Latent Infection Research Articles

Reasons for acceptance or nonparticipation in iAdhere: a trial of latent TB infection treatment.

<sec><title>BACKGROUND</title>Understanding the motivations behind clinical trial participation can help enhance recruitment strategies and determine the generalizability of trial results. This study focuses on the reasons for participating in or declining the Tuberculosis Trials Consortium Study 33 (iAdhere), a clinical trial on the treatment of latent tuberculosis infection (LTBI).</sec><sec><title>METHODS</title>A quantitative evaluation was conducted among screened patients to ascertain their reasons for participating or not in the iAdhere trial. The study gathered data from enrolled participants and those who chose not to enroll.</sec><sec><title>RESULTS</title>Among 1,002 enrolled individuals, 290 participants provided 749 reasons for enrolling. The most common reasons included access to shorter treatment regimens (56%), avoiding progression to TB disease (45%), and improving health (21%). Of the 670 eligible persons who chose not to enroll, 551 individuals provided 800 reasons, with the most common being a preference for standard therapy (17%), disinterest in study medication or TB therapy (both 13%), and the inconvenience of daily observed treatment (12%).</sec><sec><title>CONCLUSION</title>The desire for shorter treatment options and preventing active disease motivates participation in LTBI trials. The diverse reasons for declining enrolment suggest the importance of developing targeted recruitment strategies. These findings support exploring shorter treatment regimens and can guide future recruitment efforts.</sec>.

Latent tubercolosis infection in the migrant population: an Italian surveillance experience

Abstract Background The Special Reception Center (“Centro Accoglienza Straordinario” or CAS in Italian) concept was born in Italy in 2014 to receive the large number of migrants arriving in Italy. There are around 3100 centres are in Italy, of which 200+ in Tuscany. Each Center’s objective is to support migrants’ social integration through Italian language and job orientation courses. On arrival at a facility, migrants undergo diagnostic and lab tests to highlight potentially infectious diseases; among these, tuberculosis is one of the most frequently encountered. Therefore, the objective of the study is to estimate the prevalence of Latent Tuberculosis Infections (LTBIs) among migrants hosted in CAS centers. Methods From May-December 2023, Amiata Senese, Val d’Orcia and Valdichiana Senese Public Health Unit staff, according to national and departmental guidelines, implemented a number of health surveillance protocols, with close attention to latent tuberculosis infection. This protocol includes the Mantoux TB skin test at the CAS: in case of positivity, subjects are directed to further exams (chest X-ray, TB-IGRA blood test, infectious disease specialist consultation) in order to implement a therapy. Results From May-December 2023, 259 migrants (241 males and 18 females) received the TB skin tests. Average subject age was 26. Pakistan was the most represented nation of origin with 130 migrants (50%), followed by Bangladesh (9.7%) and Ivory Coast (7.3%). 77 migrants showed a positive TB skin test result (29.7%): of these 56 (i.e. 21.6% of the migrants screened) were also positive to the TB-IGRA blood test and treated for LTBI. Conclusions The high prevalence of LTBIs found in the referenced CAS indicates the need to continue/extend these surveillance protocols. Implementing successfully this procedure requires the involvement of a range of professionals from the socio-health sector within a process necessarily coordinated by the Disease Prevention Department. Key messages • Screening and surveillance of infectious diseases among migrant population represent a major public health issue for European health systems. • Detection and treatment of Latent Tubercolosis Infections require a multiprofessional and integrated approach, coordinated by the Disease Prevention Department.

The impacts of tobacco and nicotine on HIV-1 infection, inflammation, and the blood-brain barrier in the central nervous system

Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine’s role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH.

Changes in TB contact tracing during the COVID-19 pandemic. An Irish single centre experience

Abstract Contact tracing following the diagnosis of tuberculosis (TB) is a crucial process in the identification and treatment of both secondary TB cases and also infected contacts who may require treatment for latent TB infection. During the COVID-19 pandemic, Public Health and Respiratory teams in the St Vincent’s University Hospital (SVUH) TB clinic in Dublin, Ireland, noted anecdotally that there appeared to be fewer contacts screened by public health services per index active TB case identified. To investigate this, we performed a retrospective review of the TB contact tracing service in SVUH, examining and comparing contact tracing of active TB cases in the 3 years prior to the pandemic (2017-2019) and four years thereafter (2020-2023). Results from 2017-2019 calendar years, prior to the COVID-19 pandemic noted an average of 4.77 contacts per index TB case (total 107 index cases and 510 contacts). In comparison, our data from 2020-2022 noted an average of 3.03 contacts per index TB case (total 59 index cases and 179 contacts). As pandemic restrictions were lifted again, we found our 2023 data to be more comparable to that of pre-pandemic times, noting 4.54 contacts per index case (total 22 index cases and 100 contacts). The reduction in TB contacts per index cases noted during the COVID-19 pandemic may reflect work and lifestyle changes over that time, particularly an increase in remote work but also social distancing. It is interesting that as the population emerged from the isolation measures of the pandemic, contact numbers returned quickly to pre-pandemic levels. In line with global concerns, our data highlights the ongoing workload of TB contact tracing locally and the importance of resource allocation for these services. Key messages • Our Irish centre experienced a notable but temporary reduction in contacts requiring screening by public health services, per index active TB case, during the COVID-19 pandemic. • In line with global concerns, our data highlights the ongoing workload of TB contact tracing locally and the importance of resource allocation for these services.

A prolonged outbreak of tuberculosis associated with an intellectual disability daycentre in Ireland

Abstract One of the factors impeding tuberculosis elimination in low burden countries is its persistence and concentration in vulnerable populations. This is a complex, prolonged Tuberculosis (TB) outbreak in a daycentre for adults with intellectual disability in Ireland. This is a particularly vulnerable population with special considerations for Public Health (PH) management. There are eight cases of active TB, 46 cases of Latent TB Infection (LTBI) and a cumulative total of 116 contacts associated with this outbreak, with diagnosis spanning 15 years. The last three cases were identical on Whole Genome Sequencing. The index case was an Irish-born, Caucasian, social care worker, with smear positive pulmonary TB, who was symptomatic in the facility for three months prior to diagnosis. Case 2 was a household contact of the index case and the other 6 cases were Service Users (SUs) at the facility. At least five of the subsequent seven cases are secondary cases of the index case. Significant to this outbreak was the change in Irish guidance, 2010, relating to the management of contacts of cases. Following the notification of the most recent case, July 2023, the Outbreak Control Team decided a retrospective review be conducted of all SU contacts of the seven cases associated with the facility. The contacts were stratified according to hierarchical risk. A total of six contacts met the criteria for review and offered screening, re-screening or treatment as appropriate. In this outbreak 21.8% of the total contacts and 16.1% of SU contacts completed treatment for LTBI. The significance of this outbreak lies in its duration, infectivity of the index case and particular vulnerabilities of the SUs. There were issues with overcrowding and difficulties in relation to symptom recognition, diagnosis and treatment. The PH team tailored their approach to meet the SU needs, demonstrating the importance of person-centred contact tracing in the disruption of transmission. Key messages • A factor impeding tuberculosis elimination in low burden countries is it’s persistence and concentration in vulnerable populations. • Adapting a patient-centred approach to contact tracing can lead to higher participation rate and the disruption of infection transmission.

European guidelines for the management of tuberculosis screening in migrants: a systematic review

Abstract Background This systematic review assesses the current available evidence across the WHO European region on the effectiveness and cost-effectiveness of the different approaches used for TB screening and also explores the facilitators and barriers that migrants face during screening programs. Methods We conducted an extensive, comprehensive, and systematic literature search across multiple databases, including MEDLINE, Cochrane, Scopus, and ISI Web of Knowledge, without any restrictions on publication date or language. In addition, we reviewed grey literature and reports from WHO. The data were meticulously analyzed using RStudio, with a focus on screening effectiveness indicators, such as infection and disease detection rates, uptake, coverage, and cost-effectiveness economic analyses. Results Our review included 43 studies covering over 8 million migrants from 11 countries. The findings demonstrate that while screening uptake was high, coverage varied, and completion rates for preventive treatments were low. Economic analyses supported the high cost-effectiveness of the screening programs, particularly when integrating both active TB and LTBI screening strategies. Conclusions The implementation of uniform screening protocols could potentially streamline efforts, reduce TB transmission, and offer substantial public health and economic benefits, making this research highly relevant for policymakers and healthcare providers. Key messages • An important strength of this study lies in its pioneering approach of current recommendations regarding screening for latent tuberculosis infection and active TB within the WHO European region. • This is the first study that provides a comprehensive overview of screening interventions across 11 countries and incorporates studies with large sample sizes (n &amp;gt; 8 million migrants).

Latent cytomegalovirus infection associates with impairments in myocardial reperfusion, left-ventricular function, and quality of life after ST-elevation myocardial infarction

Abstract Introduction Cytomegalovirus (CMV) is a ubiquitous herpesvirus affecting the majority of adults in European countries. CMV influences T-lymphocyte biology throughout life. We have previously associated CMV status with adverse left ventricular (LV) remodeling after ST-elevation myocardial infarction (STEMI) in a single-centre study. In this study, we aimed to assess the external validity of these findings. Methods This study is a retrospective analysis of 354 patients presenting with STEMI, who were recruited to A Trial of Low-Dose Adjunctive Alteplase During Primary PCI (T-TIME) and had blood samples archived. The participants underwent immediate coronary angiography and percutaneous coronary intervention (PCI), serial cardiovascular magnetic resonance (CMR) imaging at 2-7 days and 3 months post-STEMI, and serial assessment of health-related quality of life with the standardised EQ-5D visual analogue scale (VAS). CMV IgG titre was measured in cryopreserved samples from each patient, and patients were categorised as CMV negative, low-positive or high-positive. All analyses were adjusted for infarct location. Results Of 354 patients, 175 (49.4%) were CMV IgG titre negative, 89 (25.1%) were low-positive and 90 (25.4%) were high-positive. CMV+ patients were older (62.5 vs 58.7 years) and more likely to be non-White (6.7% vs 2.3%). CMV+ patients displayed several adverse outcomes. First, myocardial reperfusion was impaired. Thrombolysis in myocardial infarction (TIMI) flow grade 3 after PCI, indicating complete reperfusion, was less common in CMV+ patients (76.0% vs 84.6%; p=0.042). CMV+ patients also had a higher TIMI frame count after PCI (p=0.021), and non-significantly less ST-segment resolution at 60 minutes (38.8% vs 48.4%; p=0.066). Impaired myocardial reperfusion appeared to lead to impaired LV function, with LV ejection fraction (LVEF) measured on early CMR lower in CMV+ patients (42.6% vs 45.3%, p=0.004). At 3 months, LV function remained impaired in CMV+ patients (LVEF: 47.8% vs 49.7%; p=0.035). This was mirrored by CMV+ patients displaying higher NT-pro BNP levels at 2-7 days (1381 vs 1172pg/mL, p=0.097) and 3 months (575 vs 338pg/mL, p=0.021). Finally, impaired LV function appeared to affect quality of life. Over 3 months, in contrast to CMV-negative patients, those with the highest CMV IgG experienced almost no improvement in quality of life, measured by change in the EQ-5D VAS (negative: +9.93; high-positive: +0.70; p=0.0002). Conclusion CMV+ patients with STEMI experience worse outcomes, with impaired reperfusion, persistently reduced LV function and less improvement in health-related quality of life over 3 months. We hypothesise that the effect of CMV is mediated through immune activation. Future research should explore the mechanisms by which CMV-specific lymphocytes interact with myocardial reperfusion and repair post-STEMI.

Expression of Immunodominant gI Protein of Duck Enteritis Virus and its Evaluation for ELISA

Background: Duck plague (DP), also known as duck viral enteritis (DVE) caused by Anatid alpha herpesvirus-1, is the major infectious viral disease reported in India very often with significant economic losses due to high morbidity and mortality. The genome is approximately 158,091 bp with a genomic arrangement pattern (UL-IRS-US-TRS) that corresponds to type-D herpesvirus. The incubation period of the disease in domestic ducks ranges from 3 to 7 days and the mortality varies from 5-100%. It has been reported that the strategies to monitor and control DVE were often frustrating because the disease tends to establish a latent infection in waterfowl and vaccination failure. The present study was taken as an attempt to develop indirect ELISA using developed recombinant gI protein to diagnose DEV in field condition. Methods: In this study, we selected a membrane glycoprotein protein I (US7) gene, that plays an important role in virion sorting, cell-cell spread and binding of IgG Fc receptor. The gI protein was cloned with pET-32a (+) and expressed in a prokaryotic (E. coli) expression system. Further, recombinant protein was purified by nickel column affinity chromatography and refolded by dialysis. The obtained concentrated protein was then evaluated for its antigenicity and reliability in an Indirect-Enzyme-linked immunosorbent assay (ELISA) for DEV antibody detection in duck sera. Result: A panel of positive, negative and vaccinal serum was evaluated which indicated the potential use of the protein in the development of a serological assay for sero- surveillance of duck plague infection.

HIV Protein Nef Induces Cardiomyopathy Through Induction of Bcl2 and p21

HIV-associated cardiovascular diseases remain a leading cause of death in people living with HIV/AIDS (PLWHA). Although antiretroviral drugs suppress the viral load, they fail to remove the virus entirely. HIV-1 Nef protein is known to play a role in viral virulence and HIV latency. Expression of Nef protein can be detected in different organs, including cardiac tissue. Despite the established role of Nef protein in HIV-1 replication, its impact on organ function inside the human body is not clear. To understand the effect of Nef at the organ level, we created a new Nef-transgenic (Nef-TG) mouse that expresses Nef protein in the heart. Our study found that Nef expression caused inhibition of cardiac function and pathological changes in the heart with increased fibrosis, leading to heart failure and early mortality. Further, we found that cellular autophagy is significantly inhibited in the cardiac tissue of Nef-TG mice. Mechanistically, we found that Nef protein causes the accumulation of Bcl2 and Beclin-1 proteins in the tissue, which may affect the cellular autophagy system. Additionally, we found Nef expression causes upregulation of the cellular senescence marker p21 and senescence-associated b-galactosidase expression. Our findings suggest that the Nef-mediated inhibition of autophagy and induction of senescence markers may promote aging in PLWHA. Our mouse model could help us to understand the effect of Nef protein on organ function during latent HIV infection.

Combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression defines parameters of chronic gammaherpesvirus infection.

Gammaherpesviruses are species-specific, ubiquitous pathogens that establish lifelong infection in their hosts and are associated with cancers, including B cell lymphomas. Type I and II interferons (IFNs) are critical for the control of acute and chronic gammaherpesvirus infection. However, the cell type-specific role of IFN signaling during natural infection is poorly defined and is masked by the altered viral pathogenesis observed in hosts with global IFN deficiencies. STAT1 is a constitutively expressed transcription factor that is critical for the effector function of type I and II IFNs. In this study, we defined the impact of B cell-specific STAT1 expression on gammaherpesvirus infection using murine gammaherpesvirus 68 (MHV68). While the acute stage of MHV68 infection was not affected, we found opposite, anatomic site-dependent effects of B cell-intrinsic STAT1 expression during chronic infection. Consistent with the antiviral role of STAT1, B cell-specific STAT1 expression attenuated the latent viral reservoir in peritoneal B cells of chronically infected mice. In contrast, STAT1 expression in splenic B cells supported the establishment of the latent MHV68 reservoir in germinal center B cells, revealing an unexpected proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection. These STAT1-dependent MHV68 chronic infection phenotypes were fully recapitulated in the peritoneal cavity but not the spleen of mice with B cell-specific deficiency of type I IFN receptor. In summary, our study uncovers the intriguing combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.IMPORTANCEInterferons (IFNs) execute broadly antiviral roles during acute and chronic viral infections. The constitutively expressed transcription factor STAT1 is a critical downstream effector of IFN signaling. Our studies demonstrate that B cell-intrinsic STAT1 expression has opposing and anatomic site-dependent roles during chronic gammaherpesvirus infection. Specifically, B cell-intrinsic STAT1 expression restricted gammaherpesvirus latent reservoir in the peritoneal cavity, consistent with the classical antiviral role of STAT1. In contrast, decreased STAT1 expression in splenic B cells led to the attenuated establishment of gammaherpesvirus latency and decreased latent infection of germinal center B cells, highlighting a novel proviral role of B cell-intrinsic STAT1 expression during chronic infection with a B cell-tropic gammaherpesvirus. Interestingly, B cell-specific type I IFN receptor deficiency primarily recapitulated the antiviral role of B cell-intrinsic STAT1 expression, suggesting the compensatory function of B cell-intrinsic type II IFN signaling or an IFN-independent proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.

Adverse drug reactions following treatment of latent tuberculosis infection: a linked national tuberculosis surveillance with claims database.

Few real-world studies explored factors associated with latent tuberculosis infection (LTBI) treatment-related adverse drug reactions (ADRs). This study evaluate ADRs that lead to the discontinuation of LTBI treatment and identify the associated factors, including age groups and drug regimens. Using the Korean national tuberculosis registry and HHC investigation database linked to the National Health Insurance Service claims database, we examined treatment discontinuation due to ADRs among HHCs on LTBI treatment from January 2015 to December 2018. Multivariable logistic regression analysis was conducted to examine factors associated with ADRs, including demographics, LTBI treatment, comorbidities, and steroid use. Among 11,913 participants initiated LTBI treatment, 633 participants (5.3%) discontinued treatment due to ADRs. The primary contributors to discontinuation were adverse skin reactions (2.0%) and abnormal liver function (1.9%). Risk associated with ADRs and abnormal liver function showed age-related increase, except for the age group 66-75 (adjusted odds ratio [AOR] 3.82, 95% confidence interval [CI] 2.31-6.31) which reported lower OR to that of age group 36-65 (AOR 4.38, 95% CI 3.09-6.21). Three months isoniazid/rifampin and 4 months rifampin exhibited a lower odds of ADRs and abnormal liver function when compared to 6-9 months isoniazid. We discovered the real-world prevalence of LTBI treatment discontinuation due to ADRs among HHCs. Our findings suggest a notably increased odds of ADRs resulting in discontinuation with age of 76 years or above, emphasizing careful attention when prescribing LTBI treatment in this population. Further studies are warranted to validate these results.

Alterations in purine and pyrimidine metabolism associated with latent tuberculosis infection: insights from gut microbiome and metabolomics analyses.

Individuals with latent tuberculosis infection (LTBI) account for almost 30% of the population worldwide and have the potential to develop active tuberculosis (ATB). Despite this, the current understanding of the pathogenesis of LTBI is limited. The gut microbiome can be altered in tuberculosis patients, and an understanding of the changes associated with the progression from good health to LTBI to ATB can provide novel perspectives for understanding the pathogenesis of LTBI by identifying microbial and molecular biomarkers associated therewith. In this study, fecal samples from healthy controls (HC), individuals with LTBI and ATB patients were collected for gut microbiome and metabolomics analyses. Compared to HC and LTBI subjects, participants with ATB showed a significant decrease in gut bacterial α-diversity. Additionally, there were significant differences in gut microbial communities and metabolism among the HC, LTBI, and ATB groups. PICRUSt2 analysis revealed that microbiota metabolic pathways involving the degradation of purine and pyrimidine metabolites were upregulated in LTBI and ATB individuals relative to HCs. Metabolomic profiling similarly revealed that purine and pyrimidine metabolite levels were decreased in LTBI and ATB samples relative to those from HCs. Further correlation analyses revealed that the levels of purine and pyrimidine metabolites were negatively correlated with those of gut microbial genera represented by Ruminococcus_gnavus_group (R. gnavus), and the levels of R. gnavus were also positively correlated with adenosine nucleotide degradation II, which is a purine degradation pathway. Moreover, a combined signature including hypoxanthine and xanthine was found to effectively distinguish between LTBI and HC samples (area under the curve [AUC] of training set = 0.796; AUC of testing set = 0.924). Therefore, through gut microbiome and metabolomic analyses, these findings provide valuable clues regarding how alterations in gut purine and pyrimidine metabolism are linked to the pathogenesis of LTBI.IMPORTANCEThis study provides valuable insight into alterations in the gut microbiome and metabolomic profiles in a cohort of adults with LTBI and ATB. Perturbed gut purine and pyrimidine metabolism in LTBI was associated with the compositional alterations of gut microbiota, which may be an impetus for developing novel diagnostic strategies and interventions targeting LTBI.

Prevalence of anti-Toxoplasma gondii antibodies in tuberculosis patients

Despite the proven association between a co-infection of Mycobacterium tuberculosis and Toxoplasma gondii, few studies address how this relationship could interfere with latent infection or prognosis of tuberculosis or toxoplasmosis. Therefore, the objective of this study was to evaluate the prevalence of anti-T. gondii antibodies in patients with tuberculosis and their clinical-epidemiological association. Methods: Were evaluated antibodies anti-T. gondii in patients diagnosed with tuberculosis and in treatment. Clinical, laboratory and radiological data were obtained from medical records. The present study demonstrated a seroprevalence of anti-T. gondii antibodies (80%), despite that, none of the characteristics evaluated among the TB patients were associated with the presence of anti-T. gondii antibodies. Hence, it’s possible to conclude that patients with tuberculosis (TB) have a high prevalence of anti-T. gondii antibodies, and it’s recommended to evaluate the presence of IgM and IgG antibodies against T. gondii in patients recently diagnosed with tuberculosis and throughout anti-TB treatment to evaluate possible complications.

Epstein-Barr virus infection induces tissue-resident memory T cells in mucosal lymphoid tissues.

EBV contributes to around 2% of all tumors worldwide. Simultaneously, more than 90% of healthy human adults persistently carry EBV without clinical symptoms. In most EBV carriers, it is thought that virus-induced tumorigenesis is prevented by cell-mediated immunity. Specifically, memory CD8+ T cells recognize EBV-infected cells during latent and lytic infection. Using a symptomatic primary infection model, similar to infectious mononucleosis (IM), we found EBV-induced CD8+ tissue resident memory T cells (TRMs) in mice with a humanized immune system. These human TRMs were preferentially established after intranasal EBV infection in nasal-associated lymphoid tissues (NALT), equivalent to tonsils, the primary site of EBV infection in humans. They expressed canonical TRM markers, including CD69, CD103, and BLIMP-1, as well as granzyme B, CD107a, and CCL5. Despite cytotoxic activity and cytokine production ex vivo, these TRMs demonstrated reduced CD27 expression and proliferation and failed to control EBV viral loads in the NALT during infection, although effector memory T cells (TEMs) controlled viral titers in spleen and blood. Overall, TRMs are established in mucosal lymphoid tissues by EBV infection, but primarily, systemic CD8+ T cell expansion seems to control viral loads in the context of IM-like infection.

The progress of Mycobacterium tuberculosis drug targets

Tuberculosis (TB) has been troubling humans for hundreds of years, is a highly infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, Mtb can infect almost all organs of the body and is one of the deadly infectious diseases in the world. At present, the first-line treatment regimen has a long treatment cycle and is prone to multiple drug resistance. Anti-tuberculosis drugs and latent tuberculosis infection (LTBI) resistance are increasing year by year, and new targets and new bioactive compounds are urgently needed to treat this disease. This review focuses on the latest reported anti-TB drug targets and related compounds in recent years, reviews the current TB drug regimen and major defects, outlines the key drug targets developed to date in Mtb, and the current situation of newly discovered anti-TB resistant forms of drugs. To provide a reference for the research and development of new anti-TB drugs and bring new treatment strategies for TB patients.

Lytic promoter activity during herpes simplex virus latency is dependent on genome location.

Herpes simplex virus 1 (HSV-1) is a significant pathogen that establishes lifelong latent infections with intermittent episodes of resumed disease. In mouse models of HSV infection, sporadic low-level lytic gene expression has been detected during latency in the absence of reactivation events that lead to production of new viruses. This viral activity during latency has been reported using a sensitive Cre-marking model for several lytic gene promoters placed in one location in the HSV-1 genome. Here, we extend these findings in the same model by examining first, the activity of an ectopic lytic gene promoter in several places in the genome and second, whether any promoters might be active in their natural context. We found that Cre expression was detected during latency from ectopic and native promoters, but only in locations near the ends of the unique long genome segment. This location is significant because it is in close proximity to the region from which latency-associated transcripts (LATs) are derived. These results show that native HSV-1 lytic gene promoters can produce protein products during latency, but that this activity is only detectable when they are located close to the LAT locus.IMPORTANCEHSV is a significant human pathogen and the best studied model of mammalian virus latency. Traditionally, the active (lytic) and inactive (latent) phases of infection were considered to be distinct, but the notion of latency being entirely quiescent is evolving due to the detection of some lytic gene expression during latency. Here, we add to this literature by finding that the activity can be found for native lytic gene promoters as well as for constructs placed ectopically in the HSV genome. However, this activity was only detectable when these promoters were located close by a region known to be transcriptionally active during latency. These data have implications for our understanding of HSV gene regulation during latency and the extent to which transcriptionally active regions are insulated from adjacent parts of the viral genome.

Management implications of latent TB among under-five children at risk: Insights from a community study in Mumbai, India.

Latent tuberculosis infection (LTBI) management is crucial to WHO's End TB Strategy. Indian guidelines recommend treating under-five children with household TB contacts after ruling out active TB, regardless of TBI testing. However, the precise LTBI burden among children in high TB burden settings like India is unknown. A community-based study in Mumbai's urban slums screened and managed under-five children at LTBI risk to understand its epidemiology and inform TB control interventions. Total 369 eligible under-five children were enrolled for the study. LTBI screening was done using Tuberculin skin test and Interferon gamma release assay. Active TB was ruled out before initiation of TB preventive therapy among LTBI positives. Statistical tests like chi-square, logistic regression analysis and Hosmer-Lemeshow test were used. Overall, LTBI prevalence among under-five children was 12.4% by IGRA and 21.4% by TST. Undernourished children had significantly lower LTBI positivity by IGRA (p = 0.027), while those with household contacts, longer contact duration and drug-resistant tuberculosis (DR-TB) exhibited proportionally greater IGRA positivity (p = <0.001). The study found a lower LTBI prevalence among under-five children compared to adults, with key risk factors being HHC, DR-TB contact, and prolonged exposure. These findings suggest the need to revise or revisit the TPT framework for this age group in India, particularly by implementing a test-and-treat approach.

Acceptability and Usability of Mobile Health Application for Enhancing Treatment Adherence in Latent TB Patients

Background: Mobile health interventions showcase effectiveness for improving treatment adherence among Latent TB Infection (LTBI) patients. However, there is a paucity of evidence regarding their acceptability and usability. This study aimed to assess the initial acceptability and usability of a mobile health application that has been designed to ensure treatment adherence in LTBI patients. Methods: A descriptive study was conducted to assess the acceptability and usability of a mobile health application, “My Treatment Friend”. A total of 82 LTBI patients were selected, and access to the application was given to them. This application provides support to LTBI patients in reporting daily medication and side effects. The basic demographic characteristics of the participants were collected through a Google form-based questionnaire. The acceptability and usability of the application were assessed using the Likert scale questionnaire and SUS tool, with samples of n=44 and n=20 participants, respectively. Results: LTBI patients found the mobile application acceptable and feasible, with an SUS score of 73, which comes under Grade B as per the SUS score sheet. The majority believed that the app was very simple to use and easy to understand. However, there is a requirement to add more features that can enhance the acceptability and usability of the application. Conclusion: The study showed the importance and usefulness of mobile applications to assist LTBI patients in finishing their prescribed treatment courses of action. Additionally, it highlights how crucial it is to build future applications using user-centered design. User-centered design may play an important role in designing mobile applications and ensuring effective engagement and satisfaction among users.

Evaluating the significance of latent tuberculosis infection treatment in high‐incidence countries

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a devastating and rapidly spreading disease. Despite years of scientific research and numerous efforts, it is still a major and resurgent health problem worldwide, with high mortality rates. Added to the concern is that TB persists as a latent infection, an occult face of TB, that becomes a potential reservoir for active tuberculosis. Since latent TB‐infected patients may eventually advance to the active form of TB, an accurate diagnosis and effective treatment of latent tuberculosis are essential for TB control. Latent tuberculosis infection (LTBI) treatment is a prominent component of TB control in low‐prevalence countries like the United States; however, its implication in high‐incidence countries like India is still challenging. Therefore, the present study aimed to evaluate the impact of implementing diagnosis and treatment of LTBI in high‐incidence countries using a mathematical model‐based approach. Through our model, we predicted the incidence rate based on the current treatment regimen in India for the year 2035, which is one of the milestones of WHO for a substantial reduction in TB incidence. We observed demographic variability in the effects of various parameters on the TB incidence rate. Finally, we formulated the putative treatment strategies to reduce the TB burden in high‐incidence scenarios. Further, we estimated the impact of these proposed treatment strategies on the drug‐resistant population in high‐incidence scenarios. The model predictions suggested molding the current treatment strategies and focused implementation of LTBI diagnosis and treatment in high‐incidence scenarios.

Unusual Presentation of Tuberculosis in the Lungs and Lymph Nodes

Abstract Introduction/Objective Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis mainly affecting the lungs. Despite treatment advancements, TB remains a major cause of morbidity. This report presents a patient with active pulmonary and lymph node TB. Methods/Case Report The patient is a 41-year-old male from Bangladesh admitted for worsening cough and shortness of breath. Earlier, he had a cough and right cervical lymphadenopathy with lymph node biopsy demonstrating noncaseating granuloma and a positive Quantiferon-Gold. Outpatient workup included negative sputum TB PCR with negative cultures. The patient was febrile, tachycardic, and oxygenating normally. D-dimer was 1484. CT angiography was negative for emboli and showed mediastinal and right hilar lymphadenopathy. Imaging was otherwise non-indicative of active TB. We started rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) therapy with bronchoalveolar lavage for additional sputum sampling and excisional lymph node biopsy to rule out malignancy. Workup for autoimmune disease and sarcoidosis was negative. An acid-fast bacilli stain of the biopsy was positive, indicating active TB. The patient was discharged on RIPE with outpatient follow-up. Results (if a Case Study enter NA) NA Conclusion Histological findings of TB demonstrate caseating granulomatous lesions. Sarcoidosis can be considered in patients with hilar or mediastinal lymphadenopathy with noncaseating granulomatous lesions. However, both active and inactive TB should be considered in the differential diagnosis with biopsy results indicating noncaseating granuloma, as infected tissues can lack the central necrosis to produce caseation. Common chest radiographic findings in TB include pulmonary consolidation, hilar and mediastinal lymphadenopathy, disseminated miliary disease, and a normal chest radiograph. Our patient had just hilar and mediastinal lymphadenopathy. While a common finding in tuberculosis, this is also present in other inflammatory pathologies, emphasizing the importance of keeping a broad differential even in settings where initial biopsy and imaging results may indicate latent infection or other diagnoses. We utilized the expertise of pathologists to identify lymph nodes with active TB infection in a patient who previously had inconsistent pathological and radiological findings. Without the help of the pathologists in this case, diagnosing and treating this patient would not have been possible, showing the necessity of histopathological correlation with clinical and radiologic findings.