The global role of G6PD in infection and immunity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. G6PD is an essential enzyme in the pentose phosphate pathway (PPP), generating NADPH needed for cellular biosynthesis and reactive oxygen species (ROS) homeostasis, the latter especially key in red blood cells (RBCs). Beyond the RBC, there is emerging evidence that G6PD exerts an immunologic role by virtue of its functions in leukocyte oxidative metabolism and anabolic synthesis necessary for immune effector function. We review these here, and consider the global immunometabolic role of G6PD activity and G6PD deficiency in modulating inflammation and immunopathology.

Ventricular Tachycardia in an Elderly Male With Brugada Syndrome.

We present a case of Brugada syndrome in a 74-year-old patient who presented with urine retention and incidentally found to have non-sustained ventricular tachycardia (NSVT) on electrocardiogram (ECG) and telemetry. To reveal characteristic type 1 Brugada pattern, right-pericardial lead was placed in the third right intercostal space. No antiarrhythmics were started, a loop recorder was implanted, and on follow-up episodes of self-terminating sustained ventricular tachycardia (VT) were noted. The patient was started on quinidine with resolution of VT.

Surgical and Medical Management of Purulent Bacterial Pericarditis With Pericardial Mass in a Young Child.

Purulent bacterial pericarditis is rare and associated with significant short- and long-term morbidity. We report a case of purulent bacterial pericarditis caused by Group A Streptococcus in an immunocompetent young child presenting with a pericardial mass. She was successfully treated with a combined medical and early surgical approach. (Level of Difficulty: Intermediate.).

Swallowing-induced atrial tachycardia: A rare demonstration on fluoroscopic esophagram.

BACKGROUND: Swallowing-associated arrhythmias are rare and most commonly present as atrial tachycardias. METHODS: We present a case of a 45-year-old female who experienced frequent episodes of palpitations and dyspnea occurring immediately after swallowing solid food. She was noted to have atrial tachycardia with deglutition that was recorded on the 12-lead electrocardiogram. She underwent fluoroscopic esophagram that demonstrated atrial tachycardia as the barium passed through the distal esophagus and gastroesophageal junction. CONCLUSION: Swallowing induced arrhythmias occur rarely and can be confirmed by EKG obtained during deglutition. Gastroesophageal evaluation is required to rule out primary esophageal disorders. Treatment of such arrhythmias is required if symptoms are intractable and can include pharmacotherapy and radiofrequency ablation.

Benign Metastasizing Leiomyoma Causing Severe Tricuspid Regurgitation and Heart Failure.

We present the case of a 51-year-old woman with severe tricuspid valve regurgitation due to aseptic tricuspid valve vegetation. She presented with bilateral lower extremity edema and a tricuspid valve vegetation was found on echocardiography. Initially, infectious and autoimmune causes of valve vegetation were considered; however, on biopsy, the mass was ultimately found to be a benign metastasizing leiomyoma (BML). Additional history revealed clinical features consistent with uterine leiomyomas, which metastasized to all leaflets the tricuspid valve, causing symptoms of heart failure. Benign metastasizing leiomyoma is rare itself, but when found, typically presents as asymptomatic pulmonary nodules. Mechanism of spread is unknown. Diagnosis is typically made long after a hysterectomy or fibroidectomy, but in our case, the BML was found prior to an actual fibroid diagnosis. By comparison, metastasis to the heart is extremely rare and has a higher potential for morbidity. Our patient required open heart surgery and tricuspid valve replacement for management of her symptoms, but her risk of further or recurrent metastasis going forward is unknown. Management strategy to prevent metastases in such cases of aggressive disease is not an established protocol and needs to be further studied.

Low Diagnostic Utility of Frequent Serial Tracheal Aspirate Cultures in the PICU.

OBJECTIVES: To determine the diagnostic outcomes of serial tracheal aspirate cultures (TACs) in the PICU. DESIGN: A retrospective chart review of TAC utilization was performed. Items recorded for each TAC included the time and date of culture acquisition, result, changes in microbial resistance patterns, antimicrobial therapy, and patient clinical course. SETTING: A single urban tertiary care children's hospital in the United States. SUBJECTS: Patients admitted to the PICU from January 1, to October 31, 2021, for whom a TAC was performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fifty unique subjects had 582 TACs performed during the study period, of which 145 (24.9%) were serially repeated within 72 hours. Of these serial TACs, 82 (56.6%) had no growth, 41 (28.3%) grew the same organism as the prior culture, with most (36/41) displaying no major change in antimicrobial susceptibilities, 11 (7.6%) grew a new organism previously grown during the admission, and 11 (7.6%) grew a new organism not previously grown during the admission. Overall, only 26 of these serial TACs (17.9%) provided new diagnostic information, whereas only five (3.4%) led to a change in management. CONCLUSIONS: Frequent serial TAC sampling in the PICU is common and infrequently yields new data that impact clinical decision-making. Considering worsening antimicrobial resistance and the role of diagnostic stewardship in mitigating it, these findings further support a 72-hour reassessment period before performing a repeat TAC in critically ill children.

HIV infection drives pro-inflammatory immunothrombotic pathway activation and organ dysfunction among adults with sepsis in Uganda.

BACKGROUND: The global burden of sepsis is concentrated in high HIV-burden settings in sub-Saharan Africa (SSA). Despite this, little is known about the immunopathology of sepsis in persons with HIV (PWH) in the region. We sought to determine the influence of HIV on host immune responses and organ dysfunction among adults hospitalized with suspected sepsis in Uganda. DESIGN: Prospective cohort study. METHODS: We compared organ dysfunction and 30-day outcome profiles of PWH and those without HIV. We quantified 14 soluble immune mediators, reflective of key domains of sepsis immunopathology, and performed whole-blood RNA-sequencing on samples from a subset of patients. We used propensity score methods to match PWH and those without HIV by demographics, illness duration, and clinical severity, and compared immune mediator concentrations and gene expression profiles across propensity score-matched groups. RESULTS: Among 299 patients, 157 (52.5%) were PWH (clinical stage 3 or 4 in 80.3%, 67.7% with known HIV on antiretroviral therapy). PWH presented with more severe physiologic derangement and shock, and had higher 30-day mortality (34.5% vs. 10.2%; P  < 0.001). Across propensity score-matched groups, PWH exhibited greater pro-inflammatory immune activation, including upregulation of interleukin (IL)-6, IL-8, IL-15, IL-17 and HMGB1 signaling, with concomitant T-cell exhaustion, prothrombotic pathway activation, and angiopoeitin-2-related endothelial dysfunction. CONCLUSIONS: Sepsis-related organ dysfunction and mortality in Uganda disproportionately affect PWH, who demonstrate exaggerated activation of multiple immunothrombotic and metabolic pathways implicated in sepsis pathogenesis. Further investigations are needed to refine understanding of sepsis immunopathology in PWH, particularly mechanisms amenable to therapeutic manipulation.

Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcriptional analyses to demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation. This response creates an oxidant-rich microenvironment conducive to the accumulation of anti-inflammatory myeloid cells. In this setting, metabolically active Kp ST258 elicits a disease-tolerant immune response. The bacteria, in turn, adapt to airway oxidants by upregulating the type VI secretion system, which is highly conserved across ST258 strains worldwide. Thus, much of the global success of Kp ST258 in hospital settings can be explained by the metabolic activity provoked in the host that promotes disease tolerance.

Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda.

BACKGROUND: The global burden of sepsis is concentrated in sub-Saharan Africa, where severe infections disproportionately affect young, HIV-infected adults and high-burden pathogens are unique. In this context, poor understanding of sepsis immunopathology represents a crucial barrier to development of locally-effective treatment strategies. We sought to determine inter-individual immunologic heterogeneity among adults hospitalized with sepsis in a sub-Saharan African setting, and characterize associations between immune subtypes, infecting pathogens, and clinical outcomes. METHODS: Among a prospective observational cohort of 288 adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to 14 soluble host immune mediators, reflective of key domains of sepsis immunopathology (innate and adaptive immune activation, endothelial dysfunction, fibrinolysis), to identify immune subtypes in randomly-split discovery (N = 201) and internal validation (N = 87) sub-cohorts. In parallel, we applied similar methods to whole-blood RNA-sequencing data from a consecutive subset of patients (N = 128) to identify transcriptional subtypes, which we characterized using biological pathway and immune cell-type deconvolution analyses. RESULTS: Unsupervised clustering consistently identified two immune subtypes defined by differential activation of pro-inflammatory innate and adaptive immune pathways, with transcriptional evidence of concomitant CD56(-)/CD16( +) NK-cell expansion, T-cell exhaustion, and oxidative-stress and hypoxia-induced metabolic and cell-cycle reprogramming in the hyperinflammatory subtype. Immune subtypes defined by greater pro-inflammatory immune activation, T-cell exhaustion, and metabolic reprogramming were consistently associated with a high-prevalence of severe and often disseminated HIV-associated tuberculosis, as well as more extensive organ dysfunction, worse functional outcomes, and higher 30-day mortality. CONCLUSIONS: Our results highlight unique host- and pathogen-driven features of sepsis immunopathology in sub-Saharan Africa, including the importance of severe HIV-associated tuberculosis, and reinforce the need to develop more biologically-informed treatment strategies in the region, particularly those incorporating immunomodulation.

Telemonitoring in heart failure patients: Systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Home telemonitoring has been used as a modality to prevent readmission and improve outcomes for patients with heart failure. However, studies have produced conflicting outcomes over the years. AIM: To determine the aggregate effect of telemonitoring on all-cause mortality, heart failure-related mortality, all-cause hospitalization, and heart failure-related hospitalization in heart failure patients. METHODS: We conducted a systematic review and meta-analysis of 38 home telemonitoring randomized controlled trials involving 14993 patients. We also conducted a sensitivity analysis to examine the effect of telemonitoring duration, recent heart failure hospitalization, and age on telemonitoring outcomes. RESULTS: Our study demonstrated that home telemonitoring in heart failure patients was associated with reduced all-cause [relative risk (RR) = 0.83, 95% confidence interval (CI): 0.75-0.92, P = 0.001] and cardiovascular mortality (RR = 0.66, 95%CI: 0.54-0.81, P < 0.001). Additionally, telemonitoring decreased the all-cause hospitalization (RR = 0.87, 95%CI: 0.80-0.94, P = 0.002) but did not decrease heart failure-related hospitalization (RR = 0.88, 95%CI: 0.77-1.01, P = 0.066). However, prolonged home telemonitoring (12 mo or more) was associated with both decreased all-cause and heart failure hospitalization, unlike shorter duration (6 mo or less) telemonitoring. CONCLUSION: Home telemonitoring using digital/broadband/satellite/wireless or blue-tooth transmission of physiological data reduces all-cause and cardiovascular mortality in heart failure patients. In addition, prolonged telemonitoring (≥ 12 mo) reduces all-cause and heart failure-related hospitalization. The implication for practice is that hospitals considering telemonitoring to reduce heart failure readmission rates may need to plan for prolonged telemonitoring to see the effect they are looking for.

Home telemonitoring in heart failure patients and the effect of study design on outcome: A literature review.

INTRODUCTION: A wide range of study designs have been utilized in evaluations of home telemonitoring and these studies have produced conflicting outcomes over the years. While some of the research has shown that telemonitoring is beneficial in reducing all-cause mortality, hospital admission, length of stay in hospital and emergency room visits, other studies have not shown such benefits. This study, therefore, aims to examine several home telemonitoring study designs and the influence of study design on study outcomes. METHOD: Articles were obtained by searching PubMed database with the term heart failure combined with the following terms: telemonitoring, telehealth, home monitoring, and remote monitoring. Searches were limited to randomized controlled trial conducted between year January 1, 2000 and February 6, 2021. The characteristics of the study designs and study outcomes were extracted and analyzed. RESULT: Our review of 34 randomized controlled trials of heart failure telemonitoring did not show any significant influence of study design on reduction in number of hospitalizations and/or decrease in mortality. Studies that were done outside North America (USA and Canada) and studies that selected patients at high risk of re-hospitalization were more likely to result in decreased hospitalization and/or mortality, though this was not statistically significant. All the studies that met our inclusion criteria were from high-income countries and only one study enrolled patients at high risk of re-hospitalization. CONCLUSION: There is a need for more studies to understand why telemonitoring studies in Europe were more likely to reduce hospital admission and mortality compared to those in North America. There is also a need for more studies on the effect of telemonitoring in patients at high risk of hospital readmission.

An acquired acyltransferase promotes Klebsiella pneumoniae ST258 respiratory infection.

Klebsiella pneumoniae ST258 is a human pathogen associated with poor outcomes worldwide. We identify a member of the acyltransferase superfamily 3 (atf3), enriched within the ST258 clade, that provides a major competitive advantage for the proliferation of these organisms in vivo. Comparison of a wild-type ST258 strain (KP35) and a Δatf3 isogenic mutant generated by CRISPR-Cas9 targeting reveals greater NADH:ubiquinone oxidoreductase transcription and ATP generation, fueled by increased glycolysis. The acquisition of atf3 induces changes in the bacterial acetylome, promoting lysine acetylation of multiple proteins involved in central metabolism, specifically Zwf (glucose-6 phosphate dehydrogenase). The atf3-mediated metabolic boost leads to greater consumption of glucose in the host airway and increased bacterial burden in the lung, independent of cytokine levels and immune cell recruitment. Acquisition of this acyltransferase enhances fitness of a K. pneumoniae ST258 isolate and may contribute to the success of this clonal complex as a healthcare-associated pathogen.

A novel study on SARS-COV-2 virus associated bradycardia as a predictor of mortality-retrospective multicenter analysis.

BACKGROUND: SARS-CoV2 has affected more than 73.8 million individuals. While SARS-CoV2 is considered a predominantly respiratory virus, we report a trend of bradycardia among hospitalized patients, particularly in association with mortality. METHODOLOGY: The multi-center retrospective analysis consisted of 1053 COVID-19 positive patients from March to August 2020. A trend of bradycardia was noted in the study population. Absolute bradycardia and profound bradycardia was defined as a sustained heart rate < 60 BPM and < 50 BPM, respectively, on two separate occasions, a minimum of 4 h apart during hospitalization. Each bradycardic event was confirmed by two physicians and exclusion criteria included: less than 18 years old, end of life bradycardia, left AMA, or taking AV Nodal blockers. Data was fetched using a SQL program through the EMR and data was analyzed using SPSS 27.0. A logistic regression was done to study the effect of bradycardia, age, gender, and BMI on mortality in the study group. RESULTS: 24.9% patients had absolute bradycardia while 13.0% had profound bradycardia. Patients with absolute bradycardia had an odds ratio of 6.59 (95% CI [2.83-15.36]) for mortality compared with individuals with a normal HR response. The logistic regression model explained 19.6% (Nagelkerke R2 ) of variance in the mortality, correctly classified 88.6% of cases, and was statistically significant X2 (5)=47.10, p < .001. For each year of age > 18, the odds of dying increased 1.048 times (95% CI [1.25-5.27]). CONCLUSION: The incidence of absolute bradycardia was found in 24.9% of the study cohort and these individuals were found to have a significant increase in mortality.

What about tocilizumab? A retrospective study from a NYC Hospital during the COVID-19 outbreak.

BACKGROUND: Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease. METHODS: In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test. RESULTS: We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7-6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4-3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18-3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1-1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09-1.53; p = 0.168). CONCLUSIONS: There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab.

P53 regulation of osteoblast differentiation is mediated through specific microRNAs.

In order to understand the role of the p53 tumor suppressor gene in microRNA expression during osteoblast differentiation, we used a screen to identify microRNAs that were altered in a p53-dependent manner. MicroRNAs from MC3T3-E1 preosteoblasts were isolated from day 0 (undifferentiated) and day 4 (differentiating) and compared to a p53 deficient MC3T3-E1 line treated similarly. Overall, one fourth of all the microRNAs tested showed a reduction of 0.6 fold, and a similar number of them were increased 1.7 fold with differentiation. P53 deficiency caused 40% reduction in expression of microRNAs in differentiating cells, while a small percent (0.03%) showed an increase. Changes in microRNAs were validated using real-time PCR and two microRNAs were selected for further analysis (miR-34b and miR-140). These two microRNAs were increased significantly during differentiation but showed a dramatic reduction in expression in a p53 deficient state. Stable expression of miR-34b and miR-140 in MC3T3-E1 cells resulted in decreases in cell proliferation rates when compared to control cells. There was a 4-fold increase in p53 levels with miR-34b expression and a less dramatic increase with miR-140. Putative target binding sites for bone specific transcription factors, Runx2 and Osterix, were found for miR-34b, while Runx2, beta catenin and type 1 collagen were found to be miR-140 targets. Western blot analyses and functional assays for the transcription factors Runx2, Osterix and Beta-catenin confirmed microRNA specific interactions. These studies provide evidence that p53 mediated regulation of osteoblast differentiation can also occur through specific microRNAs such as miR-34b and miR-140 that also directly target important bone specific genes.

Hemozoin Promotes Lung Inflammation via Host Epithelial Activation.

Respiratory distress in severe malaria is associated with high mortality, but its pathogenesis remains unclear. The malaria pigment hemozoin (HZ) is abundant in target organs of severe malaria, including the lungs, and is known to be a potent innate immune activator of phagocytes. We hypothesized that HZ might also stimulate lung epithelial activation and thereby potentiate lung inflammation. We show here that airway epithelium stimulated with HZ undergoes global transcriptional reprogramming and changes in cell surface protein expression that comprise an epithelial activation phenotype. Proinflammatory signaling is induced, and key cytoadherence molecules are upregulated, including several associated with severe malaria, such as CD36 and ICAM1. Epithelial and extracellular matrix remodeling pathways are transformed, including induction of key metalloproteases and modulation of epithelial junctions. The overall program induced by HZ serves to promote inflammation and neutrophil transmigration, and is recapitulated in a murine model of HZ-induced acute pneumonitis. Together, our data demonstrate a direct role for hemozoin in stimulating epithelial activation that could potentiate lung inflammation in malaria.IMPORTANCE Respiratory distress (RD) is a complication of severe malaria associated with a particularly high risk for death in African children infected with the parasite Plasmodium falciparum The pathophysiology underlying RD remains poorly understood, and the condition is managed supportively. The parasite-derived factor HZ accumulates in target organs of severe malaria, including the lungs, and is a potent stimulator of immune cells. Our findings demonstrate that HZ causes global activation of lung epithelial cells, a response that directly promotes lung inflammation. HZ stimulates expression of key proinflammatory and cell surface molecules, alters signaling pathways involved in epithelial-matrix remodeling, and promotes neutrophil transmigration and airway inflammation. The lung epithelial activation induced by HZ mimics patterns seen in malarial lung injury and provides new insights into the molecular pathogenesis of RD.

Characterization of pulmonary vein reconnection post Cryoballoon ablation.

BACKGROUND: The Arctic Front Cryoballoon System is a technology in which substrate alterations in patients with atrial fibrillation (AF) recurrence have not been well characterized. In this study, we evaluated sites of pulmonary vein (PV) reconnections and the accuracy of the Achieve™ circular mapping catheter in detecting these reconnections after cryoablation. METHODS: This study included 15 patients undergoing redo AF ablation after a prior single cryoablation procedure. PV reconnection sites were determined by measuring PV signals and high output pacing from 4 vectors of the Achieve catheter. The results were compared with a roving mapping catheter guided by rotational intracardiac echocardiography (ICE) in the left atrium. RESULTS: All patients had PV reconnections (2.1 ±â€¯0.8 veins/patient). The left superior PV was most commonly reconnected (n = 11), whereas the right inferior PV was least likely (n = 3). Both carinas (left: n = 11; right: n = 7) and left atrial appendage ridge (n = 11) were also frequently reconnected. Mapping with the Achieve catheter showed a positive predictive value (PPV) 100% and negative predictive value (NPV) 96% when compared with ICE guided mapping. In 2 patients, right superior PV reconnection was not identified by the Achieve. CONCLUSION: During redo AF ablation after index cryoablation, multiple PVs are usually reconnected, with both carinas and left atrial appendage ridge being common sites of reconnection. The Achieve mapping catheter was able to identify reconnection with high positive and negative predictive values.