is an atypical presentation of disseminated histoplasmosis. Opportunistic infections, including progressive disseminated histoplasmosis (PDH), may have variable and surprising presentations in patients with AIDS. This can be either a primary infection or reactivation of a latent infection. Latent infections may occur due to being unmasked by the immune reconstitution inflammatory syndrome after the initiation of combined antiretroviral therapy. PDH can be difficult to diagnose in patients with AIDS due to its variable presentation and many overlapping symptoms with other opportunistic infections. Serum and urine antigen testing are highly sensitive and typically used as the initial diagnostic test to workup suspected PDH. However, negative antigen and antibody tests do not rule out Histoplasmosis capsulatum infection and suspicion should remain high for PDH in the right clinical context. A definitive diagnosis may require biopsy-proven narrow-based budding yeast. We present an interesting patient with AIDS who presented with worsening cognitive decline and was ultimately diagnosed with PDH based on biopsy histopathology in the setting of negative antigen and antibody testing. [ABSTRACT FROM AUTHOR]

Tracking alterations in polar metabolite and lipid levels during anti-tuberculosis (TB) interventions is an emerging biomarker discovery and validation approach due to its sensitivity in capturing changes and reflecting on the host status. Here, we employed deep plasma metabolic phenotyping to explore the TB patient metabolome during three phases of treatment: at baseline, during intensive phase treatment, and upon treatment completion. Differential metabolites (DMs) in each period were determined, and the pathway-level biological alterations were explored by untargeted metabolomics-guided functional interpretations that bypassed identification. We identified 41 DMs and 39 pathways that changed during intensive phase completion. Notably, levels of certain amino acids including histidine, bile acids, and metabolites of purine metabolism were dramatically increased. The altered pathways included those involved in the metabolism of amino acids, glycerophospholipids, and purine. At the end of treatment, 44 DMs were discovered. The levels of glutamine, bile acids, and lysophosphatidylinositol significantly increased compared to baseline; the levels of carboxylates and hypotaurine declined. In addition, 37 pathways principally associated with the metabolism of amino acids, carbohydrates, and glycan altered at treatment completion. The potential of each DM for diagnosing TB was examined using a cohort consisting of TB patients, those with latent infections, and controls. Logistic regression revealed four biomarkers (taurine, methionine, glutamine, and acetyl-carnitine) that exhibited excellent performance in differential diagnosis. In conclusion, we identified metabolites that could serve as useful metabolic signatures for TB management and elucidated underlying biological processes affected by the crosstalk between host and TB pathogen during treatment. • Metabolome at three representative phases of tuberculosis treatment were investigated. • Deep phenotyping explored metabolic signatures for treatment monitoring. • Global pathway analysis revealed immunometabolism altered during treatment. • Taurine, methionine, glutamine, and acetyl-carnitine can be biomarkers for diagnosis. [ABSTRACT FROM AUTHOR]

Bovine herpesvirus 1 (BoHV-1) is a highly contagious pathogen which causes infectious bovine rhinotracheitis in cattle worldwide. Although it has the ability to evade the host's antiviral innate immune response and establish persistent latent infections, the mechanisms are not fully understood, especially the function of the tegument protein to escape innate immunity and participate in viral replication. In this study, we showed that overexpression of tegument protein UL3 facilitates BoHV-1 replication and suppresses the expression of type-I interferon (IFN-I) and IFN-stimulated genes. Then, STING was identified as the target by which UL3 inhibits the IFN-I signaling pathway, and STING was degraded through the UL3-induced autophagy pathway. Furthermore, overexpression of UL3 promotes the expression of the autophagy-related protein ATG101, thereby inducing autophagy. Further study showed that UL3 enhances the interaction between ATG101 and STING, and then the degradation of STING was reversed following ATG101 silencing in UL3-overexpressing cells during BoHV-1 infection. Our research results demonstrate a novel function of UL3 in regulating host's antiviral response and provide a potential mechanism for BoHV-1 immune evasion. • UL3 facilitates viral replication and suppresses antiviral IFN-I signaling response. • UL3 inhibits cGAS-STING pathway by inducing autophagy-mediated degradation of STING. • UL3 induces autophagy by promoting the expression of ATG101. • UL3 promotes viral replication and inhibits IFN-I response by up-regulating ATG101 to degrade STING. [ABSTRACT FROM AUTHOR]

• Quantitative changes in QuantiFERON-TB Gold (QFT) response do not stratify tuberculosis (TB) risk in QFT-positive contacts. • QFT conversion after 3 months identifies contacts at significantly increased TB risk. • QFT conversion is associated with exposure to rapidly progressive pulmonary TB. • Pre-existing latent TB infection may protect against developing TB following re-exposure. We investigated whether quantifying the serial QuantiFERON-TB Gold (QFT) response improves tuberculosis (TB) risk stratification in pulmonary TB (PTB) contacts. A total of 297 untreated adult household PTB contacts, QFT tested at baseline and 3 months after index notification, were prospectively observed (median 1460 days). Normal variance of serial QFT responses was established in 46 extrapulmonary TB contacts. This informed categorisation of the response in QFT-positive PTB contacts as converters, persistently QFT-positive with significant increase (PP increase), and without significant increase (PP no-increase). In total, eight co-prevalent TB (disease ≤3 months after index notification) and 12 incident TB (>3 months after index notification) cases were diagnosed. Genetic linkage to the index strain was confirmed in all culture-positive progressors. The cumulative 2-year incident TB risk in QFT-positive contacts was 8.4% (95% confidence interval, 3.0-13.6%); stratifying by serial QFT response, significantly higher risk was observed in QFT converters (28%), compared with PP no-increase (4.8%) and PP increase (3.7%). Converters were characterised by exposure to index cases with a shorter interval from symptom onset to diagnosis (median reduction 50.0 days, P = 0.013). QFT conversion, rather than quantitative changes of a persistently positive serial QFT response, is associated with greater TB risk and exposure to rapidly progressive TB. [ABSTRACT FROM AUTHOR]

• TBST is a new skin test using specific TB antigens as in IGRA. • TBST shows high sensitivities and specificities in clinical studies. • Limitations of studies include heterogeneous methodologies and sampling bias. • Application of TBST cannot be generalised in different population groups. • Cost effectiveness and prediction for TB infection determine the usefulness of TBST. In recent years, novel specific Mycobacteria tuberculous (TB) antigen-based skin test (TBST) has become available for clinical use. The mechanism of TBST is similar to the interferon-gamma release assay (IGRA), making it a potential alternative for identifying latent tuberculous infection (LTBI), especially in subjects with history of bacille Calmette-Guérin vaccination. Three different commercial brands have been developed in Denmark, Russia, and China. Clinical studies in the respective countries have shown promising sensitivity, specificity, and safety profile. Some studies attempted to address the applicability of TBST in specific subject groups but the discrepancy in defining LTBI and problematic methodologies undermine the generalisation of the results to other communities across the world. Limited cost-effectiveness studies for TBST have been conducted without exploring the health economics for preventing development of LTBI into active TB. Unlike IGRA, no clinical studies have addressed the correlation of TBST results (magnitude of induration) with the likelihood of development of active TB. Moreover, the different TBSTs are not widely available for clinical use. While TBST is a promising test to overcome the shortcomings of tuberculin skin tests, more clinical data are needed to support its general application globally for the diagnosis of LTBI. [ABSTRACT FROM AUTHOR]

• The QuantiFERON-CMV assay is an ELISA-based test to monitor CMV immunity. • An automated chemiluminescent immunoassay (CLIA) has been developed to measure IFNG. • CLIA and ELISA were compared for monitoring CMV immunity in transplant patients. • Both methods show substantial concordance and acceptable discrepancies. • CLIA is a good alternative for monitoring CMV-specific immunity in clinical routine. The QuantiFERON CMV (QF-CMV) assay is an interferon-gamma release assay (IGRA) used to monitor CMV-specific cell-mediated immunity (CMV-CMI) by ELISA in transplant patients. However, a chemiluminescent immunoassay (CLIA) has been developed to quantify IFNG in the QuantiFERON-Tuberculosis (TB) to detect latent TB infection. The aim of this work is to compare the results of QF-CMV by ELISA with those obtained by CLIA in an automated Liaison XL analyzer using the QuantiFERON-TB Gold Plus reagents. The QF-CMV assay had been performed by ELISA in kidney and lung transplant patients between July 2019-April 2023 at the IMIBIC/Reina Sofía Hospital (Cordoba, Spain). The remaining QF-CMV supernatants had been preserved at -80 ºC from then. Now, the IFNG levels in the same samples were determined by CLIA. One hundred and three QF-CMV supernatants from kidney (n = 50) and lung (n = 53) transplant patients were selected. An agreement of 87.4 % (kappa coefficient 0.788) between CLIA and ELISA was observed. Thirteen (12.6 %) discrepant results were detected. Some Indeterminate results by ELISA converted to Non-reactive by CLIA (0.53–0.92 IU/mL for Mitogen-Nil values). Likewise, borderline Non-reactive results by ELISA were above the 0.2 IU/mL cut-off by CLIA and then were Reactive (0.21–0.31 for CMV-Nil values). CLIA shows substantial concordance with ELISA and acceptable discrepancies. The possible higher sensitivity of CLIA returns a higher number of Reactive results, which entails potential clinical consequences. Therefore, a new threshold to confer protection against CMV infection after transplantation needs to be defined. [ABSTRACT FROM AUTHOR]

Even though anthrax is a disease of antiquity that has been studied for centuries, serious concerns have been raised about our understanding of its epidemiology. Since the 1960s, we have based the epidemiology of anthrax on the results of dose-dependent experiments, especially those involving cattle at that time. In this species the experiments demonstrated that the severity of infection was dependent upon the numbers of Bacillus anthracis spores ingested. The opinion was that ingesting only a few spores would be insufficient to cause an apparent infection; any infection that resulted would be latent (i.e., unrecognized). Based on the results of these experiments, it was accepted that the ingestion of large numbers of spores was the source of infection for hundreds of anthrax outbreaks. However, many investigations of both human and animal anthrax outbreaks have failed to identify sources of large numbers of spores, suggesting that these outbreaks are only rarely a consequence of ingestion or inhalation of large quantities of spores. This opinion piece builds upon the indirect evidence previously presented in an article focused on the existence of latent infections. Much of the evidence for the existence of latent infections was predicated upon a reduction of host resistance, which revealed how latent infections could be a source of more severe forms of the infection. That is, a latent infection can be the source of a severe infection, but the cause of the severe infection is the reduced host resistance. That first article concentrated on the arguments for latent infections, while this article concentrates on the arguments for host resistance. Host resistance is virtually impossible to measure objectively in the field. To provide a subjective measure of host resistance during anthrax outbreaks, we suggest the use of the opinions of livestock owners and or their veterinary practitioners and or field workers during investigations of anthrax outbreaks. When veterinary personal work in the field they are much like field biologists. In some ways field biologists better appreciate environmental factors, population ecology and other perspectives that are of use to epidemiologists. The more diverse the information the better the epidemiology is understood. To this effect we present our personal anecdotal and theoretical ideas from our experiences as well as a collection of bibliographic observations from others'. Our conclusions are that a combination of latent infections and reduced host resistance based on the host's relationship with its environment would better explain the epidemiology of severe infections in anthrax outbreaks for which large quantities of spores have not been located. This applies especially if the area has a history of the disease and/or if necropsies have shown the presence of latent infections in otherwise normal animals in the area and/or if environmental conditions are considered stressful and include intense insect activity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hyperspectral imaging can detect anthracnose infection at dormant stage in mango. • HSI and support vector machine rightly classified degrees of anthracnose symptoms. • Symptom distribution maps facilitate visualization of symptom severities in mango. • Detecting a pre-symptomatic anthracnose infection is a key advantage of the HSI. Anthracnose is the major plant disease causing an economic loss of mango fruit. Anthracnose symptom is not visible at a quiescent stage and the infected fruit often enters the food chain before the infection is known. Detection of a pre-symptomatic anthracnose infection is thus, crucial to prevent the infected fruit from entering the food chain. This research applied hyperspectral imaging (HSI) spectroscopy integrated with machine learning (ML) including principal component analysis (PCA) and support vector machine (SVM) for rapid identification of quiescent infection of anthracnose in mango fruit. Mango fruit (Nam Dok Mai Si Thong) was artificially infected with Colletotrichum gloeosporioides and stored at 20 °C and 90 % RH. The HSI was used to collect the spectral and spatial data of the samples. PCA and SVM were respectively performed to explore the hyperspectral data and to classify different symptom severities. The obtained spectral data can be recognized as fingerprints ascribing to the metabolites produced by C. gloeosporioides and the decomposed fruit tissues caused by the fungal infection. The HSI integrated with ML was able to not only detect the anthracnose infection at a latent stage before the onset of disease symptoms but also correctly classify different symptom severities. The symptom maps were also constructed using false-color image processing to simplify the data visualization of different symptom severities. The capability of detecting a pre-symptomatic anthracnose infection is a key advantage of the developed ML-assisted HSI. [ABSTRACT FROM AUTHOR]

Background/purpose: Reactivation of herpes viruses poses threat to corneal graft survival. This study evaluated the presence of herpes simplex virus type 1 (HSV-1), HSV type 2 (HSV-2), and cytomegalovirus (CMV) DNA in recipient corneas and the aqueous humor of patients undergoing penetrating keratoplasty (PKP), and the impact on graft survival.Methods: This retrospective study reviewed 90 eyes of 71 patients underwent PKP between 2008 and 2016. Cornea and aqueous humor samples were sent for polymerase chain reaction (PCR) testing for viral DNA. The main outcomes were PCR results and graft survival.Results: Recipient corneas tested positive for HSV-1 in 47 eyes (52.2%), for HSV-2 in 24 eyes (26.7%), and for CMV in seven eyes (7.8%). Aqueous humor tested positive for HSV-1 in 44 eyes (48.9%), for HSV-2 in 25 eyes (27.8%), and for CMV in eight eyes (8.9%). The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure (p = 0.005), whereas corneal HSV-1 DNA was not. The presence of HSV-2 DNA had no significant impact on graft survival. Aqueous CMV DNA was associated with higher risk of graft failure in univariate model, but not in multivariate model.Conclusion: There were high positive rates of HSV-1, HSV-2, and CMV DNA in recipient corneas and aqueous humor at the time of PKP, even among patients not suspected of latent viral infection. The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure. [ABSTRACT FROM AUTHOR]