The diagnostic dilemma for atypical presentation of progressive human Mpox.

BACKGROUND: Human mpox has increasingly been reported worldwide since May 2022, with higher incidence in men who have sex with men (MSM) and persons living with HIV (PLHIV) with presentation typical for generalized macules and papules. CASE PRESENTATION: We are describing a case of human mpox, which presented as widespread, atypical round verrucous lesions that went undiagnosed in the community for six months and was treated with antibacterials and antifungals given the similarity to skin manifestations associated with endemic mycoses. CONCLUSIONS: Suspicion for human mpox should be high in young MSM and PLHIV who present with rash and mpox should be ruled out earlier.

Correlation between Monocyte Gene Expression and Inflammation on Brain Imaging in Patients with Solitary Cerebral Cysticercus Granuloma.

Prior work has shown that 14 monocyte genes are upregulated in patients with different forms of parenchymal neurocysticercosis, including solitary cysticercus granuloma (SCG). The aim of this study was to investigate whether changes in inflammation associated with SCG seen on follow-up brain imaging are also reflected in changes in expression of these 14 genes. Peripheral blood CD14+ monocytes were isolated from 20 patients with SCG at initial diagnosis and at clinical and imaging follow-up of 6 months or more. Expressions of 14 target monocyte genes were determined by quantitative polymerase chain reaction at each visit. At a median follow-up of 14 months, the SCG had resolved in 11 patients, was persistent in four patients, and had calcified in five patients. Edema seen in the initial imaging in 17 patients had resolved in 15 patients and was markedly reduced in two patients. The expression levels of the monocyte genes LRRFIP2, TAXIBP1, and MZB1 were significantly lower at follow-up, regardless of the status of SCG on follow-up imaging. Our findings show that expression levels of monocyte genes involved with inflammatory processes decrease in patients with SCG concomitant with follow-up imaging that reveals a reduction in inflammation as revealed by complete or near-complete resolution of edema, as well as resolution or reduction in the enhancement of the granuloma.

Septic encephalopathy in the elderly - biomarkers of potential clinical utility.

Next to acute sickness behavior, septic encephalopathy is the most frequent involvement of the brain during infection. It is characterized by a cross-talk of pro-inflammatory cells across the blood-brain barrier, by microglial activation and leukocyte migration, but not by the entry of infecting organisms into the brain tissue. Septic encephalopathy is very frequent in older persons because of their limited cognitive reserve. The predominant clinical manifestation is delirium, whereas focal neurological signs and symptoms are absent. Electroencephalography is a very sensitive method to detect functional abnormalities, but these abnormalities are not specific for septic encephalopathy and of limited prognostic value. Routine cerebral imaging by computer tomography usually fails to visualize the subtle abnormalities produced by septic involvement of the brain. Magnetic resonance imaging is by far more sensitive to detect vasogenic edema, diffuse axonal injury or small ischemic lesions. Routine laboratory parameters most suitable to monitor sepsis, but not specific for septic encephalopathy, are C-reactive protein and procalcitonin. The additional measurement of interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor-α increases the accuracy to predict delirium and an unfavorable outcome. The most promising laboratory parameters to quantify neuronal and axonal injury caused by septic encephalopathy are neurofilament light chains (NfL) and S100B protein. Neuron-specific enolase (NSE) plasma concentrations are strongly influenced by hemolysis. We propose to determine NSE only in non-hemolytic plasma or serum samples for the estimation of outcome in septic encephalopathy.

Progressive cognitive impairment after recovery from neuroinvasive and non-neuroinvasive Listeria monocytogenes infection.

Background: Neuro-cognitive impairment is a deleterious complication of bacterial infections that is difficult to treat or prevent. Listeria monocytogenes (Lm) is a neuroinvasive bacterial pathogen and commonly used model organism for studying immune responses to infection. Antibiotic-treated mice that survive systemic Lm infection have increased numbers of CD8+ and CD4+ T-lymphocytes in the brain that include tissue resident memory (TRM) T cells, but post-infectious cognitive decline has not been demonstrated. We hypothesized that Lm infection would trigger cognitive decline in accord with increased numbers of recruited leukocytes. Methods: Male C57BL/6J mice (age 8 wks) were injected with neuroinvasive Lm 10403s, non-neuroinvasive Δhly mutants, or sterile saline. All mice received antibiotics 2-16d post-injection (p.i.) and underwent cognitive testing 1 month (mo) or 4 mo p.i. using the Noldus PhenoTyper with Cognition Wall, a food reward-based discrimination procedure using automated home cage based observation and monitoring. After cognitive testing, brain leukocytes were quantified by flow cytometry. Results: Changes suggesting cognitive decline were observed 1 mo p.i. in both groups of infected mice compared with uninfected controls, but were more widespread and significantly worse 4 mo p.i. and most notably after Lm 10403s. Impairments were observed in learning, extinction of prior learning and distance moved. Infection with Lm 10403s, but not Δhly Lm, significantly increased numbers of CD8+ and CD4+ T-lymphocytes, including populations expressing CD69 and TRM cells, 1 mo p.i. Numbers of CD8+, CD69+CD8+ T-lymphocytes and CD8+ TRM remained elevated at 4 mo p.i. but numbers of CD4+ cells returned to homeostatic levels. Higher numbers of brain CD8+ T-lymphocytes showed the strongest correlations with reduced cognitive performance. Conclusions: Systemic infection by neuroinvasive as well as non-neuroinvasive Lm triggers a progressive decline in cognitive impairment. Notably, the deficits are more profound after neuroinvasive infection that triggers long-term retention of CD8+ T-lymphocytes in the brain, than after non-neuroinvasive infection, which does not lead to retained cells in the brain. These results support the conclusion that systemic infections, particularly those that lead to brain leukocytosis trigger a progressive decline in cognitive function and implicate CD8+ T-lymphocytes, including CD8+TRM in the etiology of this impairment.

Non-Small Cell Lung Cancer Presenting as Anterior Nasal Mass and Epistaxis.

Lung malignancy presentation with an uncommon metastatic site is a diagnostic challenge and often associated with poor prognosis. Nasal cavity is a rare metastatic site for any type of lung cancer. We report an unusual case of poorly differentiated adenosquamous carcinoma of the lung with widespread metastasis presenting as a right vestibular nasal mass with epistaxis. A 76-year-old male patient with chronic obstructive pulmonary disease and 80 pack-year smoking history presented with spontaneous epistaxis. He reported a new rapidly growing right-sided nasal vestibular mass first noticed 2 weeks prior. Physical examination showed fleshy mass with crusting in right nasal vestibule along with a left nasal domus mass. Imaging revealed an ovoid mass in the right anterior nostril and a large mass in the right upper lobe of the lung (RULL) along with thoracic vertebral sclerotic metastasis and large left frontal lobe hemorrhagic lesion with severe vasogenic edema. Positron emission tomography scan showed large right upper lobe mass and suspected to be the primary malignancy along with widespread metastasis. Biopsy of the nasal lesion revealed poorly differentiated non-small cell carcinoma with squamous and glandular features. The diagnosis of very poorly differentiated adenosquamous carcinoma of the lung with widespread metastasis was made. In conclusion, unusual metastatic sites with unknown primary lesions require a thorough diagnostic workup involving biopsy and extensive imaging. Lung cancer with unusual metastatic sites is inherently aggressive and associated with poor prognosis. Multidisciplinary treatment modalities should be employed keeping in view the functional status and comorbidities of the patient.

Systemic Listeria monocytogenes infection in aged mice induces long-term neuroinflammation: the role of miR-155.

BACKGROUND: Understanding mechanisms of pathologic neuroinflammation is essential for improving outcomes after central nervous system infections. Brain tissue-resident memory T cells (bTRM) are recruited during central nervous system infection and promote pathogen control as well as noxious inflammation. Our prior studies in young mice showed optimal recruitment of CD8+ bTRM during neuroinvasive Listeria monocytogenes (Lm) infection required miR-155, and was significantly inhibited by anti-miR-155 oligonucleotides. Since Lm is an important pathogen in the elderly, we hypothesized anti-miR-155 would also inhibit accumulation of CD8+ bTRM in aged mice infected with Lm. METHODS: Young (2 mo) and aged (> 18 mo) male C57BL/6 mice were infected intra-peritoneally with wild-type Lm, or avirulent Lm mutants lacking the genes required for intracellular motility (ΔactA) or phagosomal escape (Δhly), then were given antibiotics. Brain leukocytes and their intracellular cytokine production were quantified by flow cytometry >28d post-infection (p.i.). The role of miR-155 was tested by injecting mice with anti-miR-155 or control oligonucleotides along with antibiotics. RESULTS: Aged mice had significantly more homeostatic CD8+ bTRM than did young mice, which did not increase after infection with wild-type Lm despite 50% mortality, whereas young mice suffered no mortality after a larger inoculum. For direct comparison of post-infectious neuroinflammation after the same inoculum, young and aged mice were infected with 107 CFU ΔactA Lm. This mutant caused no mortality and significantly increased CD8+ bTRM 28d p.i. in both groups, whereas bone marrow-derived myeloid cells, particularly neutrophils, increased only in aged mice. Notably, anti-miR-155 reduced accumulation of brain myeloid cells in aged mice after infection, whereas CD8+ bTRM were unaffected. CONCLUSIONS: Systemic infection with Lm ΔactA is a novel model for studying infection-induced brain inflammation in aged mice without excessive mortality. CD8+ bTRM increase in both young and aged mice after infection, whereas only in aged mice bone marrow-derived myeloid cells increase long-term. In aged mice, anti-miR-155 inhibits brain accumulation of myeloid cells, but not CD8+ bTRM. These results suggest young and aged mice differ in manifestations and mechanisms of infection-induced neuroinflammation and give insight for developing therapies to ameliorate brain inflammation following severe infection in the elderly.

Bordetella bronchiseptica infections in patients with HIV/AIDS: A case report and review of the literature.

RATIONALE: Bordetella bronchiseptica is a common cause of upper respiratory tract infections in domesticated dogs and cats and a rare zoonotic pathogen in immunocompromised humans. With increasing numbers of people acquiring pets and spending time with them in confined spaces due to COVID-19 lockdowns, it is important to be aware of adverse health consequences brought about by this interaction. We present a case of B bronchiseptica pneumonia in a patient with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and review key characteristics of an additional 30 cases of B bronchiseptica infections in 29 patients with HIV/AIDS that were identified by literature review. PATIENT CONCERNS: A 61-year-old male with HIV/AIDS who was not on antiretroviral therapy and had advanced immunosuppression with a CD4+ T-lymphocyte count of 3 cells/µL sought medical attention for multiple somatic issues including subjective fevers, shortness of breath, and intermittent chest pain. DIAGNOSIS: Computed tomography of the chest identified bilateral nodular opacities in the lower lobes with scattered areas of ground glass opacities. B bronchiseptica was identified in sputum culture by mass spectrometry followed by supplementary biochemical testing. INTERVENTIONS: Empiric broad-spectrum antibiotics were initiated and changed to levofloxacin after susceptibility testing was completed. OUTCOMES: The patient was discharged after symptomatic improvement with levofloxacin. LESSONS: Pneumonia with interstitial infiltrates in the setting of advanced CD4 lymphocyte depletion is the most common clinical syndrome caused by B bronchiseptica in patients with HIV/AIDS, and may be accompanied by sepsis. Advanced immune suppression, as well as chronic medical conditions, for example, alcoholism, diabetes, and renal failure that compromise host defenses are also commonly found in cases of B bronchiseptica infection in patients who do not have HIV infection. Reported animal contact among patients was not universal. Isolates were susceptible to aminoglycosides, carbapenems, fluoroquinolones, but typically resistant to most cephalosporins.

Monocyte Gene Expression Distinguishes Enhancing Brain Parenchymal Cysticercal Granulomas From Tuberculomas.

BACKGROUND: In patients with enhancing brain parenchymal lesions, parenchymal neurocysticercosis (pNCC) is often difficult to distinguish from tuberculoma, necessitating biopsy or empirical therapy. METHODS: In a prospective study, peripheral blood monocytes were isolated from patients with definitive pNCC (n = 39) and brain tuberculomas (n = 20). Patients with tuberculomas were diagnosed by the presence of concurrent systemic tuberculosis (n = 7), pathological or bacteriological confirmation (n = 5), and resolution of typical brain lesions following a therapeutic trial of antituberculous therapy (n = 8). Expressions of 14 NCC-associated monocyte genes were determined by quantitative polymerase chain reaction and analyzed for diagnostic usefulness between the 2 groups. RESULTS: Expression of 7 genes (TAX1BP1, RAP1A, PLCG2, TOR3A, GBP1P1, LRRFIP2, and FEZ2) was significantly higher in pNCC patients than in tuberculoma patients, with TAX1BP1 and RAP1A expressions more than 22- and 5-fold higher in pNCC patients. TAX1BP1 had the highest sensitivity of 66.7% at a specificity of 100% in discriminating pNCC from tuberculoma. A combination of TAX1BP1 and RAP1A increased the sensitivity to 84.6%, and including GBP1P1 with TAX1BP1 and RAP1A further increased sensitivity to 87.2% while maintaining specificity of 100%. CONCLUSIONS: Expression of a panel of genes in blood monocytes distinguishes pNCC from brain tuberculomas in patients with enhancing brain lesions.

Endothelial Dysfunction and Impaired Neurovascular Coupling Responses Precede Cognitive Impairment in a Mouse Model of Geriatric Sepsis.

Sepsis is a life-threatening condition, the incidence of which is significantly increased in elderly patients. One of the long-lasting effects of sepsis is cognitive impairment defined as a new deficit or exacerbation of preexisting deficits in global cognition or executive function. Normal brain function is dependent on moment-to-moment adjustment of cerebral blood flow to match the increased demands of active brain regions. This homeostatic mechanism, termed neurovascular coupling (NVC, also known as functional hyperemia), is critically dependent on the production of vasodilator NO by microvascular endothelial cells in response to mediators released from activated astrocytes. The goal of this study was to test the hypothesis that sepsis in aging leads to impairment of NVC responses early after treatment and that this neurovascular dysfunction associates with impairments in cognitive performance and vascular endothelial dysfunction. To test this hypothesis, we used a commonly studied bacterial pathogen, Listeria monocytogenes, to induce sepsis in experimental animals (males, 24 months of age) and subjected experimental animals to a standard clinical protocol of 3 doses of ampicillin i.p. and 14 days of amoxicillin added to the drinking water. NVC responses, endothelial function and cognitive performance were measured in septic and age-matched control groups within 14 days after the final antibiotic treatment. Our data demonstrate that sepsis in aging significantly impairs NVC responses measured in somatosensory cortex during whisker stimulation, significantly impairs endothelial function in isolated and pressure cannulated aorta rings in response to acetylcholine stimulation. No significant impairment of cognitive function in post-sepsis aged animals has been observed when measured using the PhenoTyper homecage based system. Our findings suggest that sepsis-associated endothelial dysfunction and impairment of NVC responses may contribute to long-term cognitive deficits in older sepsis survivors.

Misclassification Error-Adjusted Prevalence of Injection Drug Use Among Infective Endocarditis Hospitalizations in the United States: A Serial Cross-Sectional Analysis of the 2007-2016 National Inpatient Sample.

Administrative health databases have been used to monitor trends in infective endocarditis hospitalization related to nonprescription injection drug use (IDU) using International Classification of Diseases (ICD) code algorithms. Because no ICD code for IDU exists, drug dependence and hepatitis C virus (HCV) have been used as surrogate measures for IDU, making misclassification error (ME) a threat to the accuracy of existing estimates. In a serial cross-sectional analysis, we compared the unadjusted and ME-adjusted prevalences of IDU among 70,899 unweighted endocarditis hospitalizations in the 2007-2016 National Inpatient Sample. The unadjusted prevalence of IDU was estimated with a drug algorithm, an HCV algorithm, and a combination algorithm (drug and HCV). Bayesian latent class models were used to estimate the median IDU prevalence and 95% Bayesian credible intervals and ICD algorithm sensitivity and specificity. Sex- and age group-stratified IDU prevalences were also estimated. Compared with the misclassification-adjusted prevalence, unadjusted estimates were lower using the drug algorithm and higher using the combination algorithm. The median ME-adjusted IDU prevalence increased from 9.7% (95% Bayesian credible interval (BCI): 6.3, 14.8) in 2008 to 32.5% (95% BCI: 26.5, 38.2) in 2016. Among persons aged 18-34 years, IDU prevalence was higher in females than in males. ME adjustment in ICD-based studies of injection-related endocarditis is recommended.

Evaluation of the Cherokee Nation Hepatitis C Virus Elimination Program in the First 22 Months of Implementation.

Importance: In 2019, hepatitis C virus (HCV) infection contributed to more deaths in the US than 60 other notifiable infectious diseases combined. The incidence of and mortality associated with HCV infection are highest among American Indian and Alaska Native individuals. Objective: To evaluate the association of the Cherokee Nation (CN) HCV elimination program with each element of the cascade of care: HCV screening, linkage to care, treatment, and cure. Design, Setting, and Participants: This cohort study used data from the CN Health Services (CNHS), which serves approximately 132 000 American Indian and Alaska Native individuals residing in the 14-county CN reservation in rural northeastern Oklahoma. Data from the first 22 months of implementation (November 1, 2015, to August 31, 2017) of an HCV elimination program were compared with those from the pre-elimination program period (October 1, 2012, to October 31, 2015). The analysis included American Indian and Alaska Native individuals aged 20 to 69 years who accessed care through the CNHS between October 1, 2012, and August 31, 2017. Cure data were recorded through April 15, 2018. Exposure: The CN HCV elimination program. Main Outcomes and Measures: The main outcomes were the proportions of the population screened for HCV, diagnosed with current HCV infection, linked to care, treated, and cured during the initial 22 months of the elimination program period and the pre-elimination program period. Data from electronic health records and an HCV treatment database were analyzed. The cumulative incidence of HCV infection in this population was estimated using bayesian analyses. Results: Among the 74 039 eligible individuals accessing care during the elimination program period, the mean (SD) age was 36.0 (13.5) years and 55.9% were women. From the pre-elimination program period to the elimination program period, first-time HCV screening coverage increased from 20.9% to 38.2%, and identification of current HCV infection and treatment in newly screened individuals increased from a mean (SD) of 170 (40) per year to 244 (4) per year and a mean of 95 (133) per year to 215 (9) per year, respectively. During the implementation period, of the 793 individuals with current HCV infection accessing the CNHS, 664 were evaluated (83.7%), 394 (59.3%) initiated treatment, and 335 (85.0%) had documented cure. In less than 2 years, the 85% 3-year goal was reached for cure (85.0%), and the goal for linkage to care was nearly reached (83.7%), whereas screening (44.1%) and treatment initiation (59.3%) required more time and resources. Conclusions and Relevance: This cohort study found that after 22 months of implementation, the CNHS community-based HCV elimination program was associated with an improved cascade of care. The facilitators and lessons learned in this program may be useful to other organizations planning similar programs.

Management of nontuberculous mycobacterial infections of the eye and orbit: A retrospective case series.

PURPOSE: To provide an update on different management approaches for Nontuberculous Mycobacterial (NTM) infections of the eye and orbit. OBSERVATIONS: A total of 9 eyes from 8 patients were found to meet study criteria. Of these 9 eyes, 6 eyes (66%) involved Mycobacterium abscessus, 2 (22%) involved M. chelonae, and 1 (11%) involved M. fortuitum. In 8 (88%) eyes, NTM infection was treated with a combination of antibiotics and removal of involved foreign body or tissue (e.g. scleral buckle, intraocular lens, orbital implant, or granuloma). One case was observed on topical therapy alone due to low suspicion for clinically significant infection. In 1 patient, a second culture-positive infection was found in the contralateral eye requiring treatment. CONCLUSIONS AND IMPORTANCE: Depending on the clinical presentation, optimal treatment of ocular and orbital NTM infections may require combination anti-mycobacterial antibiotics (topical and systemic), surgical removal of implanted material or tissue, or both.

Neuroinvasive Listeria monocytogenes infection triggers accumulation of brain CD8+ tissue-resident memory T cells in a miR-155-dependent fashion.

BACKGROUND: Brain inflammation is a key cause of cognitive decline after central nervous system (CNS) infections. A thorough understanding of immune responses to CNS infection is essential for developing anti-inflammatory interventions that improve outcomes. Tissue-resident memory T cells (TRM) are non-recirculating memory T cells that provide surveillance of previously infected tissues. However, in addition to protecting the brain against reinfection, brain TRM can contribute to post-infectious neuroinflammation. We hypothesized that accumulation of CD8+ TRM in the brain could be reduced by inhibiting microRNA (miR)-155, a microRNA that influences development of cytotoxic CD8+ T lymphocytes during infection. METHODS: C57BL/6J mice were infected by intraperitoneal injection with a lethal inoculum of Listeria monocytogenes (Lm) then treated with antibiotics. Flow cytometry was used to quantify specific populations of brain leukocytes 28-29 days (d) post-infection (p.i.). To test the degree to which miR-155 altered leukocyte influxes into the brain, infected mice were injected with a miR-155 inhibitor or locked nucleic acid (LNA) scramble control 2d, 4d, 6d, and 8d p.i. along with antibiotic treatment. Bacterial loads in spleen and liver and body weights were measured up to 7d p.i. Brain leukocytes were analyzed 14d and 28d p.i. Confirmatory studies were performed in mutated mice lacking miR-155 (miR-155-/-) RESULTS: Lm infection significantly increased the numbers of brain CD3+CD8+ lymphocytes at 28d p.i. These cells were extravascular, and displayed markers characteristic of TRM, with the predominant phenotype of CD44+CD62L-CD69+CX3CR1-. Further analysis showed that > 75% of brain TRM also expressed CD49a, PD-1, Ly6C, CD103, and CD127. Mice injected with miR-155 inhibitor lost less weight through 7d p.i. than did control mice, whereas bacterial loads in brain, liver, and spleen were not different from controls. By 28d p.i., the numbers of brain CD8+ TRM cells were significantly decreased in mice treated with the inhibitor compared with controls. Similarly, miR-155-/- mice showed significantly reduced numbers of brain CD8+ TRM cells by 28d p.i. CONCLUSIONS: Brain CD8+ TRM populations are established during neuroinvasive Lm infection. Accumulation of brain CD8+ TRM cells is reduced by blocking miR-155 and in miR-155-/- mice, indicating that this molecule has a critical role in development of these specialized cells. Administering anti-miR-155 during infection could provide a novel avenue for reducing post-infectious neuroinflammation.

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform.

A major source of epilepsy is Neurocysticercosis (NCC), caused by Taenia solium infection. Solitary cysticercus granuloma (SCG), a sub-group of NCC induced epilepsy, is the most common form of NCC in India. Current diagnostic criteria for SCG epilepsy require brain imaging which may not be available in communities where the disease is endemic. Identification of serum changes and potential biomolecules that could distinguish SCG epilepsy from idiopathic generalized epilepsy (IE), without the initial need for imaging, could assist in disease identification, understanding, and treatment. The objective here was to investigate, using mass spectrometry (MS), sera biomolecule differences between patients with SCG epilepsy or IE to help distinguish these disorders based on physiological differences, to understand underlying phenotypes and mechanisms, and to lay ground work for future therapeutic and biomarker analyses. Sera were obtained from patients with SCG or IE (N = 29 each group). Serum mass peak profiling was performed with electrospray ionization (ESI) MS, and mass peak area means in the two groups were compared using leave one [serum sample] out cross validation (LOOCV). Serum LOOCV analysis identified significant differences between SCG and IE patient groups (p = 10-20), which became non-significant (p = 0.074) when the samples were randomly allocated to the groups and reanalyzed. Tandem MS/MS peptide analysis of serum mass peaks from SCG or IE patients was performed to help identify potential peptide/protein biochemical and phenotypic changes involving these two forms of epilepsy. Bioinformatic analysis of these peptide/protein changes suggested neurological, inflammatory, seizure, blood brain barrier, cognition, ion channel, cell death, and behavior related biochemical systems were being altered in these disease states. This study provides groundwork for aiding in distinguishing SCG and IE patients in minimally invasive, lower-cost manners, for improving understanding of underlying epilepsy mechanisms, and for further identifying discriminatory biomarkers and potential therapeutic targets.

Validity of ICD-based algorithms to estimate the prevalence of injection drug use among infective endocarditis hospitalizations in the absence of a reference standard.

BACKGROUND: International Classification of Diseases (ICD) code algorithms are routinely used to estimate the frequency of illicit injection drug use (IDU)-associated hospitalizations in administrative health datasets despite a lack of evidence regarding their validity. We aimed to measure the sensitivity and specificity of ICD code algorithms used to estimate the prevalence of current/recent IDU among infective endocarditis (IE) hospitalizations without a reference standard. METHODS: We reviewed medical records of 321 patients aged 18-64 years old from an urban academic hospital with an IE diagnosis between 2007 and 2017. Diagnostic tests for IDU included self-reported IDU in medical records; a drug use, abuse and dependence (UAD) ICD algorithm; a Hepatitis C Virus (HCV) ICD algorithm; and a combination drug UAD/HCV ICD algorithm. Sensitivity, specificity and the misclassification error (ME)-adjusted IDU prevalence were estimated using Bayesian latent class models. RESULTS: The combination algorithm had the highest sensitivity and lowest specificity. Sensitivity increased for the drug UAD algorithm in the ICD-10 period compared to the ICD-9 period. The ME-adjusted current/recent IDU prevalence estimated using the drug UAD and HCV algorithms was 23 % (95 % Bayesian credible interval: 16 %, 31 %). The unadjusted prevalence estimate from the drug UAD algorithm underestimated the ME-adjusted prevalence, while the combination algorithm overestimated it. CONCLUSION: The validity of ICD code algorithms for IDU among IE hospitalizations is imperfect and differs between ICD-9 and ICD-10. Commonly used ICD-based algorithms could lead to substantially biased prevalence estimates in IDU-associated hospitalizations when using administrative health data.

Validity of International Classification of Diseases codes in identifying illicit drug use target conditions using medical record data as a reference standard: A systematic review.

BACKGROUND: The twenty-first century opioid crisis has spurred interest in using International Classification of Diseases (ICD) code algorithms to identify patients using illicit drugs from administrative healthcare data. We conducted a systematic review of studies that validated ICD code algorithms for illicit drug use against a reference standard of medical record data. METHODS: Systematic searches of MEDLINE, EMBASE, PsycINFO, and Web of Science were conducted for studies published between 1980 and 2018 in English, French, Italian, or Spanish. We included validation studies of ICD-9 or ICD-10 code algorithms for an illicit drug use target condition (e.g., illicit drug use, abuse, or dependence (UAD), illicit drug use-related complications) given the sensitivity or specificity was reported or could be calculated. Bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies Version 2 (QUADAS-2) tool. RESULTS: Six of the 1210 articles identified met the inclusion criteria. For validation studies of broad UAD (n = 4), the specificity was nearly perfect, but the sensitivity ranged from 47% to 83%, with higher sensitivities tending to occur in higher prevalence populations. For validation studies of injection drug use (IDU)-associated infective endocarditis (n = 2), sensitivity and specificity were poor due to the lack of an ICD code for IDU. For all six studies, the risk of bias for the QUADAS-2 "reference standard" and "flow/timing domains" was scored as "unclear" due to insufficient reporting. CONCLUSIONS: Few studies have validated ICD code algorithms for illicit drug use target conditions, and available evidence is challenging to interpret due to inadequate reporting. PROSPERO Registration: CRD42019118401.

Vaccine strain Listeria monocytogenes bacteremia occurring 31 months after immunization.

BACKGROUND: Listeria monocytogenes is a food-borne, facultative intracellular bacterium that causes severe diseases such as sepsis and meningoencephalitis in immunocompromised hosts. Because it stimulates robust T-lymphocyte-mediated responses, attenuated L. monocytogenes are candidate vaccine vectors for tumor immunotherapy. CASE: We report a case of bacteremia caused by vaccine strain L. monocytogenes (Axalimogene filolisbac) occurring 31 months after immunization against human papilloma virus (HPV) associated cervical cancer. CONCLUSION: Receipt of a L. monocytogenes-based vaccine is a novel risk factor for delayed L. monocytogenes bacteremia.

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155.

MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δhly or ΔactA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155-/-) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155-/- mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155-/- mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155-/- microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155-/- microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.

Distinguishing neurocysticercosis epilepsy from epilepsy of unknown etiology using a minimal serum mass profiling platform.

Neurocysticercosis is associated with epilepsy in pig-raising communities with poor sanitation. Current internationally recognized diagnostic guidelines for neurocysticercosis rely on brain imaging, a technology that is frequently not available or not accessible in areas endemic for neurocysticercosis. Minimally invasive and low-cost aids for diagnosing neurocysticercosis epilepsy could improve treatment of neurocysticercosis. The goal of this study was to test the extent to which patients with neurocysticercosis epilepsy, epilepsy of unknown etiology, idiopathic headaches and among different types of neurocysticercosis lesions could be distinguished from each other based on serum mass profiling. For this, we collected sera from patients with neurocysticercosis-associated epilepsy, epilepsy of unknown etiology, recovered neurocysticercosis, and idiopathic headaches then performed binary group comparisons among them using electrospray ionization mass spectrometry. A leave one [serum sample] out cross validation procedure was employed to analyze spectral data. Sera from neurocysticercosis patients was distinguished from epilepsy of unknown etiology patients with a p-value of 10-28. This distinction was lost when samples were randomized to either group (p-value = 0.22). Similarly, binary comparisons of patients with neurocysticercosis who has different types of lesions showed that different forms of this disease were also distinguishable from one another. These results suggest neurocysticercosis epilepsy can be distinguished from epilepsy of unknown etiology based on biomolecular differences in sera detected by mass profiling.

Comparison of monocyte gene expression among patients with neurocysticercosis-associated epilepsy, Idiopathic Epilepsy and idiopathic headaches in India.

BACKGROUND: Neurocysticercosis (NCC), a neglected tropical disease, inflicts substantial health and economic costs on people living in endemic areas such as India. Nevertheless, accurate diagnosis using brain imaging remains poorly accessible and too costly in endemic countries. The goal of this study was to test if blood monocyte gene expression could distinguish patients with NCC-associated epilepsy, from NCC-negative imaging lesion-free patients presenting with idiopathic epilepsy or idiopathic headaches. METHODS/PRINCIPAL FINDINGS: Patients aged 18 to 51 were recruited from the Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, India, between January 2013 and October 2014. mRNA from CD14+ blood monocytes was isolated from 76 patients with NCC, 10 Recovered NCC (RNCC), 29 idiopathic epilepsy and 17 idiopathic headaches patients. A preliminary microarray analysis was performed on six NCC, six idiopathic epilepsy and four idiopathic headaches patients to identify genes differentially expressed in NCC-associated epilepsy compared with other groups. This analysis identified 1411 upregulated and 733 downregulated genes in patients with NCC compared to Idiopathic Epilepsy. Fifteen genes up-regulated in NCC patients compared with other groups were selected based on possible relevance to NCC, and analyzed by qPCR in all patients' samples. Differential gene expression among patients was assessed using linear regression models. qPCR analysis of 15 selected genes showed generally higher gene expression among NCC patients, followed by RNCC, idiopathic headaches and Idiopathic Epilepsy. Gene expression was also generally higher among NCC patients with single cyst granulomas, followed by mixed lesions and single calcifications. CONCLUSIONS/SIGNIFICANCE: Expression of certain genes in blood monocytes can distinguish patients with NCC-related epilepsy from patients with active Idiopathic Epilepsy and idiopathic headaches. These findings are significant because they may lead to the development of new tools to screen for and monitor NCC patients without brain imaging.