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This is the first report of the occurrence of blueberry virus L (BlVL) in Japan and the complete nucleotide sequence of a Japanese isolate. BlVL was detected using reverse transcription-polymerase chain reaction in 35 of 52 highbush blueberry shrubs at Iwate University Research Farm, Japan, and in aphids (Aphis gossypii) on a BlVL-infected blueberry shrub. In the aphid transmission test of BlVL, the aphids transmitted the virus to uninfected blueberry bushes. No symptoms were observed in shrubs infected with the virus by aphid inoculation or by graft inoculation, suggesting that BlVL causes latent infection in highbush blueberry. [ABSTRACT FROM AUTHOR]

Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) preventive treatment (TPT) effectively prevents the progression from TB infection to TB disease. This study explores factors associated with TPT non-completion in Cambodia using 6-years programmatic data (2018–2023) retrieved from the TB Management Information System (TB-MIS). Out of 14,262 individuals with latent TB infection (LTBI) initiated with TPT, 299 (2.1%) did not complete the treatment. Individuals aged between 15–24 and 25–34 years old were more likely to not complete the treatment compared to those aged < 5 years old, with aOR = 1.7, p = 0.034 and aOR = 2.1, p = 0.003, respectively. Individuals initiated with 3-month daily Rifampicin and Isoniazid (3RH) or with 6-month daily Isoniazid (6H) were more likely to not complete the treatment compared to those initiated with 3-month weekly Isoniazid and Rifapentine (3HP), with aOR = 2.6, p < 0.001 and aOR = 7, p < 0.001, respectively. Those who began TPT at referral hospitals were nearly twice as likely to not complete the treatment compared to those who started the treatment at health centers (aOR = 1.95, p = 0.003). To improve TPT completion, strengthen the treatment follow-up among those aged between 15 and 34 years old and initiated TPT at referral hospitals should be prioritized. The national TB program should consider 3HP the first choice of treatment. [ABSTRACT FROM AUTHOR]

Introduction: Drug persistence may be a surrogate marker that reflects both long-term efficacy and safety in clinical settings, and tuberculosis (TB) is considered as one of the most important opportunistic infections after the biological treatment in rheumatoid arthritis (RA). We aimed to compare drug persistence and incidence of TB between tumor necrosis factor alpha (TNFα) inhibitors and tocilizumab in patients with RA using data from the Korean Health Insurance Review and Assessment Service database. Methods: In this analysis, 5449 patients with RA who started TNFα inhibitors, such as adalimumab, etanercept, infliximab, and golimumab or tocilizumab, as the first-line biological therapy between January 2014 and December 2017 were analyzed and followed up until December 2019. Drug persistence was defined as the duration from initiation to first discontinuation, and TB was defined as the prescription of > 2 anti-TB medications after the initiation of biologics. Results: TNFα inhibitors and tocilizumab were prescribed in 4202 (adalimumab, 1413; etanercept, 1100; infliximab, 769; golimumab 920) and 1247 patients with RA, respectively. During the analysis period, 2090 (49.7%) and 477 (38.3%) patients with RA discontinued TNFα inhibitors and tocilizumab, respectively, and 42 patients with RA developed TB (TNFα inhibitors, 33; tocilizumab, 9). After adjustment for confounding factors, TNFα inhibitors were significantly associated with a higher risk of discontinuation compared with tocilizumab (hazard ratio (HR) 1.63, p < 0.001). In subgroup analysis, all types of TNFα inhibitors, except for infliximab, demonstrated a significantly lower persistence rate compared with tocilizumab. There was no significant difference in TB incidence between tocilizumab and TNFα inhibitors. In subgroup analysis, infliximab has a significantly higher risk of TB compared with tocilizumab (HR 2.84, p = 0.02). Conclusion: In this analysis, tocilizumab had longer persistence than TNFα inhibitors with a similar incidence of TB. Our analysis has limitations: (1) The HIRA database lacks clinical details like disease activity and joint damage extent, potentially influencing the analysis results. (2) Reasons for discontinuing biological agents were not available. (3) TB diagnoses may be inaccurate because of missing microbiological results. (4) We did not analyze the impact of treating latent TB infection on TB development post-biological treatment, despite mandatory screening in Korea. [ABSTRACT FROM AUTHOR]

Objective: This study utilized a data-driven Bayesian model to automatically identify distinct latent disease factors represented by overlapping glucose metabolism patterns from 18F-Fluorodeoxyglucose PET (18F-FDG PET) to analyze heterogeneity among patients with TLE. Methods: We employed unsupervised machine learning to estimate latent disease factors from 18F-FDG PET scans, representing whole-brain glucose metabolism patterns in seventy patients with TLE. We estimated the extent to which multiple distinct factors were expressed within each participant and analyzed their relevance to epilepsy burden, including seizure onset, duration, and frequency. Additionally, we established a predictive model for clinical prognosis and decision-making. Results: We identified three latent disease factors: hypometabolism in the unilateral temporal lobe and hippocampus (factor 1), hypometabolism in bilateral prefrontal lobes (factor 2), and hypometabolism in bilateral temporal lobes (factor 3), variably co-expressed within each patient. Factor 3 demonstrated the strongest negative correlation with the age of onset and duration (r = − 0.33, − 0.38 respectively, P < 0.05). The supervised classifier, trained on latent disease factors for predicting patient-specific antiepileptic drug (AED) responses, achieved an area under the curve (AUC) of 0.655. For post-surgical seizure outcomes, the AUC was 0.857, and for clinical decision-making, it was 0.965. Conclusions: Decomposing 18F-FDG PET-based phenotypic heterogeneity facilitates individual-level predictions relevant to disease monitoring and personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

The study aims to accurately identify differentially expressed genes (DEGs) and biological pathways in mycobacterial infections through bioinformatics for deeper disease understanding. Differentially expressed genes (DEGs) was explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Unique DEGs were submitted on least absolute shrinkage and selection operator (LASSO) regression analysis. 1,057 DEGs from two GSE datasets were identified, which were closely connected with NTM/ latent TB infection (LTBI)/active TB disease (ATB). It was demonstrated that these DEGs are mainly associated with detoxification processes, and virus and bacterial infections. Moreover, the METTL7B gene was the most informative marker for distinguishing LTBI and ATB with an area under the curve (AUC) of 0.983 (95%CI: 0.964 to 1). The significantly upregulated HBA1/2 genes were the most informative marker for distinguishing between individuals of IGRA-HC/NTM and LTBI (P < 0.001). Moreover, the upregulated HBD gene was also differ between IGRA-HC/NTM and ATB (P < 0.001). We have identified gene signatures associated with Mycobacterium infection in whole blood, which could be significant for understanding the molecular mechanisms and diagnosis of NTM, LTBI, or ATB. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic came with many setbacks, be it to a country's economy or the global missions of organizations like WHO, UNICEF or GTFCC. One of the setbacks is the rise in cholera cases in developing countries due to the lack of cholera vaccination. This model suggested a solution by introducing another public intervention, such as adding Chlorine to water bodies and vaccination. A novel delay differential model of fractional order was recommended, with two different delays, one representing the latent period of the disease and the other being the delay in adding a disinfectant to the aquatic environment. This model also takes into account the population that will receive a vaccination. This study utilized sensitivity analysis of reproduction number to analytically prove the effectiveness of control measures in preventing the spread of the disease. This analysis provided the mathematical evidence for adding disinfectants in water bodies and inoculating susceptible individuals. The stability of the equilibrium points has been discussed. The existence of stability switching curves is determined. Numerical simulation showed the effect of delay, resulting in fluctuations in some compartments. It also depicted the impact of the order of derivative on the oscillations. [ABSTRACT FROM AUTHOR]

The World Health Organization End TB strategy aims for a 90% reduction of tuberculosis (TB) incidence by 2035. Systematic testing and treatment of latent TB infection (LTBI) among contacts of active TB patients is recommended as one of the ways to curtail TB incidence. However, there is a shortage of tools to accurately diagnose LTBI. We assessed the appropriateness of whole blood host transcriptomic markers (TM) to diagnose LTBI among household contacts of bacteriologically confirmed index cases compared to HIV negative healthy controls (HC). QuantiFERON-TB Gold Plus Interferon gamma release assay (IGRA) and reverse-transcriptase quantitative PCR were used to determine LTBI and quantify TM expression respectively. Association between TM expression and LTBI was evaluated by logistic regression modelling. A total of 100 participants, 49 TB exposed (TBEx) household contacts and 51 HC, were enrolled. Twenty-five (51%) TBEx individuals tested positive by IGRA, and were denoted as LTBI individuals, and 37 (72.5%) HC were IGRA-negative. Expression of 11 evaluated TM was significantly suppressed among LTBI compared to HC. Out of the 11 TM, ZNF296 and KLF2 expression were strongly associated with LTBI and successfully differentiated LTBI from HC. Paradoxically, 21 (49%) TBEx participants who tested IGRA negative exhibited the same pattern of suppressed TM expression as IGRA positive (LTBI-confirmed individuals). Results suggest that suppression of gene expression underlies LTBI and may be a more sensitive diagnostic biomarker than standard-of-care IGRA. [ABSTRACT FROM AUTHOR]

Herpes zoster (HZ) is caused by reactivation of latent infection of varicella zoster virus (VZV) in sensory (cranial, dorsal root) ganglia. Major risk factors for HZ are increasing age and immunosuppression. HZ ophthalmicus (HZO) is a subset of HZ with involvement of the ophthalmic division of the fifth cranial trigeminal nerve. Approximately 4–20% of patients with HZ develop HZO. Approximately 50% of patients with HZO develop ocular disease, among whom up to 25% develop chronic or recurrent disease. Common manifestations of ocular disease include conjunctivitis, keratitis, and uveitis, whereas optic neuropathy and retinitis are uncommon. Due to the potential for vision impairment, ocular involvement requires urgent ophthalmic consultation. Early recognition and timely treatment with antivirals may prevent ocular complications. HZO is preventable by vaccination against HZ. Vaccine efficacy/effectiveness studies have been largely conducted for HZ with few studies assessing HZO. Both the recombinant adjuvanted vaccine (RZV) and live-attenuated vaccine (ZVL) significantly reduce the incidence of HZ and HZO in older adults. RZV is more effective than ZVL. Data on the effectiveness of vaccines for prevention of recurrent disease in patients with HZO are limited; however, vaccination is recommended. Despite recommendations to vaccinate individuals likely to benefit from an HZ vaccine, coverage for adults remains suboptimal. Barriers to vaccination include patient beliefs about HZ or HZ vaccines, and factors related to healthcare providers. In particular, the lack of a recommendation from their primary care physician is often cited by patients as a reason for remaining unvaccinated. By encouraging vaccination against HZ, physicians not only prevent HZ and HZO but also potential vision loss due to HZO. Graphical abstract available for this article. Plain Language Summary: Shingles, also known as herpes zoster, is a common and painful rash that develops when the virus that causes chickenpox in children reactivates, most often in adults. When shingles affects the eye or the area surrounding the eye, it is called herpes zoster ophthalmicus, or HZO for short. Up to one-fifth of people with shingles have HZO, and this risk increases with age and in people with other conditions that affect their immune system. Common signs and symptoms include a rash on the face, pain, fever, and headache, as well as symptoms in the eye, such as discomfort, redness, and discharge. HZO has the potential to cause permanent vision loss, and because of this, it is important that people with symptoms are referred to an eye doctor ("ophthalmologist") as soon as possible. Early diagnosis of HZO is essential for effective treatment and prevention of the more serious complications it can cause. Treatment within 3 days of the symptoms occurring, with medications known as antivirals, can shorten the duration of a shingles episode and help relieve the pain. To help prevent the risk of shingles and its subtypes like HZO, vaccination is recommended. Two vaccines are currently approved for the prevention of shingles in adults. Although these vaccinations are recommended, some people do not have them for various reasons, which include their own personal beliefs about vaccinations or that their doctor has not recommended it to them. It is important that vaccinations against shingles are recommended to all patients eligible to receive one. [ABSTRACT FROM AUTHOR]

The 2021 tuberculosis (TB) preventive treatment guidelines in India included silicosis as a screening group, yet latent TB infection (LTBI) testing for silica-dust-exposed individuals is underemphasized. Focusing on an estimated 52 million silica-dust-exposed workers, particularly agate-stone workers in Khambhat, Gujarat, our study aims to estimate LTBI prevalence, identify predictors, and gather insights from TB and silicosis experts. Employing a sequential explanatory mixed-methods approach, a cross-sectional study involved 463 agate-stone workers aged ≥ 20 years in Khambhat, using IGRA kits for LTBI testing. In-depth interviews with experts complemented quantitative findings. Among agate-stone workers, 58% tested positive for LTBI, with predictors including longer exposure, type of work, and BCG vaccination. Our findings reveal a nearly double burden of LTBI compared to the general population, particularly in occupations with higher silica dust exposure. Experts advocate for including silica-dust-exposed individuals in high-risk groups for LTBI testing, exploring cost-effective alternatives like improved skin sensitivity tests, and shorter TB preventive treatment regimens to enhance compliance. Future research should explore upfront TB preventive treatment for silica-dust-exposed individuals with high LTBI prevalence and optimal exposure duration. This study underscores the urgent need for policy changes and innovative approaches to TB prevention among silica-dust-exposed populations, impacting global occupational health strategies. [ABSTRACT FROM AUTHOR]

Varicella-zoster virus (VZV), a common pathogen with humans as the sole host, causes primary infection and undergoes a latent period in sensory ganglia. The recurrence of VZV is often accompanied by severe neuralgia in skin tissue, which has a serious impact on the life of patients. During the acute infection of VZV, there are few related studies on the pathophysiological mechanism of skin tissue. In this study, transcriptome sequencing data from the acute response period within 2 days of VZV antigen stimulation of the skin were used to explore a model of the trajectory of skin tissue changes during VZV infection. It was found that early VZV antigen stimulation caused activation of mainly natural immune-related signaling pathways, while in the late phase activation of mainly active immune-related signaling pathways. JAK-STAT, NFκB, and TNFα signaling pathways are gradually activated with the progression of infection, while Hypoxia is progressively inhibited. In addition, we found that dendritic cell-mediated immune responses play a dominant role in the lesion damage caused by VZV antigen stimulation of the skin. This study provides a theoretical basis for the study of the molecular mechanisms of skin lesions during acute VZV infection. [ABSTRACT FROM AUTHOR]

Mathematical models play a crucial role in controlling and preventing the spread of diseases. Based on the communication characteristics of diseases, it is necessary to take into account some essential epidemiological factors such as the time delay that takes an individual to progress from being latent to become infectious, the infectious age which refers to the duration since the initial infection and the occurrence of reinfection after a period of improvement known as relapse, etc. Moreover, age-structured models serve as a powerful tool that allows us to incorporate age variables into the modeling process to better understand the effect of these factors on the transmission mechanism of diseases. In this paper, motivated by the above fact, we reformulate an SEIR model with relapse and age structure in both latent and infected classes. Then, we investigate the asymptotic behavior of the model by using the stability theory of differential equations. For this purpose, we introduce the basic reproduction number R 0 of the model and show that this threshold parameter completely governs the stability of each equilibrium of the model. Our approach to show global attractivity is based on the fluctuation lemma and Lyapunov functionals method with some results on the persistence theory. The conclusion is that the system has a disease-free equilibrium which is globally asymptotically stable if R 0 < 1 , while it has only a unique positive endemic equilibrium which is globally asymptotically stable whenever R 0 > 1 . Our results imply that early diagnosis of latent infection with decrease in both transmission and relapse rates may lead to control and restrict the spread of disease. The theoretical results are illustrated with numerical simulations, which indicate that the age variable is an essential factor affecting the spread of the epidemic. [ABSTRACT FROM AUTHOR]

Infection with the apicomplexan protozoan Toxoplasma gondii can be life-threatening in immunocompromised hosts. Transmission frequently occurs through the oral ingestion of T. gondii bradyzoite cysts, which transition to tachyzoites, disseminate, and then form cysts containing bradyzoites in the central nervous system, resulting in latent infection. Encapsulation of bradyzoites by a cyst wall is critical for immune evasion, survival, and transmission. O-glycosylation of the protein CST1 by the mucin-type O-glycosyltransferase T. gondii (Txg) GalNAc-T3 influences cyst wall rigidity and stability. Here, we report X-ray crystal structures of TxgGalNAc-T3, revealing multiple features that are strictly conserved among its apicomplexan homologues. This includes a unique 2nd metal that is coupled to substrate binding and enzymatic activity in vitro and cyst wall O-glycosylation in T. gondii. The study illustrates the divergence of pathogenic protozoan GalNAc-Ts from their host homologues and lays the groundwork for studying apicomplexan GalNAc-Ts as therapeutic targets in disease. A Toxoplasma gondii mucin-type O-glycosyltransferase uses a unique catalytic mechanism to modify bradyzoite cyst wall proteins. A second metal coupled to substrate binding is required for catalysis, while an active site glutamate suggests a double-displacement mechanism. [ABSTRACT FROM AUTHOR]

Context: Human estrogen-related receptor γ (hERRγ) is a key protein involved in various endocrines and metabolic signaling. Numerous environmental endocrine-disrupting chemicals (EDCs) can impact related physiological activities through receptor signaling pathways. Focused on hERRγ with 4-isopropylphenol, bisphenol-F (BPF), and BP(2,2)(Un) complexes, we executed molecular docking and multiple molecular dynamics (MD) simulations along with molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) and solvation interaction energy (SIE) calculation to study the detailed dynamical structural characteristics and interactions between them. Molecular docking showed that hydrogen bonds and hydrophobic interactions were the prime interactions to keep the stability of BPF-hERRγ and hERRγ-BP(2,2)(Un) complexes. Through MD simulations, we observed that all complexes reach equilibrium during the initial 50 ns of simulation, but these three EDCs lead to local structure changes in hERRγ. Energy results further identified key residues L268, V313, L345, and F435 around the binding pockets through CH-π, π-π, and hydrogen bonds interactions play an important stabilizing role in the recognition with EDCs. And most noticeable of all, hydrophobic methoxide groups in BP(2,2)(Un) is useful for decreasing the binding ability between EDCs and hERRγ. These results may contribute to evaluate latent diseases associated with EDCs exposure at the micro level and find potential substitutes. Method: Autodock4.2 was used to conduct the molecular docking, sietraj program was performed to calculate the energy, and VMD software was used to visualize the structure. Amber18 was conducted to perform the MD simulation and other analyses. [ABSTRACT FROM AUTHOR]

Patients with hematological malignancies who also have a hepatitis B virus (HBV) infection need to be aware of the potential risk of HBV reactivation when undergoing anti-cancer treatments. Among these treatments, CAR T-cell therapy has gained significant attention as a promising option, but it also raises concerns regarding HBV reactivation. This review aims to provide an overview of published reports on HBV reactivation during CAR T-cell therapy, along with an assessment of the effectiveness of prophylactic antiviral therapy. Additionally, we propose a systematic approach for monitoring and managing HBV reactivation during CAR T-cell therapy to enhance the safety of this treatment for patients with HBV infection. [ABSTRACT FROM AUTHOR]

We hypothesize that children characterized by deprived factors have poorer health outcomes. We aim to identify clustering of determinants and estimate risk of early childhood diseases. This 1993–2019 longitudinal cohort study combines three Canadian pediatric cohorts and their families. Mothers and children are clustered using latent class analysis (LCA) by 16 indicators in three domains (maternal and newborn; socioeconomic status [SES] and neighbourhood; environmental exposures). Hazard ratios (HR) of childhood asthma, allergic rhinitis (AR), and eczema are quantified with Cox proportional hazard (PH) regression. Rate ratios (RR) of children's health services use (HSU) are estimated with Poisson regression. Here we report the inclusion of 15,724 mother–child pairs; our LCA identifies four mother-clusters. Classes 1 and 2 mothers are older (30–40 s), non-immigrants with university education, living in high SES neighbourhoods; Class 2 mothers have poorer air quality and less greenspace. Classes 3 and 4 mothers are younger (20–30 s), likely an immigrant/refugee, with high school-to-college education, living in lower SES neighborhoods with poorer air quality and less greenspace. Children's outcomes differ by Class, in comparison to Class 1. Classes 3 and 4 children have higher risks of asthma (HR 1.24, 95% CI 1.11–1.37 and HR 1.39, 95% CI 1.22–1.59, respectively), and similar higher risks of AR and eczema. Children with AR in Class 3 have 20% higher all-cause physician visits (RR = 1.20, 95% CI 1.10–1.30) and those with eczema have 18% higher all-cause emergency department visits (RR = 1.18, 95% CI 1.09–1.28) and 14% higher all-cause physician visits (RR = 1.14, 95% CI 1.09–1.19). Multifactorial-LCA mother-clusters may characterize associations of children's health outcomes and care, adjusting for interrelationships. [ABSTRACT FROM AUTHOR]

Herpes simplex virus 1 (HSV-1) latent infection entails repression of viral lytic genes in neurons. By functional screening using luciferase-expressing HSV-1, we identify ten neuron-specific microRNAs potentially repressing HSV-1 neuronal replication. Transfection of miR-9, the most active candidate from the screen, decreases HSV-1 replication and gene expression in Neuro-2a cells. Ectopic expression of miR-9 from lentivirus or recombinant HSV-1 suppresses HSV-1 replication in male primary mouse neurons in culture and mouse trigeminal ganglia in vivo, and reactivation from latency in the primary neurons. Target prediction and validation identify transcription factors Oct-1, a known co-activator of HSV transcription, and all three Onecut family members as miR-9 targets. Knockdown of ONECUT2 decreases HSV-1 yields in Neuro-2a cells. Overexpression of each ONECUT protein increases HSV-1 replication in Neuro-2a cells, human induced pluripotent stem cell-derived neurons, and primary mouse neurons, and accelerates reactivation from latency in the mouse neurons. Mutagenesis, ChIP-seq, RNA-seq, ChIP-qPCR and ATAC-seq results suggest that ONECUT2 can nonspecifically bind to viral genes via its CUT domain, globally stimulate viral gene transcription, reduce viral heterochromatin and enhance the accessibility of viral chromatin. Thus, neuronal miR-9 promotes viral epigenetic silencing and latency by targeting multiple host transcription factors important for lytic gene activation. Here, the authors identify neuron-specific miR-9 that potentially blocks HSV-1 neuronal replication by targeting host OCT-1 and ONECUT transcription factors involved in epigenetic activation of HSV-1 productive-cycle genes. Thus miR-9 promotes viral epigenetic silencing and latent infection in neurons. [ABSTRACT FROM AUTHOR]

Background: The war in Ukraine has led to significant migration to neighboring countries, raising public health concerns. Notable tuberculosis (TB) incidence rates in Ukraine emphasize the immediate requirement to prioritize approaches that interrupt the spread and prevent new infections. Methods: We conducted a prospective genomic surveillance study to assess migration's impact on TB epidemiology in the Czech Republic and Slovakia. Mycobacterium tuberculosis isolates from Ukrainian war refugees and migrants, collected from September 2021 to December 2022 were analyzed alongside 1574 isolates obtained from Ukraine, the Czech Republic, and Slovakia. Results: Our study revealed alarming results, with historically the highest number of Ukrainian tuberculosis patients detected in the host countries. The increasing number of cases of multidrug-resistant TB, significantly linked with Beijing lineage 2.2.1 (p < 0.0001), also presents substantial obstacles to control endeavors. The genomic analysis identified the three highly related genomic clusters, indicating the recent TB transmission among migrant populations. The largest clusters comprised war refugees diagnosed in the Czech Republic, TB patients from various regions of Ukraine, and incarcerated individuals diagnosed with pulmonary TB specialized facility in the Kharkiv region, Ukraine, pointing to a national transmission sequence that has persisted for over 14 years. Conclusions: The data showed that most infections were likely the result of reactivation of latent disease or exposure to TB before migration rather than recent transmission occurring within the host country. However, close monitoring, appropriate treatment, careful surveillance, and social support are crucial in mitigating future risks, though there is currently no evidence of local transmission in EU countries. [ABSTRACT FROM AUTHOR]

Purpose: To describe a complex case of ocular tuberculosis reactivation with anterior uveitis, choroiditis and inflammatory choroidal neovascular membrane (CNVM) following immune checkpoint inhibitor (ICPI) treatment of malignant mucosal melanoma. Methods: A retrospective collection of medical history, clinical findings and multimodal imaging with literature review of the topic was conducted. Results: A 52-year-old Romanian female developed reduced vision and photophobia after three cycles of ICPI therapy comprised of ipilimumab and nivolumab. Bilateral anterior uveitis, multiple left eye choroidal lesions and a CNVM were confirmed using slit-lamp examination with ancillary multimodal imaging. Retinal changes in the right eye as well as a history of previously treated posterior uveitis and high-risk ethnicity increased clinical suspicion for ocular tuberculosis (TB) reactivation. The diagnosis was confirmed by TB positivity on polymerase chain reaction (PCR) analysis of lung aspirate followed by significant clinical improvement on systemic anti-tubercular therapy (ATT), systemic steroids and anti-vascular endothelial growth factor (VEGF) therapy. Conclusions: ICPIs can cause a myriad of ocular issues, both by primary immunomodulatory effects as well as secondary reactivation of latent disease. [ABSTRACT FROM AUTHOR]

The HIV-1 Tat protein hijacks the Super Elongation Complex (SEC) to stimulate viral transcription and replication. However, the mechanisms underlying Tat activation and inactivation, which mediate HIV-1 productive and latent infection, respectively, remain incompletely understood. Here, through a targeted complementary DNA (cDNA) expression screening, we identify PRMT2 as a key suppressor of Tat activation, thus contributing to proviral latency in multiple cell line latency models and in HIV-1-infected patient CD4+ T cells. Our data reveal that the transcriptional activity of Tat is oppositely regulated by NPM1-mediated nucleolar retention and AFF4-induced phase separation in the nucleoplasm. PRMT2 preferentially methylates Tat arginine 52 (R52) to reinforce its nucleolar sequestration while simultaneously counteracting its incorporation into the SEC droplets, thereby leading to its functional inactivation to promote proviral latency. Thus, our studies unveil a central and unappreciated role for Tat methylation by PRMT2 in connecting its subnuclear distribution, liquid droplet formation, and transactivating function, which could be therapeutically targeted to eradicate latent viral reservoirs. The mechanisms regulating Tat function for HIV-1 replication remain poorly understood. Here, the authors reveal that the transcriptional activity of Tat is modulated by a PRMT2-licensed switch between its nucleolar sequestration and phase separation into the nucleoplasmic Super Elongation Complex (SEC) droplets. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) preventive therapy (TPT) is an effective strategy to eliminate TB in low-incidence settings. Shorter TPT regimens incorporating the antimicrobial class of rifamycins are designed to improve adherence and completion rates but carry the risk of modifications to the gut microbiota. We enrolled six subjects diagnosed with latent TB infection (LTBI) who accepted to initiate TPT. We also enrolled six healthy volunteers unexposed to the rifamycins. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region) to document the immediate effect of rifamycin-based TPT on the gut microbiota composition and tracked recovery to baseline two months after TPT. Overall, TPT accounted for 17% of the variance in gut microbial community dissimilarity. This rifamycin-based TPT induced dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacteria phyla. Recovery of the gut microbial composition was incomplete two months after TPT. Robust clinical studies are necessary to comprehensively catalogue TPT-induced gut microbiota dysbiosis to inform strategies to mitigate potential long-term sequelae of this important TB control intervention. [ABSTRACT FROM AUTHOR]

Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in adults with high heterogeneity. Recent studies have manifested that the occurrence and development of DLBCL is related to hepatitis B virus (HBV) infection. As a medium-to-high prevalence area of HBV infection in China, the importance and exact mechanism of HBV infection in the occurrence of DLBCL have attracted considerable attention. HBV-associated DLBCL has unique clinical characteristics, poor treatment effect and inferior prognosis. HBV reactivation caused by DLBCL treatment also needs for constant vigilance. In this review we summarize the current research progress in the epidemiology, pathogenesis, clinical characteristics, HBV reactivation and antiviral therapies of HBV-associated DLBCL, in order to provide reference for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3–4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety of secukinumab (SEC) in the treatment of patients with axial spondyloarthritis (axSpA) and concurrent hepatitis B virus (HBV) infection or latent tuberculosis infection (LTBI). Methods: This is a retrospective cohort study. Adult axSpA patients with HBV infection or LTBI receiving SEC treatment for at least 3 months from March 2020 to July 2022 in Guangdong Provincial People's Hospital were included. Patients were screened for HBV infection and LTBI before SEC treatment. During follow-up, reactivation of HBV infection and LTBI was monitored. Relevant data were collected and analyzed. Results: A total of 43 axSpA patients with HBV infection or LTBI were included, of whom 37 were with HBV infection, 6 were with LTBI. Six out of thirty-seven (16.2%) patients with axSpA and concurrent HBV infection exhibited HBV reactivation after 9.0 ± 5.7 months of SEC treatment. Among them, 3 patients had chronic HBV infection and received anti-HBV prophylaxis, 2 patients had chronic HBV infection but did not receive anti-HBV prophylaxis, and 1 patient had occult HBV infection and did not receive antiviral prophylaxis. None of the 6 axSpA patients with LTBI developed reactivation of LTBI, whether received anti-TB prophylaxis or not. Conclusions: HBV reactivation can occur in axSpA patients with different types of HBV infection undergoing SEC treatment, whether receive antiviral prophylaxis or not. Close monitoring of HBV reactivation in axSpA patients with HBV infection undergoing SEC treatment is mandatory. Anti-HBV prophylaxis may be beneficial. In contrast, SEC may be safe in axSpA patients with LTBI, even in patients not receiving anti-TB prophylaxis. Key Points •Currently, most evidence about the safety of SEC in patients with HBV infection and LTBI were from patients with psoriasis. Our study adds data about the safety of SEC in Chinese axSpA patients with concurrent HBV infection or LTBI in real-world clinical setting. •Our study showed that HBV reactivation can occur in axSpA patients with different types of HBV infection undergoing SEC treatment, whether receive antiviral prophylaxis or not. •Close monitoring of serum HBV markers, HBV DNA load, and liver function is mandatory in axSpA patients with chronic, occult, and resolved HBV infection undergoing SEC treatment. Anti-HBV prophylaxis may be beneficial in all HBsAg-positive patients and HBsAg-negative, HBcAb-positive patients at high risk of HBV reactivation who are receiving SEC therapy. •None of the axSpA patients with LTBI, whether received anti-TB prophylaxis or not, developed reactivation of LTBI in our study. SEC may be safe in axSpA patients with LTBI, even in patients not receiving anti-TB prophylaxis. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV), the main contributor of the ongoing AIDS epidemic, remains one of the most challenging and complex viruses to target and eradicate due to frequent genome mutation and immune evasion. Despite the development of potent antiretroviral therapies, HIV remains an incurable infection as the virus persists in latent reservoirs throughout the body. To innovate a safe and effective cure strategy for HIV in humans, animal models are needed to better understand viral proliferation, disease progression, and therapeutic response. Nonhuman primates infected with simian immunodeficiency virus (SIV) provide an ideal model to study HIV infection and pathogenesis as they are closely related to humans genetically and express phenotypically similar immune systems. Examining the clinical outcomes of novel treatment strategies within nonhuman primates facilitates our understanding of HIV latency and advances the development of a true cure to HIV. [ABSTRACT FROM AUTHOR]

The high inter-individual heterogeneity in individuals with depression limits neuroimaging studies with case-control approaches to identify promising biomarkers for individualized clinical decision-making. We put forward a framework integrating the normative model and non-negative matrix factorization (NMF) to quantitatively assess altered gray matter morphology in depression from a dimensional perspective. The proposed framework parses altered gray matter morphology into overlapping latent disease factors, and assigns patients distinct factor compositions, thus preserving inter-individual variability. We identified four robust disease factors with distinct clinical symptoms and cognitive processes in depression. In addition, we showed the quantitative relationship between the group-level gray matter morphological differences and disease factors. Furthermore, this framework significantly predicted factor compositions of patients in an independent dataset. The framework provides an approach to resolve neuroanatomical heterogeneity in depression. The neuroanatomical heterogeneity of depression is not well understood. Here, the authors identify four latent factors which characterise different patterns of gray matter morphology and are related to clinical symptoms. [ABSTRACT FROM AUTHOR]

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4+ and CD8+ T cells. Co-culturing CD4+ with autologous CD8+ T cells from ART-suppressed HIV+ donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8+ T cells. This trispecific antibody mediates CD4+ and CD8+ T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection. One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure. [ABSTRACT FROM AUTHOR]

Background: Some evidence reveled that chronic infection with Toxoplasma gondii (T. gondii) has recently been associated with infertility in human and experimental model. This baseline study aimed to investigate serological evidence of Toxoplasma infection among infertile women who admitted to the in vitro fertilization (IVF) clinic at Imam Khomeini Hospital, Mazandaran province, Sari, northern Iran. Subjects and Methods: In this retrospective (descriptive-analytical) study, all infertile women referred to the IVF clinic during 2010–2019 (10 years), constitute the study population. All data including demographic and some related characteristics were collected into a questionnaire and registered at the Iranian National Registry Center for Toxoplasmosis (INRCT) at the Mazandaran University of Medical Sciences, northern Iran. The existence of anti-Toxoplasma antibodies (IgG and IgM) was explored using a commercially available enzyme-linked immune sorbent assay (ELISA) kit (PishtazTeb, Iran), based on the manufacturer's protocol. Results: Of 520 infertile women, anti-T. gondii IgG, IgM and both IgG and IgM antibodies were detected among 342/520 (65.77%), 1/520 (0.19) and 4/520 (0.77) infertile women, respectively. Primary and secondary infertility was detected in 74.56% and 25.44% of IgG seropositive infertile women, respectively. Also, most of the IgG seropositive subjects had no history of abortion, polycystic ovary syndrome (PCO), fibroma, contraceptive use and varicocele in spouse as primary cause of infertility. Furthermore, serum levels of prolactin and antimullerian (AMH) hormones were normal in 81.29 and 80.12% of infertile women with anti- T. gondii IgG, respectively. There was also a statistically significant difference between the seroprevalence of Toxoplasma infection and these variables associated to primary infertility (P < 0.05). Conclusion: According to the high prevalence (about two thirds) of chronic T. gondii infection among infertile women, particularly those with a history of abortion and primary infertility, it can be concluded that latent Toxoplasma infection pose a risk to infertile woman in the study area. Therefore, we advise that screening and treatment of Toxoplasma infection among infertile women must be favorably considered. [ABSTRACT FROM AUTHOR]

To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or higher genome loads than in the previously known sites of murine cytomegalovirus latency. Whereas murine cytomegalovirus gene transcription in PDGFRα-positive fibroblastic cells is almost completely silenced at 5 months post-infection, these cells give rise to reactivated virus ex vivo, arguing that they support latent murine cytomegalovirus infection. Notably, PDGFRα-positive fibroblastic cells also support productive virus replication during primary murine cytomegalovirus infection. Mechanistically, Stat1-deficiency promotes lytic infection but abolishes latent persistence of murine cytomegalovirus in PDGFRα-positive fibroblastic cells in vivo. In sum, fibroblastic cells have a dual role as a site of lytic murine cytomegalovirus replication and a reservoir of latent murine cytomegalovirus in vivo and STAT1 is required for murine cytomegalovirus latent persistence in vivo. Fibroblasts are an established cell type permissive for cytomegalovirus infection. Here the authors identify a population of fibroblast cells that can support murine cytomegalovirus lytic and latent virus infection in vivo and propose STAT1 as critically involved in murine cytomegalovirus latency. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer adversely affects nutrition and immunity, while increasing the risk of tuberculosis (TB). This study investigated the incidence and risk factors for TB in gastric cancer patients who had undergone gastrectomy or endoscopic submucosal dissection (ESD). Methods: This retrospective cohort study was conducted using Korean national insurance claims data. We defined three study groups (total gastrectomy, subtotal gastrectomy, and ESD) of patients diagnosed with gastric cancer plus a cancer-free control group. The latent TB infection (LTBI) screening status, TB incidence, and potential confounders in each cohort were analyzed, and the risk of TB was analyzed using a Cox proportional hazard model. Results: LTBI tests were performed in less than 1% of all patients, and the TB incidence rates were 473.8, 287.4, 199.4, 111.1 events/100,000 person-years in the total gastrectomy, subtotal gastrectomy, ESD, and control cohorts, respectively. Compared to the control cohort, the total gastrectomy cohort showed the highest hazard ratio (HR) for TB incidence (HR: 2.896, 95% CI: 2.559–2.337), while the ESD cohort showed a significantly increased risk (HR: 1.578, 95% CI: 1.957–1.980). Age, body mass index, and lack of exercise were risk factors in all cohorts. Comorbidities were also considered risk factors, depending on the cohort type. Conclusions: Patients who underwent gastrectomy or ESD had an increased risk of TB, and this risk was correlated with the scope of gastrectomy. Considering the low rate of LTBI diagnostic tests and increased risk of TB in the study cohorts, more specific and practical guidelines for TB management are required for gastric cancer patients. [ABSTRACT FROM AUTHOR]

In this work we define a modified SEIR model that accounts for the spread of infection during the latent period, infections from asymptomatic or pauci-symptomatic infected individuals, potential loss of acquired immunity, people's increasing awareness of social distancing and the use of vaccination as well as non-pharmaceutical interventions like social confinement. We estimate model parameters in three different scenarios—in Italy, where there is a growing number of cases and re-emergence of the epidemic, in India, where there are significant number of cases post confinement period and in Victoria, Australia where a re-emergence has been controlled with severe social confinement program. Our result shows the benefit of long term confinement of 50% or above population and extensive testing. With respect to loss of acquired immunity, our model suggests higher impact for Italy. We also show that a reasonably effective vaccine with mass vaccination program are successful measures in significantly controlling the size of infected population. We show that for a country like India, a reduction in contact rate by 50% compared to a reduction of 10% reduces death from 0.0268 to 0.0141% of population. Similarly, for a country like Italy we show that reducing contact rate by half can reduce a potential peak infection of 15% population to less than 1.5% of population, and potential deaths from 0.48 to 0.04%. With respect to vaccination, we show that even a 75% efficient vaccine administered to 50% population can reduce the peak number of infected population by nearly 50% in Italy. Similarly, for India, a 0.056% of population would die without vaccination, while 93.75% efficient vaccine given to 30% population would bring this down to 0.036% of population, and 93.75% efficient vaccine given to 70% population would bring this down to 0.034%. [ABSTRACT FROM AUTHOR]

The JC Polyomavirus (JCPyV) is a virus of global distribution and is usually kept under control by the immune system. In patients with AIDS, a latent JCPyV infection can reactivate and develop into progressive multifocal leukoencephalopathy (PML). Around half of the patients with PML die within 2 years since the diagnosis, yet in rare cases, the disease advances significantly quicker and seems to be insusceptible to any medical actions. In our clinic, we observed two cases of such course in HIV-positive patients in the AIDS stage. On admission, both patients had mild neurological symptoms such as dizziness, vision disturbances, and muscle weakness. Both had extremely low CD4 lymphocyte count (7 cells/μL, 40 cells/μL) and high HIV-1 viral load (VL) (50,324 copies/ml, 78,334 copies/ml). PML was confirmed by PCR for JCPyV DNA in cerebrospinal fluid (CSF) coupled with clinical and radiological features. Despite receiving though antiretroviral (ARV) treatment paired with intra-venous (IV) steroids, the disease progressed rapidly with neurological manifestations exacerbating throughout the few weeks following the admission. Eventually, both patients developed respiratory failure and died within less than 3 months after the onset of the neurological symptoms. Even though such curse of the disease is not common, it should be a warning to all how deadly both PML and AIDS can be and remind doctors to offer testing even to asymptomatic patients. [ABSTRACT FROM AUTHOR]

Keywords: Opportunistic infection; Histoplasmosis capsulatum; Tumor necrosis factor; Inflammatory bowel disease; Immunosuppression; Biologic tumor necrosis factor-alpha inhibitors EN Opportunistic infection Histoplasmosis capsulatum Tumor necrosis factor Inflammatory bowel disease Immunosuppression Biologic tumor necrosis factor-alpha inhibitors 380 384 5 02/09/23 20230201 NES 230201 Introduction Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disease that is usually classified either ulcerative colitis (UC) or Crohn's disease (CD). Providers should be aware of the association of biologic therapy, particularly TNF-alpha inhibitor therapy, with opportunistic infections and consider invasive fungal infections such as histoplasmosis in the differential diagnosis, even in areas of the country where histoplasmosis is less commonly encountered. Abbreviations IBD Inflammatory bowel disease UC Ulcerative colitis (UC) CD Crohn's disease TNF Tumor necrosis factor CT Computerized topography ID Infectious disease Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. If IBD symptoms recur during treatment, the decision to resume TNF-alpha inhibitor therapy versus switching to a biologic with a different mechanism of action should be discussed with the infectious disease provider and patient. [Extracted from the article]

Purpose: Information is limited about adherence to practice guidelines in patients with hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV infection receiving anticancer treatment. Methods: Newly diagnosed adult cancer patients were enrolled in a multicenter, prospective cohort study (SWOG S1204) during 2013–2017 to evaluate the prevalence of HBV, HCV, or HIV in patients initiating anticancer treatment. At 6 months, records of virus-positive patients were reviewed for antiviral therapy use; anticancer treatment dose reduction; and HBV reactivation (elevated viral load). Categorical variables were compared using chi-square or Fisher’s exact test. Results: Of 3055 enrolled patients with viral testing, 230 had chronic or past HBV, HCV, or HIV with 6-month follow-up data (chronic HBV, 15 patients; past HBV, 158; HCV, 49; HIV, 30). Twenty percent (3/15) of chronic HBV and 11% (17/158) of past HBV patients were co-infected with HCV and/or HIV. Rates of antiviral therapy use by 6 months were as follows: chronic HBV, 85% (11/13); past HBV receiving anti-B cell therapy, 60% (3/5); past HBV receiving systemic anticancer therapy without anti-B cell therapy, 8% (8/105); HCV, 6% (2/35); and HIV, 90% (19/21). Among patients with available data, anticancer treatment dose was reduced in 1 of 145 patients with past HBV and 1 of 42 with HCV. HBV reactivation occurred in 1 of 15 patients with chronic HBV; this patient was not receiving antiviral therapy. Conclusion: Many patients with cancer and viral infections either do not receive guideline-recommended antiviral treatment or receive antiviral treatment that is not recommended in guidelines. Further education is needed to improve adherence to guidelines. [ABSTRACT FROM AUTHOR]

After treatment with moxifloxacin, linezolid, and vancomycin, the patient still had recurrent fever, multiple swollen LNs, and skin lesions. Considering the rare reports of NTM infections in immunocompetent patients, we further detected the genetic susceptibility to mycobacterial diseases and immunological condition of the patient. The patient described here had pulmonary infections for a long time before having skin lesions and multiple swollen LNs. Susceptibility testing is desirable to adjust the treatment according to patients' conditions and realize personalized treatment [[1], [3]]. [Extracted from the article]

Almost 2 years into the pandemic and with vaccination of children significantly lagging behind adults, long-term pediatric humoral immune responses to SARS-CoV-2 are understudied. The C19.CHILD Hamburg (COVID-19 Child Health Investigation of Latent Disease) Study is a prospective cohort study designed to identify and follow up children and their household contacts infected in the early 2020 first wave of SARS-CoV-2. We screened 6113 children < 18 years by nasopharyngeal swab-PCR in a low-incidence setting after general lockdown, from May 11 to June 30, 2020. A total of 4657 participants underwent antibody testing. Positive tests were followed up by repeated PCR and serological testing of all household contacts over 6 months. In total, the study identified 67 seropositive children (1.44%); the median time after infection at first presentation was 83 days post-symptom onset (PSO). Follow-up of household contacts showed less than 100% seroprevalence in most families, with higher seroprevalence in families with adult index cases compared to pediatric index cases (OR 1.79, P = 0.047). Most importantly, children showed sustained seroconversion up to 9 months PSO, and serum antibody concentrations persistently surpassed adult levels (ratio serum IgG spike children vs. adults 90 days PSO 1.75, P < 0.001; 180 days 1.38, P = 0.01; 270 days 1.54, P = 0.001). In a low-incidence setting, SARS-CoV-2 infection and humoral immune response present distinct patterns in children including higher antibody levels, and lower seroprevalence in families with pediatric index cases. Children show long-term SARS-CoV-2 antibody responses. These findings are relevant to novel variants with increased disease burden in children, as well as for the planning of age-appropriate vaccination strategies. [ABSTRACT FROM AUTHOR]

Age-associated B cells (ABCs; CD19+CD11c+T-bet+) are a unique population that are increased in an array of viral infections, though their role during latent infection is largely unexplored. Here, we use murine gammaherpesvirus 68 (γHV68) to demonstrate that ABCs remain elevated long-term during latent infection and express IFNγ and TNF. Using a recombinant γHV68 that is cleared following acute infection, we show that ABCs persist in the absence of latent virus, though their expression of IFNγ and TNF is decreased. With a fluorescent reporter gene-expressing γHV68 we demonstrate that ABCs are infected with γHV68 at similar rates to other previously activated B cells. We find that mice without ABCs display defects in anti-viral IgG2a/c antibodies and are more susceptible to reactivation of γHV68 following virus challenges that typically do not break latency. Together, these results indicate that ABCs are a persistent effector subset during latent viral infection that impedes γHV68 reactivation. [ABSTRACT FROM AUTHOR]

Canine babesiosis is a tick-borne disease caused by Babesia spp., which infects and destroys healthy erythrocytes, leading to mortality and morbidity in dogs. The diagnosis of babesiosis is tedious and time-consuming, especially in latent and chronic infections. Here, a recombinase polymerase amplification combined with a lateral flow dipstick (RPA-LFD) assay was developed for rapid and accurate detection of Babesia spp. in canine blood specimens based on the 18S rRNA region. The RPA-LFD assay using rpaBab264 gave specificity to Babesia spp. in dogs (B. vogeli and B. gibsoni) without cross-amplification to other parasites (apicomplexans and non-apicomplexans), with detection limit of at least 22.5 copies/μl (0.1 fg/µl) at 40 °C for at least 10 min. The whole process of DNA amplification by RPA and readout by LFD did not exceed 30 min. To determine the performance of the RPA-LFD assay, a total of 30 clinical samples was examined and compared with conventional PCR (cPCR) and multiplex HRM (mHRM). Eight dogs (26.67%) were detected as positive by RPA-LFD, while seven and six were found positive by cPCR and mHRM, respectively. RPA-LFD and cPCR showed high agreement with Babesia spp. detection with kappa > 0.9. We confirmed that the dogs were infected by B. vogeli from sequences of positive PCR results. Our findings suggested that RPA-LFD using the rpaBab264 assay offered a rapid, accurate, cost-effective and simple method for Babesia spp. detection that is feasibly applicable to be rapid kit at a pet hospital or point-of-care testing. [ABSTRACT FROM AUTHOR]

Interferon-gamma release assays performance can be impaired by host-related, technical and environmental factors, but data in young children are limited. We performed a cross-sectional study of children < 5 years-of-age at risk of tuberculosis (TB), using QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. The impact of the following was evaluated: (i) host-related [age; hematological parameters; erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); and tobacco smoke exposure (TSE) based on serum cotinine concentrations], (ii) technical (pre-analytical delay) and (iii) environmental factors (annual season; monthly temperatures). Of 204 children, 35 (17.2%) were diagnosed with latent TB infection or TB disease. QFT-GIT results were indeterminate in 14 (6.9%) patients. In multivariate analysis, younger age and higher ESR were associated with lower positive control responses (beta: 0.247, p = 0.002 and − 0.204, p = 0.007, respectively), and increasing age was associated with lower rates of indeterminate QFT-GIT results [OR (95% CI) 0.948 (0.903–0.996) per month, p = 0.035]. In children with positive QFT-GIT results, average monthly temperatures correlated with antigen responses (r = 0.453, p = 0.020); also, antigen responses were lower in winter than in other seasons (p = 0.027). Serum cotinine concentrations determined in a subgroup of patients (n = 41) indicated TSE in 36 (88%), positive control responses being lower in children with TSE (p = 0.034). In children < 5 years-of-age, young age, elevated ESR, temperature, annual season and TSE can affect the performance of QFT-GIT assays. [ABSTRACT FROM AUTHOR]

Epigenetic changes are required for normal development, yet the nature and respective contribution of factors that drive epigenetic variation in humans remain to be fully characterized. Here, we assessed how the blood DNA methylome of 884 adults is affected by DNA sequence variation, age, sex and 139 factors relating to life habits and immunity. Furthermore, we investigated whether these effects are mediated or not by changes in cellular composition, measured by deep immunophenotyping. We show that DNA methylation differs substantially between naïve and memory T cells, supporting the need for adjustment on these cell-types. By doing so, we find that latent cytomegalovirus infection drives DNA methylation variation and provide further support that the increased dispersion of DNA methylation with aging is due to epigenetic drift. Finally, our results indicate that cellular composition and DNA sequence variation are the strongest predictors of DNA methylation, highlighting critical factors for medical epigenomics studies. Many studies assess epigenetic marks in white blood cells, but it is unclear how much immune factors affect the epigenome. Here, the authors show that fine-scale blood cell composition and cytomegalovirus infection affect the DNA methylome of adults. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) belongs to the subfamily Gammaherpesvirinae and was the first human tumor virus to be discovered. The global rate of EBV infection in adults exceeds 90%. EBV can participate in the regulation of multiple genes and signal pathways through its latency genes. Many studies have shown that CXCR4 is involved in the development of gastric cancer, but there have been few studies on the specific mechanisms involved in EBV-associated gastric cancer (EBVaGC). In this study, we explored the mechanism by which EBV-encoded products maintain latent EBV infection through interaction with CXCR4 and investigated the role of CXCR4 in EBV-positive cells. The results show that there is a positive feedback between the EBV-encoded products and CXCR4, and LMP2A can activate CXCR4 through the NF-κB pathway. In addition, CXCR4 can be fed back to LMP2A and EBNA1 through the ERK signaling pathway. At the same time, CXCR4 can promote the proliferation and migration of EBV-positive cells, reduce the expression of the immediate early protein BZLF1, the late protein EBV gp350, and the viral capsid antigen, and play an important role in maintaining the incubation period of EBV infection. These findings are applicable to the further targeted therapy of EBVaGC. [ABSTRACT FROM AUTHOR]

The yellow mosaic disease (YMD) of blackgram caused by Mungbean yellow mosaic virus has emerged as a serious threat to grain legume production, especially in Southeastern Asia. Seasonal incidence of YMD with its vector population was assessed in three different agroclimatic zones of Tamil Nadu in India for three consecutive cropping seasons namely, Rabi 2018 (October–December), Summer 2019 (March–May), and Kharif 2019 (June–August) at three different time intervals viz., 20, 40, and 60 days after sowing (DAS). For all three seasons, disease incidence and whitefly count were recorded for a resistant and susceptible variety of blackgram in fields without any vector control intervention. The highest disease incidence (87%) was observed in the Panpozhi location during the summer season followed by Vamban and Coimbatore locations. The whitefly count was made through both visual count and yellow sticky traps. The whitefly population was highest at 20 DAS and decreased with the increasing age of crop for all the three locations assessed. Molecular epidemiology was analyzed by determining latent infection of mungbean yellow mosaic virus (MYMV) using molecular diagnosis. Latent infection was found to be well pronounced in the Coimbatore location during the Kharif season, where the crop was asymptomatic in both the resistant and susceptible varieties for all the three time periods assessed. The latent infection of MYMV observed in Coimbatore and Vamban ranged from 16.6 to 83.3% in both resistant and susceptible varieties for all three seasons. In Panpozhi, the latent infection of MYMV ranged from 16.6 to 66.6% for the susceptible variety (CO-5) for all three seasons observed. However, in the Panpozhi location, the resistant variety (VBN-8) failed to record any latent infection. [ABSTRACT FROM AUTHOR]

Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body. These cells are resistant to therapy that can destroy intensely dividing cells and to the host immune system. A cascade of reactions that allows cells to enter and exit dormancy is triggered by regulatory factors from the microenvironment in niches that harbor the cells. A ratio of forbidding and permitting signals dictates whether the cells become dormant or start proliferation. The only difference between the cell dormancy regulation in normal and pathological conditions is that pathogens, mycobacteria, and cancer cells can influence their own fate by changing their microenvironment. Certain mechanisms of these processes are considered in the review. [ABSTRACT FROM AUTHOR]

Purpose: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI).We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024.A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms.Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis.Methods: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI).We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024.A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms.Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis.Results: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI).We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024.A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms.Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis.Conclusion: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI).We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024.A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms.Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis. [ABSTRACT FROM AUTHOR]

Prior to immunosuppression, patients should be screened for latent I S. stercoralis i infection with I Strongyloides i serology and stool for ova, cysts, and parasites, especially if they originate from or have traveled to endemic countries [[3], [5]]. To the Editor: I Streptococcus gallolyticus i is a bowel commensal and an opportunistic pathogen associated with invasive infections including bacteraemia and infective endocarditis [[1]]. The patient had numerous risk factors for I S. stercoralis i infection, highlighting the importance of screening patients for latent infections prior to commencing immunosuppression. [Extracted from the article]

Purpose: For an integrated care programme to be successful, preferences of the stakeholders involved should be aligned. The aim of this study is to investigate to which extent outcomes beyond health are valued and to study the heterogeneity of preferences of those involved in integrated care. Methods: A discrete choice experiment (DCE) was conducted to elicit preferences for eight Triple Aim outcomes, i.e., physical functioning, psychological well-being, social relationships & participation, enjoyment of life, resilience, person-centeredness, continuity of care and total health and social care costs. Stakeholders were recruited among Dutch persons with multi-morbidity, informal caregivers, professionals, payers, and policymakers. A Bayesian mixed-logit model was used to analyse the data. Subsequently, a latent class analysis was performed to identify stakeholders with similar preferences. Results: 739 stakeholders completed the DCE. Enjoyment of life was perceived as the most important outcome (relative importance: 0.221) across stakeholders, while total health and social care costs were perceived as least important (0.063). The latent class analysis identified four classes. The first class (19.9%) put most weight on experience with care outcomes. The second class (39%) favoured enjoyment of life. The third class (18%) focused relatively more on physical health. The fourth class (24%) had the least consistent preferences. Conclusion: This study has highlighted the heterogeneity in views of stakeholders in integrated care on what is important in health(care) for persons with multi-morbidity. To accurately value integrated care a variety of outcomes beyond health–e.g., enjoyment of life and experience with care–should be taken into account. [ABSTRACT FROM AUTHOR]

Bacterial wilt (BW) of potato caused by Ralstonia solanacearum (Rs) has been and continues to be a devastating disease of potato and related crops worldwide particularly vegetatively propagated ones. In Ethiopia, potato BW has spread to many areas due to absence of an effective seed potato system with fair seed certification, disease monitoring, and containment. Seed potato in Ethiopia is generally visually inspected resulting in failure to detect Rs in latently infected stock assumed clean by visual assessments. Consequently, a study was conducted to assess the extent of Rs latent infection in seed potato in major seed potato producing cooperatives in southern, southwestern, and central highlands of Ethiopia using Nitrocellulose membrane ELISA. A total of 41,600 tuber samples were collected between 2015 and 2016 from 121 fields of 57 registered seed potato grower cooperatives representing 107.05 ha distributed in 14 districts. Results of latent Rs infection indexing indicated that 58.3% of analysed samples were infected, more so during the March–June 2015 cropping season. The prevalence of latent infection was not significantly (P ≥ 0.05) influenced by potato variety or altitude at which the sample was collected but occurred randomly across altitude. The disease was evident even in samples collected at altitudes as high as 3000 m above sea level. Two samples collected at more than 3000 m above sea level were clean. However, these were too few to assume there is no BW above this altitude. In the absence of a reliable and sustainable seed potato testing for latent infection, farmers seed group cooperatives (FSGCs) who are the main producers of seed potato in Ethiopia as quality declared seed (QDS) will continue to disseminate Rs even in seed produced at extremely high altitude agro-ecologies. Consequently, it is recommended that QDS from FSGCs should be subjected to mandatory latent Rs infection indexing before they can be distributed as trusted potato planting stock despite the cost that would be involved. This should be complemented with BW infection containment effort combining biological, agronomic, policy, and social contexts. [ABSTRACT FROM AUTHOR]

More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER+). A clinical challenge of ER+ BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER+ and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER+ BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER+ BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential. The study of tumour dormancy is limited by suitable in vivo models. Here the authors show that mammary intraductal breast cancer (BC) xenografts model estrogen receptor α-positive (ER+) BC dormancy and rapid metastatic progression characteristic of triple-negative (TN) BC. The dormant disseminated ER+ BC cells display characteristics of epithelial-mesenchymal plasticity and forced expression of E-cadherin allows them to overcome dormancy. [ABSTRACT FROM AUTHOR]

Despite remarkable success in the prevention and treatment of tuberculosis (TB), it remains one of the most devastating infectious diseases worldwide. Management of TB requires an efficient and timely diagnostic strategy. In this study, we comprehensively characterized the plasma lipidome of TB patients, then selected candidate lipid and lipid-related gene biomarkers using a data-driven, knowledge-based framework. Among 93 lipids that were identified as potential biomarker candidates, ether-linked phosphatidylcholine (PC O–) and phosphatidylcholine (PC) were generally upregulated, while free fatty acids and triglycerides with longer fatty acyl chains were downregulated in the TB group. Lipid-related gene enrichment analysis revealed significantly altered metabolic pathways (e.g., ether lipid, linolenic acid, and cholesterol) and immune response signaling pathways. Based on these potential biomarkers, TB patients could be differentiated from controls in the internal validation (random forest model, area under the curve [AUC] 0.936, 95% confidence interval [CI] 0.865–0.992). PC(O-40:4), PC(O-42:5), PC(36:0), and PC(34:4) were robust biomarkers able to distinguish TB patients from individuals with latent infection and healthy controls, as shown in the external validation. Small changes in expression were identified for 162 significant lipid-related genes in the comparison of TB patients vs. controls; in the random forest model, their utilities were demonstrated by AUCs that ranged from 0.829 to 0.956 in three cohorts. In conclusion, this study introduced a potential framework that can be used to identify and validate metabolism-centric biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer (PCa) is one of the leading causes of death among men worldwide. The current methods utilized to screen for prostate cancer may not have sufficient sensitivity in distinguishing aggressive from indolent diseases, which affect the quality of life of patients in the short and long term. The overdiagnosis of cases and overtreatment are prevalent due to the heterogeneity of the disease in terms of latent and progressive variants, as well as in the tissue types present in biopsy samples. Methods: The purpose of this review is to discuss the potential clinical benefits of incorporating high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS) modalities to overcome the current challenges in the diagnosis, prognostication, and monitoring of PCa. [ABSTRACT FROM AUTHOR]