The Clinical Efficacy of Different Relaxation Exercises on Intraocular Pressure Reduction: A Meta-Analysis.

Objective: The aim of this study was to synthesize the available evidence on the clinical efficacy of different relaxation exercises on intraocular pressure (IOP) reduction. Methods: A systemic search of PubMed, Embase, Cochrane CENTRAL, and Web of Science was undertaken from the earliest record to 10 April 2024. Peer-reviewed studies that reported on healthy individuals and glaucoma patients engaging in relaxation exercises for at least three weeks were included. The primary outcome was changes in IOP levels from baseline, before the commencement of relaxation exercises, to post-exercise. Our statistical analysis employed a random-effects model, with effect sizes reported using Hedges' g. Results: Twelve studies were included, totaling 764 eyes (mean participant age ranging from 21.07 to 69.50 years). Relaxation exercises significantly reduced IOP, with Hedges' g being -1.276 (95% CI: -1.674 to -0.879) and I2 = 84.4%. Separate subgroup analyses showed that breathing exercises (Hedges' g = -0.860, p < 0.0001), mindfulness-based stress reduction (MBSR) (Hedges' g = -1.79, p < 0.0001), and ocular exercises (Hedges' g = -0.974, p < 0.0001) were associated with reduced IOP levels. The reduction in IOP following the relaxation exercises was found to be associated with baseline IOP either greater than (Hedges' g = -1.473, p < 0.0001) or less than 21 mmHg (Hedges' g = -1.22, p < 0.0001). Furthermore, this effect persisted with follow-up durations of less than (Hedges' g = -1.161, p < 0.0001) and more than one month (Hedges' g = -1.324, p < 0.0001). Conclusions: The current meta-analysis indicates that relaxation exercises can significantly reduce IOP levels. Relaxation exercises are a potential class of novel treatments for glaucoma patients that deserve further evaluation.

Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma.

BACKGROUND: Non-neuronal cholinergic system (NNCS) contributes to various inflammatory airway diseases. However, the role of NNCS in severe asthma (SA) remains largely unexplored. OBJECTIVE: To explore airway NNCS in SA. METHODS: In this prospective cohort study based on the Australasian Severe Asthma Network in a real-world setting, patients with SA (n = 52) and non-SA (n = 104) underwent clinical assessment and sputum induction. The messenger RNA (mRNA) levels of NNCS components and proinflammatory cytokines in the sputum were detected using real-time quantitative polymerase chain reaction, and the concentrations of acetylcholine (Ach)-related metabolites were evaluated using liquid chromatography coupled with tandem mass spectrometry. Asthma exacerbations were prospectively investigated during the next 12 months. The association between NNCS and future asthma exacerbations was also analyzed. RESULTS: Patients with SA were less controlled and had worse airway obstruction, a lower bronchodilator response, higher doses of inhaled corticosteroids, and more add-on treatments. The sputum mRNA levels of NNCS components, such as muscarinic receptors M1R-M5R, OCT3, VACHT, and ACHE; proinflammatory cytokines; and Ach concentration in the SA group were significantly higher than those in the non-SA group. Furthermore, most NNCS components positively correlated with non-type (T) 2 inflammatory profiles, such as sputum neutrophils, IL8, and IL1B. In addition, the mRNA levels of sputum M2R, M3R, M4R, M5R, and VACHT were independently associated with an increased risk of moderate-to-severe asthma exacerbations. CONCLUSION: This study indicated that the NNCS was significantly activated in SA, leading to elevated Ach and was associated with clinical features, non-T2 inflammation, and future exacerbations of asthma, highlighting the potential role of the NNCS in the pathogenesis of SA. CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-16009529 (http://www.chictr.org.cn).

The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.

Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/Cys192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1ß release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.

Impact of occupational noise exposure on the hearing level in hospital staffs: a longitudinal study.

The study aimed to evaluate the impact of occupational noise on hearing loss among healthcare workers using audiometry. A longitudinal study was conducted with a six-month follow-up period in a hospital with 21 participants, divided into high-noise-exposure (HNE) and low-noise-exposure (LNE) groups. Mean noise levels were higher in the HNE group (70.4 ± 4.5 dBA), and hearing loss was measured using pure-tone audiometry at baseline and follow-up. The HNE group had significantly higher mean threshold levels at frequencies of 0.25 kHz, 0.5 kHz, 4.0 kHz, and an average of 0.5, 1, 2, and 4 kHz (all p-values < 0.05) after the follow-up period. After adjusting for confounding factors, the HNE group had significantly higher hearing loss levels at 0.25 kHz, 0.5 kHz, and average frequencies of 0.5, 1, 2, and 4 kHz compared to the LNE group at the second measurement. Occupational noise levels above 65 dBA over six months were found to cause significant threshold changes at frequencies of 0.25 kHz, 0.5 kHz, and an average of 0.5-4.0 kHz. This study highlights the risk of noise-induced hearing loss among healthcare workers and emphasizes the importance of implementing effective hearing conservation programs in the workplace. Regular monitoring and assessment of noise levels and hearing ability, along with proper use of personal protective equipment, are crucial steps in mitigating the impact of occupational noise exposure on the hearing health of healthcare workers.

Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signaling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signaling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signaling induces TSLP mRNA expression via the PERK-C/EBP homologous protein (CHOP) signaling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP that is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma.NEW & NOTEWORTHY TSLP is an epithelial-derived cytokine and a key regulator in the pathogenesis of severe uncontrolled asthma. We demonstrate a novel mechanism by which endoplasmic reticulum stress signaling upregulates airway epithelial TSLP mRNA expression via the PERK-CHOP signaling pathway and enhances TLR3-mediated TSLP protein secretion.

Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death.

Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro- and anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of death remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil lytic pyroptotic death. The tightly regulated GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specifically precludes pyroptosis and skews neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by controlling the mode of neutrophil death, GSDME dictates host inflammatory outcomes, providing a potential therapeutic target for infectious and inflammatory diseases.

Clinical Subtypes of Neutrophilic Asthma: A Cluster Analysis From Australasian Severe Asthma Network.

BACKGROUND: Clinical heterogeneity may exist within asthma subtypes defined by inflammatory markers. However, the heterogeneity of neutrophilic asthma (NA) remains largely unexplored. OBJECTIVE: To explore potential clusters and the stability of NA. METHODS: Participants with NA from the Australasian Severe Asthma Network underwent a multidimensional assessment. They were then asked to participate in a 12-month longitudinal cohort study. We explored potential clusters using a hierarchical cluster analysis and validated the differential future risk of asthma exacerbations in the identified clusters. A decision tree analysis was developed to predict cluster assignments. Finally, the stability of prespecified clusters was examined within 1 month. RESULTS: Three clusters were identified in 149 patients with NA. Cluster 1 (n = 99; 66.4%) was characterized by female-predominant nonsmokers with well-controlled NA, cluster 2 (n = 16; 10.7%) by individuals with comorbid anxiety/depressive symptoms with poorly controlled NA, and cluster 3 by older male smokers with late-onset NA. Cluster 2 had a greater proportion of participants with severe exacerbations (P = .005), hospitalization (P = .010), and unscheduled visits (P = .013) and a higher number of emergency room visits (P = .039) than that of the other two clusters. The decision tree assigned 92.6% of participants correctly. Most participants (87.5%; n = 7) in cluster 2 had a stable NA phenotype, whereas participants of clusters 1 and 3 had variable phenotypes. CONCLUSIONS: We identified three clinical clusters of NA, in which cluster 2 represents an uncontrolled and stable NA subtype with an elevated risk of exacerbations. These findings have clinical implications for the management of NA.

Prevalence of uveitis in syphilis patients in Taiwan.

Few population-based studies have looked at the risk of uveitis among syphilis patients. Our study addresses the knowledge gap by reporting on uveitis risk in syphilis patients through a retrospective cohort study. The Taiwan National Health Insurance database was used for this study, covering the period from January 1st, 2009, to December 31st, 2020. We created a 1:4 propensity score matched cohort between the syphilis patients and controls, which accounted for gender, age, and comorbidities. The primary endpoint was the incidence of newly recorded uveitis. The assessment of uveitis risk in syphilis patients included the use of the Kaplan-Meier method and multivariate Cox proportional hazard model. A total of 31,597 syphilis patients and 126,379 matched comparisons were recruited. The uveitis incidence rate from our syphilis patients was 1.25 per 1000 person-years. The uveitis incidence rate from our non-syphilis group was 0.8 per 1000 person-years. After matching, the syphilis group was found to have a higher risk of developing uveitis (adjusted hazard ratio (aHR) [95% CI]: 1.57 [1.36-1.81], P < .001). Among males and individuals aged 20-34 years, subgroup analysis showed an increased risk of uveitis in the presence of syphilis infection. The Kaplan-Meier survival curve showed a significant difference in uveitis incidence between syphilis and non-syphilis groups (log-rank test P < .001). In summary, our study revealed that Taiwanese syphilis patients were at a higher risk of developing uveitis. These results highlight the need for regular ocular monitoring and screening in individuals with syphilis.

TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study.

Reports on uveitis after COVID-19 have been limited. Our objective was to examine the risk of uveitis among COVID-19 patients. This was a retrospective cohort study based on the TriNetX platform. The exposure group was patients with positive laboratory test result for SARS-CoV-2 and the comparison group was those tested negative for COVID-19 throughout the study period. The endpoint is the new diagnoses of uveitis. This study composed of 2 105 424 patients diagnosed with COVID-19 (55.4% female; 62.5% white; mean age at index 40.7 years) and 2 105 424 patients (55.4% female; 62.4% white; mean age at index 40.7 years) who never had COVID-19. There was significantly increased risk of new diagnosis of uveitis since the first month after diagnosis of COVID-19 compared with matched controls (HR: 1.18, 95% CI: 1.03-1.34) up to 24 months (HR: 1.16, 95% CI: 1.09-1.22). Our findings strengthen those previously raised by case series with a larger and multicenter study. We found that uveitis was significantly associated with COVID-19 infection. Our findings reiterate the need for careful investigation as well as increased awareness from ophthalmologists in considering the possibility of COVID-19 in vulnerable patients with new presentation of uveitis.

Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor.

The emergence of novel betacoronaviruses has posed significant financial and human health burdens, necessitating the development of appropriate tools to combat future outbreaks. In this study, we have characterized a human cell line, IGROV-1, as a robust tool to detect, propagate, and titrate betacoronaviruses SARS-CoV-2 and HCoV-OC43. IGROV-1 cells can be used for serological assays, antiviral drug testing, and isolating SARS-CoV-2 variants from patient samples. Using time-course transcriptomics, we confirmed that IGROV-1 cells exhibit a robust innate immune response upon SARS-CoV-2 infection, recapitulating the response previously observed in primary human nasal epithelial cells. We performed genome-wide CRISPR knockout genetic screens in IGROV-1 cells and identified Aryl hydrocarbon receptor (AHR) as a critical host dependency factor for both SARS-CoV-2 and HCoV-OC43. Using DiMNF, a small molecule inhibitor of AHR, we observed that the drug selectively inhibits HCoV-OC43 infection but not SARS-CoV-2. Transcriptomic analysis in primary normal human bronchial epithelial cells revealed that DiMNF blocks HCoV-OC43 infection via basal activation of innate immune responses. Our findings highlight the potential of IGROV-1 cells as a valuable diagnostic and research tool to combat betacoronavirus diseases.

NLRP3 is essential for neutrophil polarization and chemotaxis in response to leukotriene B4 gradient.

Neutrophil recruitment to sites of infection and inflammation is an essential process in the early innate immune response. Upon activation, a subset of neutrophils rapidly assembles the multiprotein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome forms at the microtubule organizing center, which promotes the formation of interleukin (IL)-1ß and IL-18, essential cytokines in the immune response. We recently showed that mice deficient in NLRP3 (NLRP3-/-) have reduced neutrophil recruitment to the peritoneum in a model of thioglycolate-induced peritonitis. Here, we tested the hypothesis that this diminished recruitment could be, in part, the result of defects in neutrophil chemotaxis. We find that NLRP3-/- neutrophils show loss of cell polarization, as well as reduced directionality and velocity of migration toward increasing concentrations of leukotriene B4 (LTB4) in a chemotaxis assay in vitro, which was confirmed through intravital microscopy of neutrophil migration toward a laser-induced burn injury of the liver. Furthermore, pharmacologically blocking NLRP3 inflammasome assembly with MCC950 in vitro reduced directionality but preserved nondirectional movement, indicating that inflammasome assembly is specifically required for polarization and directional chemotaxis, but not cell motility per se. In support of this, pharmacological breakdown of the microtubule cytoskeleton via nocodazole treatment induced cell polarization and restored nondirectional cell migration in NLRP3-deficient neutrophils in the LTB4 gradient. Therefore, NLRP3 inflammasome assembly is required for establishment of cell polarity to guide the directional chemotactic migration of neutrophils.

Upper Respiratory Tract OC43 Infection Model for Investigating Airway Immune-Modifying Therapies.

Respiratory virus infections initiate and transmit from the upper respiratory tract (URT). Coronaviruses, including OC43, are a major cause of respiratory infection and disease. Failure to mount an effective antiviral immune response in the nasal mucosa increases the risk of severe disease and person-to-person transmission, highlighting the need for URT infection models to support the development of nasal treatments that improve coronavirus antiviral immunity. We aimed to determine if OC43 productively infected the mouse URT and would therefore be a suitable model to assess the efficacy and mechanism of action of nasal-targeting immune-modifying treatments. We administered OC43 via intranasal inoculation to wild-type Balb/c mice and assessed virus airway tropism (by comparing total respiratory tract vs. URT-only virus exposure) and characterized infection-induced immunity by quantifying specific antiviral cytokines and performing gene array assessment of immune genes. We then assessed the effect of immune-modulating therapies, including an immune-stimulating TLR2/6 agonist (INNA-X) and the immune-suppressing corticosteroid fluticasone propionate (FP). OC43 replicated in nasal respiratory epithelial cells, with peak viral RNA observed 2 days after infection. Prophylactic treatment with INNA-X accelerated expression of virus-induced IFN-λ and IFN-stimulated genes. In contrast, intranasal FP treatment increased nasal viral load by 2.4 fold and inhibited virus-induced IFN and IFN-stimulated gene expression. Prior INNA-X treatment reduced the immune-suppressive effect of FP. We demonstrate that the mouse nasal epithelium is permissive to OC43 infection and strengthen the evidence that TLR2 activation is a ß-coronavirus innate immune determinant and therapeutic target.

Clinical Efficacy of Omidenepag Isopropyl for Primary Open-Angle Glaucoma, Normal Tension Glaucoma, or Ocular Hypertension: A Meta-Analysis.

Purpose: To investigate the clinical efficacy of omidenepag isopropyl (OMDI) among glaucoma patients in terms of increased intraocular pressure (IOP) changes through a meta-analysis. Methods: Studies investigating the clinical efficacy of OMDI toward glaucoma patients were systemically searched. Inclusion criteria include recruiting studies that consisted of glaucoma or normal tension glaucoma patients who received OMDI treatment at least 4 weeks in duration. The primary outcome was to compare changes in IOP levels at baseline before OMDI treatment and after OMDI treatment. Results: Six studies were included with a total of 358 eyes. Our results showed OMDI monotherapy resulted in significant decreased IOP among patients with ocular hypertension, with weighted mean difference post-OMDI treatment being -4.684 (95% confidence interval: -6.010 to -3.358) and I2 of 91.092%. Separate subgroup analyses also showed initial IOP greater than 21 mmHg and those within the age group greater than 65 years old to be correlated with significant reduction in IOP post-OMDI. Randomized control trial (RCTs) design was also found to be superior compared with non-RCT in terms of investigating IOP changes after OMDI. The country of origin of the recruited studies and OMDI dosage frequencies were also found to have no effect on overall IOP changes after OMDI treatment. Conclusions: The current meta-analysis indicates OMDI to be a clinically effective treatment for glaucoma patients in terms of lowering IOP levels.

Tinnitus as a Potential Risk Factor for Uveitis: A 14-Year Nationwide Population-Based Cohort Study in Taiwan.

BACKGROUND: Tinnitus and uveitis have shared commonality in pathophysiology in terms of autoimmunity. However, no studies that have linked any association between the conditions of tinnitus and uveitis. METHODS: This is a retrospective study conducted from the Taiwan National Health Insurance database in order to investigate whether tinnitus patients are at increased risk of uveitis. Patients newly diagnosed with tinnitus between 2001 and 2014 were recruited and followed up until 2018. The endpoint of interest was a diagnosis of uveitis. RESULTS: A total of 31,034 tinnitus patients and 124,136 matched comparisons were analyzed. Tinnitus patients were found to have a significantly higher cumulative incidence for uveitis than those without the diagnosis of tinnitus with incidence rate of 1.68 (95% CI 1.55-1.82) per 10 000 person-months for tinnitus group and 1.48 (95% CI 1.42-1.54) per 10 000 person-months for non-tinnitus group. CONCLUSION: Tinnitus patients were found to have increased risk of developing uveitis.

Inflammatory and antiviral responses to influenza A virus infection are dysregulated in pregnant mice with allergic airway disease.

Influenza A virus (IAV) infections are increased during pregnancy especially with asthma as a comorbidity, leading to asthma exacerbations, secondary bacterial infections, intensive care unit admissions, and mortality. We aimed to define the processes involved in increased susceptibility and severity of IAV infections during pregnancy, especially with asthma. We sensitized mice to house dust mite (HDM), induced pregnancy, and challenged with HDM to induce allergic airway disease (AAD). At midpregnancy, we induced IAV infection. We assessed viral titers, airway inflammation, lung antiviral responses, mucus hypersecretion, and airway hyperresponsiveness (AHR). During early IAV infection, pregnant mice with AAD had increased mRNA expression of the inflammatory markers Il13 and IL17 and reduced mRNA expression of the neutrophil chemoattractant marker Kc. These mice had increased mucous hyperplasia and increased AHR. miR155, miR574, miR223, and miR1187 were also reduced during early infection, as was mRNA expression of the antiviral ß-defensins, Bd1, Bd2, and Spd and IFNs, Ifnα, Ifnß, and Ifnλ. During late infection, Il17 was still increased as was eosinophil infiltration in the lungs. mRNA expression of Kc was reduced, as was neutrophil infiltration and mRNA expression of the antiviral markers Ifnß, Ifnλ, and Ifnγ and Ip10, Tlr3, Tlr9, Pkr, and Mx1. Mucous hyperplasia was still significantly increased as was AHR. Early phase IAV infection in pregnancy with asthma heightens underlying inflammatory asthmatic phenotype and reduces antiviral responses.NEW & NOTEWORTHY Influenza A virus (IAV) infection during pregnancy with asthma is a major health concern leading to increased morbidity for both mother and baby. Using murine models, we show that IAV infection in pregnancy with allergic airway disease is associated with impaired global antiviral and antimicrobial responses, increased lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Targeting specific ß-defensins or microRNAs (miRNAs) may prove useful in future treatments for IAV infection during pregnancy.

Method for Visualization of Emergency Granulopoiesis in the Zebrafish Embryo.

Emergency granulopoiesis (EG) is a response to severe inflammation in which increased neutrophils are generated in the hematopoietic tissue. Photolabeling is utilized to distinguish newly developed neutrophils from existing neutrophils. However, this technique requires a strong laser line and labels subsets of the existing neutrophils. Here we create a transgenic zebrafish line that expresses a time-dependent switch from green fluorescent protein (GFP) to red fluorescent protein (RFP) in neutrophils, which allows quantification of EG using simple GFP/RFP ratiometric imaging.

Diagnosis and Treatment of Tubercular Uveitis in Taiwan - Consensus of Expert Panels.

There is currently a lack of guidelines with regard to tubercular uveitis (TBU) management in Taiwan. We therefore propose an evidence-based consensus on the management for TBU. The Taiwan Ocular Inflammation Society conducted a meeting that included nine ophthalmologist and one infection disease expert that focused on three broad areas of (1) nomenclature for TBU, (2) assessment and diagnosis for TBU, and (3) treatment of TBU. Brief literature review on TBU diagnosis and management was conducted that informed this panel meeting in order to make decisions on each consensus statements. In terms of our results, a consensus statements and recommendations for the diagnosis and management of TBU were developed. This consensus statement provides an algorithmic approach toward diagnosing and managing TBU. These statements are meant to enhance but not replace individual clinician-patient interactions and to facilitate real-world clinical practice improvement in terms of TBU patients care.