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BACKGROUND:Myriad infectious and noninfectious causes of encephalomyelitis (EM) have similar clinical manifestations, presenting serious challenges to diagnosis and treatment. Metabolomics of cerebrospinal fluid (CSF) was explored as a method of differentiating among neurological diseases causing EM using a single CSF sample. METHODOLOGY/PRINCIPAL FINDINGS:1H NMR metabolomics was applied to CSF samples from 27 patients with a laboratory-confirmed disease, including Lyme disease or West Nile Virus meningoencephalitis, multiple sclerosis, rabies, or Histoplasma meningitis, and 25 controls. Cluster analyses distinguished samples by infection status and moderately by pathogen, with shared and differentiating metabolite patterns observed among diseases. CART analysis predicted infection status with 100% sensitivity and 93% specificity. CONCLUSIONS/SIGNIFICANCE:These preliminary results suggest the potential utility of CSF metabolomics as a rapid screening test to enhance diagnostic accuracies and improve patient outcomes.

Abstract Background Traumatic injuries occurring in agricultural settings are often associated with infections caused by unusual organisms. Such agents may be difficult to isolate, identify, and treat effectively. Case report A 4-year-old boy developed an extensive infection of his knee and distal femur following a barnyard pitchfork injury. Ultimately the primary infecting agent was determined to be Myceliophthora thermophila, a thermophilic melanized hyphomycete, rarely associated with human infection, found in animal excreta. Because of resistance to standard antifungal agents including amphotericin B and caspofungin, therapy was instituted with a prolonged course of terbinafine and voriconazole. Voriconazole blood levels demonstrated that the patient required a drug dosage (13.4 mg/kg) several fold greater than that recommended for adults in order to attain therapeutic blood levels. Conclusion Unusual pathogens should be sought following traumatic farm injuries. Pharmacokinetic studies may be of critical importance when utilizing antifungal therapy with agents for which little information exists regarding drug metabolism in children.

The first wave of the 2009 influenza H1N1 pandemic (H1N1pdm) in Milwaukee, WI has been recognized as the largest reported regional outbreak in the United States. The epidemiologic and clinical characteristics of this large first wave outbreak from April 28th 2009-July 25th 2009, studied using both passive and targeted surveillance methodologies are presented. A total of 2791 individuals with H1N1pdm infection were identified; 60 % were 5-18 years old. The 5-18 year and 0-4 year age groups had high infection (1131 and 1101 per 100,000) and hospitalization (49 and 12 per 100,000) rates respectively. Non-Hispanic blacks and Hispanics had the highest hospitalization and infection rates. In targeted surveillance, infected patients had fever (78%), cough (80%), sore throat (38%), and vomiting or diarrhea (8%). The "influenza like illness" definition captured only 68 % of infected patients. Modeling estimates that 10.3 % of Milwaukee population was infected in the first wave and 59% were asymptomatic. The distinct epidemiologic profile of H1N1pdm infections observed in the study has direct implications for predicting the burden of infection and hospitalization in the next waves of H1N1pdm. Careful consideration of demographic predictors of infection and hospitalization with H1N1pdm will be important for effective preparedness for subsequent influenza seasons. [ABSTRACT FROM AUTHOR]

Rabies is the deadliest viral infection known, with no reliable treatment, and although it is entirely preventable, rabies continues to kill more than 60,000 people every year, mostly children in countries where dog rabies is endemic. America is only 1 generation away from the time when rabies killed more than 10,000 animals and 50 Americans every year, but 3 to 5 Americans continue to die annually from rabies. Distressingly, > 50,000 Americans undergo rabies prevention therapy every year after exposure to potentially rabid animals. While enormous progress has been made, more must be done to defeat this ancient but persistent, fatal zoonosis. In the US, lack of public awareness and ambivalence are the greatest dangers imposed by rabies, resulting in unnecessary exposures, anxiety, and risk. Veterinarians have a special role in informing and reassuring the public about prevention and protection from rabies. This summary of current facts and future advances about rabies will assist veterinarians in informing their clients about the disease. [ABSTRACT FROM AUTHOR]

Background Cardiac fibrosis complicates SARS-CoV-2 infections and has been linked to arrhythmic complications in survivors. Accordingly, we sought evidence of increased HSP47 (heat shock protein 47), a stress-inducible chaperone protein that regulates biosynthesis and secretion of procollagen in heart tissue, with the goal of elucidating molecular mechanisms underlying cardiac fibrosis in subjects with this viral infection. Methods and Results Using human autopsy tissue, immunofluorescence, and immunohistochemistry, we quantified Hsp47 + cells and collagen α 1(l) in hearts from people with SARS-CoV-2 infections. Because macrophages are also linked to inflammation, we measured CD163 + cells in the same tissues. We observed irregular groups of spindle-shaped HSP47 + and CD163 + cells as well as increased collagen α 1(I) deposition, each proximate to one another in "hot spots" of ≈40% of hearts after SARS-CoV-2 infection (HSP47 + P <0.05 versus nonfibrotics and P <0.001 versus controls). Because HSP47 + cells are consistent with myofibroblasts, subjects with hot spots are termed "profibrotic." The remaining 60% of subjects dying with COVID-19 without hot spots are referred to as "nonfibrotic." No control subject exhibited hot spots. Conclusions Colocalization of myofibroblasts, M2(CD163 + ) macrophages, and collagen α 1(l) may be the first evidence of a COVID-19-related "profibrotic phenotype" in human hearts in situ. The potential public health and diagnostic implications of these observations require follow-up to further define mechanisms of viral-mediated cardiac fibrosis.

Background: Rabies is a highly fatal disease. Once symptoms develop, death usually occurs within days. Survivors were occasionally reported in the literatures. Ante-mortem diagnosis remains a challenge in most rabies endemic countries. A novel, accurate diagnostic assay is highly desirable., Methods: We used metagenomic next-generation sequencing (mNGS) to examine the cerebrospinal fluid (CSF) samples of a 49-year-old patient with rabies and validated the results by TaqMan PCR and RT-PCR/Sanger sequencing., Results: Metagenomic next-generation sequencing identified sequence reads uniquely aligned to the rabies virus (RABV). PCR confirmed the presence of the partial RABV N gene in the CSF. Phylogenetic analysis showed that the RABV grouped as an Asian clade, which is the most broadly distributed clade in China., Conclusion: Metagenomic next-generation sequencing may be a useful screening tool for the etiological diagnosis of rabies, especially in the absence of timely rabies laboratory testing or in patients with no exposure history., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Mo, Feng, Willoughby, Weng, Wang, Li, Gao, Tian and Peng.)

Rabies is the deadliest viral infection known, with no reliable treatment, and although it is entirely preventable, rabies continues to kill more than 60,000 people every year, mostly children in countries where dog rabies is endemic. America is only 1 generation away from the time when rabies killed more than 10,000 animals and 50 Americans every year, but 3 to 5 Americans continue to die annually from rabies. Distressingly, > 50,000 Americans undergo rabies prevention therapy every year after exposure to potentially rabid animals. While enormous progress has been made, more must be done to defeat this ancient but persistent, fatal zoonosis. In the US, lack of public awareness and ambivalence are the greatest dangers imposed by rabies, resulting in unnecessary exposures, anxiety, and risk. Veterinarians have a special role in informing and reassuring the public about prevention and protection from rabies. This summary of current facts and future advances about rabies will assist veterinarians in informing their clients about the disease.

This report outlines recommendations for the clinical use of the three smallpox vaccines stored in the U.S. Strategic National Stockpile for persons who are exposed to smallpox virus or at high risk for smallpox infection during a postevent vaccination program following an intentional or accidental release of the virus. No absolute contraindications exist for smallpox vaccination in a postevent setting. However, several relative contraindications exist among persons with certain medical conditions. CDC recommendations for smallpox vaccine use were developed in consideration of the risk for smallpox infection, risk for an adverse event following vaccination, and benefit from vaccination. Smallpox vaccines are made from live vaccinia viruses that protect against smallpox disease. They do not contain variola virus, the causative agent of smallpox. The three smallpox vaccines stockpiled are ACAM2000, Aventis Pasteur Smallpox Vaccine (APSV), and Imvamune. Surveillance and containment activities including vaccination with replication-competent smallpox vaccine (i.e., vaccine viruses capable of replicating in mammalian cells such as ACAM2000 and APSV) will be the primary response strategy for achieving epidemic control. Persons exposed to smallpox virus are at high risk for developing and transmitting smallpox and should be vaccinated with a replication-competent smallpox vaccine unless severely immunodeficient. Because of a high likelihood of a poor immune response and an increased risk for adverse events, smallpox vaccination should be avoided in persons with severe immunodeficiency who are not expected to benefit from vaccine, including bone marrow transplant recipients within 4 months of transplantation, persons infected with HIV with CD4 cell counts <50 cells/mm3, and persons with severe combined immunodeficiency, complete DiGeorge syndrome, and other severely immunocompromised states requiring isolation. If antivirals are not immediately available, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in persons with severe immunodeficiency. Persons without a known smallpox virus exposure might still be at high risk for developing smallpox infection depending on the magnitude of the outbreak and the effectiveness of the public health response. Such persons will be defined by public health authorities and should be screened for relative contraindications to smallpox vaccination. Relative contraindications include atopic dermatitis (eczema), HIV infection (CD4 cell counts of 50-199 cells/mm3), other immunocompromised states, and vaccine or vaccine-component allergies. Persons with relative contraindications should be vaccinated with Imvamune when available and authorized for use by the Food and Drug Administration. These recommendations will be updated as new data on smallpox vaccines become available and further clinical guidance for other medical countermeasures including antivirals is developed.

On 17 April 2009, novel swine origin influenza A virus (S-OIV) cases appeared within the United States. Most influenza A diagnostic assays currently utilized in local clinical laboratories do not allow definitive subtype determination. Detailed subtype analysis of influenza A positive samples in our laboratory allowed early confirmation of a large outbreak of S-OIV in southeastern Wisconsin (SEW). The initial case of S-OIV in SEW was detected on 28 April 2009. All influenza A samples obtained during the 16 week period prior to 28 April 2009, and the first four weeks of the subsequent epidemic were sub typed. Four different multiplex assays were employed, utilizing real time PCR and end point PCR to fully subtype human and animal influenza viral components. Specific detection of S-OIV was developed within days. Data regarding patient demographics and other concurrently circulating viruses were analyzed. During the first four weeks of the epidemic, 679 of 3726 (18.2%) adults and children tested for influenza A were identified with S-OIV infection. Thirteen patients (0.34%) tested positive for seasonal human subtypes of influenza A during the first two weeks and none in the subsequent 2 weeks of the epidemic. Parainfluenza viruses were the most prevalent seasonal viral agents circulating during the epidemic (of those tested), with detection rates of 12% followed by influenza B and RSV at 1.9% and 0.9% respectively. S-OIV was confirmed on day 2 of instituting subtype testing and within 4 days of report of national cases of S-OIV. Novel surge capacity diagnostic infrastructure exists in many specialty and research laboratories around the world. The capacity for broader influenza A sub typing at the local laboratory level allows timely and accurate detection of novel strains as they emerge in the community, despite the presence of other circulating viruses producing identical illness. This is likely to become increasingly important given the need for appropriate subtype driven anti-viral therapy and the potential shortage of such medications in a large epidemic.

Background: Traumatic injuries occurring in agricultural settings are often associated with infections caused by unusual organisms. Such agents may be difficult to isolate, identify, and treat effectively., Case Report: A 4-year-old boy developed an extensive infection of his knee and distal femur following a barnyard pitchfork injury. Ultimately the primary infecting agent was determined to be Myceliophthora thermophila, a thermophilic melanized hyphomycete, rarely associated with human infection, found in animal excreta. Because of resistance to standard antifungal agents including amphotericin B and caspofungin, therapy was instituted with a prolonged course of terbinafine and voriconazole. Voriconazole blood levels demonstrated that the patient required a drug dosage (13.4 mg/kg) several fold greater than that recommended for adults in order to attain therapeutic blood levels., Conclusion: Unusual pathogens should be sought following traumatic farm injuries. Pharmacokinetic studies may be of critical importance when utilizing antifungal therapy with agents for which little information exists regarding drug metabolism in children.

Some congenital cytomegalovirus (CMV) infections lead to neonatal disease, whereas others have no associated sequelae. To explore a possible role for viral genes as determinants of virulence, portions of the UL144 tumor necrosis factor (TNF)-alpha-like receptor gene, the US28 beta-chemokine receptor gene, and the UL55 envelope glycoprotein B gene from 33 patients with congenital CMV infection were sequenced. Three major UL144 subtypes (A, B, and C) and 2 recombinants (A/C and A/B) were detected. Infection with the least common UL144 subtypes (A, C, A/C, and A/B) was associated with unfavorable disease outcome (P=.04). There was no association between specific subtypes of the US28 and UL55 genes and outcome (P=.864 and P=.765, respectively). Multiple genotypes (implying multiple infections) were detected in tissues from 8 of 10 autopsies. Therefore, polymorphism in the CMV-encoded TNF-alpha-like receptor appears to be associated with congenital CMV disease. Other CMV polymorphisms should be further evaluated for potential relevance to neonatal infection, transplantation, and acquired immunodeficiency syndrome-associated CMV diseases.