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Cyprinid herpesvirus 2 (CyHV-2) is a virus that causes mass mortality in economically important Carassius spp. However, there have been no comprehensive studies into host susceptibility or permissivity with respect to developmental stage, and the major portal of viral entry into the host is still unclear. To help bridge these knowledge gaps, we developed the first ever recombinant strain of CyHV-2 expressing bioluminescent and fluorescent reporter genes. Infection of Carassius auratus hosts with this recombinant by immersion facilitated the exploitation of various in vivo imaging techniques to establish the spatiotemporal aspects of CyHV-2 replication at larval, juvenile, and adult developmental stages. While less susceptible than later developmental stages, larvae were most permissive to CyHV-2 replication, leading to rapid systemic infection and high mortality. Permissivity to CyHV-2 decreased with advancing development, with adults being the least permissive and, thus, also exhibiting the least mortality. Across all developmental stages, the skin was the most susceptible and permissive organ to infection at the earliest sampling points post-infection, indicating that it represents the major portal of entry into these hosts. Collectively these findings provide important fundamental insights into CyHV-2 pathogenesis and epidemiology in Carassius auratus with high relevance to other related economically important virus-host models.

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Background: Cutaneous tuberculosis (CTB) and its paucibacillary forms are rare and difficult to diagnose, especially in immunocompromised patients with significant comorbidity. The aim of the study was to introduce the modern concept of the microbiome and diagnostic chain into clinical practice (patient-centered care) with the presentation of an atypical form of cutaneous tuberculosis with necrotizing non-healing ulcers leading to polymicrobial infection. Methods: The study material included samples from sputum, broncho-alveolar lavage and skin ulcer, taken from a patient developing cutaneous tuberculosis. The microbiological investigation was performed, and identification of the isolates was carried out using genotyping and the matrix-assisted laser desorption ionization-time of flight mass spectrometry. Results: The immunocompromised patient with humoral abnormality (plasma cell dyscrasia) and severe paraproteinemia developed multiorgan tuberculosis. Although cutaneous manifestation preceded systemic and pulmonary symptoms (approximately half a year), the mycobacterial genotyping confirmed the same MTB strain existence in skin ulcers and the respiratory system. Therefore, the infectious chain: transmission, the portal of entry, and bacterial spreading in vivo, were unclear. Microbial diversity found in wound microbiota (among others Gordonia bronchialis, Corynebacterium tuberculostearicum, Staphylococcus haemolyticus, and Pseudomonas oryzihabitans) was associated with the spread of a skin lesion. The in vitro biofilm-forming capacity of strains isolated from the wound may represent the potential virulence of these strains. Thus, the role of polymicrobial biofilm may be crucial in ulcer formation and CTB manifestation. Conclusions: Severe wound healing as a unique biofilm-forming niche should be tested for Mycobacterium (on species and strain levels) and coexisting microorganisms using a wide range of microbiological techniques. In immunodeficient patients with non-typical CTB presentation, the chain of transmission and MTB spread is still an open issue for further research.

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PURPOSE: Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human pathogen that can cause severe invasive (iGAS) infections. Throat carriage has been assumed to possibly lead to hematogenous seeding. Retrospective studies may estimate the incidence of throat carriage in iGAS patients inaccurately. In this study we aimed to gather data on the presence of GAS in the throat among iGAS patients in a prospective setting. METHODS: We conducted a prospective clinical study covering iGAS infections in adult patients in two university hospitals in Finland from June 2018 to July 2020. Recruited patients' throats were swabbed for culture and isothermal amplification tests (IAT) to search for GAS. The study was registered at ClinicalTrials.gov as ID NCT03507101. RESULTS: We enrolled 45 patients. Throat swabs were obtained from 39/45 (87%) patients. Ten patients (22%) had a positive IAT for GAS. They were statistically significantly more likely to be male (9/10 [90%] vs 13/29 [45%], p = .024). Several different emm types caused the iGAS infections. CONCLUSIONS: GAS was frequently observed in throat swabs of patients with iGAS infection. This may suggest that hematogenous seeding from the nasopharynx is a possible portal of entry.

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Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.

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INTRODUCTION AND OBJECTIVES: The aim of this study was to determine the prevalence of colorectal disease in Enterococcus faecalis infective endocarditis (EFIE) patients. METHODS: An observational, retrospective, multicenter study was performed at 4 referral centers. From the moment that a colonoscopy was systematically performed in EFIE in each participating hospital until October 2018, we included all consecutive episodes of definite EFIE in adult patients. The outcome was an endoscopic finding of colorectal disease potentially causing bacteremia. RESULTS: A total of 103 patients with EFIE were included; 83 (81%) were male, the median age was 76 [interquartile range 67-82] years, and the median age-adjusted Charlson comorbidity index was 5 [interquartile range 4-7]. The presumed sources of infection were unknown in 63 (61%), urinary in 20 (19%), gastrointestinal in 13 (13%), catheter-related bacteremia in 5 (5%), and others in 2 (2%). Seventy-eight patients (76%) underwent a colonoscopy, and 47 (60%) had endoscopic findings indicating a potential source of bacteremia. Thirty-nine patients (83%) had a colorectal neoplastic disease, and 8 (17%) a nonneoplastic disease. Of the 45 with an unknown portal of entry who underwent a colonoscopy, gastrointestinal origin was identified in 64%. In the subgroup of 25 patients with a known source of infection and a colonoscopy, excluding those with previously diagnosed colorectal disease, 44% had colorectal disease. CONCLUSIONS: Performing a colonoscopy in all EFIE patients, irrespective of the presumed source of infection, could be helpful to diagnose colorectal disease in these patients and to avoid a new bacteremia episode (and eventually infective endocarditis) by the same or a different microorganism.

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OBJECTIVES: To develop pediatric direct admission guidelines and prioritize outcomes to evaluate the safety and effectiveness of hospital admission processes. STUDY DESIGN: We conducted deliberative discussions at 1 children's hospital and 2 community hospitals, engaging parents of hospitalized children and inpatient, outpatient, and emergency department physicians and nurses to identify shared and dissenting perspectives regarding direct admission processes and outcomes. Discussions were audio-recorded, professionally transcribed, and analyzed using a general inductive approach. We then convened a national panel to prioritize guideline components and outcome measures using a RAND/UCLA Modified Delphi approach. RESULTS: Forty-eight stakeholders participated in 6 deliberative discussions. Emergent themes related to effective multistakeholder communication, resources needed for high quality direct admissions, written direct admission guidelines, including criteria to identify children appropriate for and inappropriate for direct admission, and families' needs. Building on these themes, Delphi panelists endorsed 71 guideline components as both appropriate and necessary at children's hospitals and community hospitals and 13 outcomes to evaluate hospital admission systems. Guideline components include (1) pre-admission communication, (2) written guidelines, (3) hospital resources to optimize direct admission processes, (4) special considerations for pediatric populations that may be at particular risk of nosocomial infection and/or stress in emergency departments, (5) communication with families referred for direct admission, and (6) quality reviews to evaluate admission systems. CONCLUSIONS: These direct admission guidelines can be adapted by hospitals and health systems to inform hospital admission policies and protocols. Multistakeholder engagement in evaluation of hospital admission processes may improve transitions of care and health system integration.

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BACKGROUND: Elizabethkingia miricola is a rare Gram-negative bacterium found in water and clinical specimens. Typical culturing methods often misidentify Elizabethkingia spp. as Flavobacterium or Chryseobacterium. Although diagnosis is based on culturing samples taken from sterile sites, such as blood, a proper identification of this bacterium requires an expertise that goes beyond the capabilities of a typical clinical laboratory. CASE PRESENTATION: A 35-year-old woman diagnosed with common variable immunodeficiency was admitted to our center. Previous treatment with antibiotics (amoxicillin plus clavulanate, first and third generation of cephalosporins, macrolides) and systemic corticosteroids (up to 120 mg/day of prednisolone) failed to arrest the spread of inflammation. Gingival recession was observed in her oral cavity, resulting in an apparent lengthening of her teeth. In addition to typical commensal bacteria, including streptococci and neisseriae, strains of Rothia mucilaginosa and Elizabethkingia miricola were identified upon a detailed microbiological examination using a MALDI-TOF MS Biotyper system. The presence of the latter strain correlated with severe periodontitis, lack of IgA in her saliva and serum, a very low IgG concentration (< 50 mg/dl), IgM-paraproteinemia, decreases in C3a and C5a and microvascular abnormality. High-dose immunoglobulin (to maintain IgG > 500 mg/dl) and targeted levofloxacin treatment resulted in immune system reconstitution, oral healing, and eradication of the Elizabethkingia infection. CONCLUSIONS: E. miricola rarely causes disease in healthy individuals. However, the overgrowth of commensal bacteria, lack of IgG/IgA, microvasculopathy and complement cascade activation in patients with humoral immunodeficiency may facilitate Elizabethkingia invasion. Overuse of antibiotics, particularly beta-lactams, may cause mucosal colonization by E. miricola, followed by its multiplication combined with periodontitis that prompts bacterial translocation. MALDI-TOF Biotyper analysis may become a method of choice for identification of Elizabethkingia infections.

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The piriformis fossa is the ideal portal of entry for antegrade interlocking nailing. Localizing this portal can be difficult and its eccentricity leads to complications. This prospective comparative study was designed to compare an innovative way to obtain the ideal portal from inside the medullary canal in cases of plate failure and compare it to the classic antegrade portal. It included 41 cases (19 antegrade and 22 retrograde). The retrograde portal was significantly better in terms of entry time, radiation time, blood-loss, and wound length. The proper portal was rapidly and easily achieved in all retrograde cases without complications; while four in antegrade cases had complications. Minimum follow-up was 2 years. Level of evidence III.

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Bacteraemia caused by Escherichia coli are particularly frequent and severe, contrasting with the commensal character of the strains found in the digestive tract. A better understanding of the relationships between strains of both origins is needed to unravel the pathogenesis of this disease. Two hundred and forty-three commensal strains were compared to 243 bacteraemic strains isolated from adult hosts matched in terms of gender and age, and from similar location and epoch. Phylogenetic grouping, O-type determination, virulence factor content and antibiotic resistance were compared. Compared to commensal strains, the bacteraemic strains were characterized by a higher proportion of B2, C and D phylogroups, and a lower proportion of A, E and F phylogroups. They also had a lower proportion of the B2 subgroup IV (STc141), a higher proportion of virulence factors, and a higher frequency of antibiotic resistance. These differences were more marked for the bacteraemic strains of urinary tract origin with the presence of specific clones, whereas the bacteraemic strains of digestive origin remained non-significantly different from the commensal strains, except for their antibiotic resistance. Thus, two levels of specialization from commensal strains were demonstrated in the bacteraemic strains: resistance to antibiotics in all cases, and virulence for those of urinary tract origin.

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In this study, we assessed pirAB toxin transcription in Photorhabdus luminescens laumondii (strain TT01) (Enterobacteriaceae) by comparing mRNA abundance under in vivo and in vitro conditions. In vivo assays considered both natural and forced infections with two lepidopteran hosts: Galleria mellonella and Manduca sexta. Three portals of entry were utilized for the forced infection assays: (a) integument; (b) the digestive route (via mouth and anus); and (c) the tracheal route (via spiracles). We also assessed plu4093-2 transcription during the course of a natural infection; this is when the bacteria are delivered by Heterorhabditis bacteriophora nematodes. Transcript abundance in G. mellonella was higher than in M. sexta at two of the observed time points: 15 and 18 h. Expression of pirAB plu4093-2 reached above endogenous control levels at 22 h in G. mellonella but not in M. sexta. Overall, pirAB plu4093-2 transcripts were not as highly expressed in M. sexta as in G. mellonella, from 15 to 22 h. This is the first study to directly compare pirAB plu4093-2 toxin transcript production considering different portals of entry.

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BACKGROUND: The purpose of this study was to define the relationship between the humeral neck-shaft angle (NSA) and variations in the ideal entry portal aligned with the long axis of the intramedullary canal of the proximal humerus. METHODS: Three-dimensional images of 36 cadaveric humeri with various NSAs were reconstructed by a computerized surgical simulation program. The anteroposterior, mediolateral, and linear distances between a line from the center of the proximal medullary canal to the bicipital groove were measured. Differences among humeri with various NSAs were analyzed. RESULTS: The intramedullary axis line was located a mean of 9 ± 2 mm posteriorly and 11 ± 3 mm medially from the bicipital groove. The axis line was 9 ± 2 mm posterior and 11 ± 2 mm medial with a standard NSA. The axis line in humeri with a varus NSA was 8 ± 2 mm posteriorly and 9 ± 2 mm medially, whereas the axis line was 10 ± 3 mm posteriorly and 14 ± 3 mm medially with a valgus NSA. The differences in the mediolateral distances between the groups were significant (P < .00009). CONCLUSION: Care should be taken in choosing the entry portal position in humeri with various NSAs as the entry portal position differs according to the NSA. It is recommended that the location of the entry portal be moved toward the center of the humeral head to align with the centerline of the intramedullary canal in humeri with a valgus NSA in particular.

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With increasing reports of Salmonella infection, we are forced to question whether the fecal-oral route is the major route of infection and consider the possibility that airborne Salmonella infections might have a major unappreciated role. Today's large-scale poultry production, with densely stocked and enclosed production buildings, is often accompanied by very high concentrations of airborne microorganisms. Considering that the upper and lower respiratory lymphoid tissue requires up to 6 weeks to be fully developed, these immune structures seem to have a very minor role in preventing pathogen infection. In addition, the avian respiratory system in commercial poultry has anatomic and physiologic properties that present no challenge to the highly adapted Salmonella. The present review evaluates the hypothesis that transmission by the fecal-respiratory route may theoretically be a viable portal of entry for Salmonella in poultry. First, we update the current knowledge on generation of Salmonella bioaerosols, and the transport and fate of Salmonella at various stages of commercial poultry production. Further, emphasis is placed on survivability of Salmonella in these bioaerosols, as a means to assess the transport and subsequent risk of exposure and infection of poultry. Additionally, the main anatomic structures, physiologic functions, and immunologic defense in the avian respiratory system are discussed to understand the potential entry points inherent in each component that could potentially lead to infection and subsequent systemic infection of poultry by Salmonella. In this context, we also evaluate the role of the mucosal immune system as essentially one large interconnected network that shares information distally, since understanding of this sort of communication between mucosal sites is fundamental to establish the next phase of disease characterization, and perhaps immunization and vaccine development. Further characterization of the respiratory tract with regard to transmission of Salmonella under field conditions may be of critical importance in developing interventional strategies to reduce transmission of this important zoonotic pathogen in poultry.

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Outbreaks of an unidentified ciliate have occurred on several occasions in blue crabs from Chesapeake Bay held during winter months in flow-through systems. The parasite was initially thought to be Mesanophrys chesapeakensis, but molecular analysis identified it as Orchitophyra stellarum, a facultative parasite of sea stars (Asteroidea). We investigated the host-parasite association of O. stellarum in the blue crab host. Crabs were inoculated with the ciliate, or they were held in bath exposures after experimentally induced autotomy of limbs in order to determine potential mechanisms for infection. Crabs inoculated with the ciliate, or exposed to it after experimental autotomy, rapidly developed fatal infections. Crabs that were not experimentally injured, but were exposed to the ciliate, rarely developed infections; thus, indicating that the parasite requires a wound or break in the cuticle as a portal of entry. For comparative purposes, fiddler crabs, Uca minax, were inoculated with the ciliate in a dose-titration experiment. Low doses of the ciliate (10 per crab) were sometimes able to establish infections, but high intensity infections developed quickly at doses over 500 ciliates per crab. Chemotaxis studies were initiated to determine if the ciliate preferentially selected blue crab serum (BCS) over other nutrient sources. Cultures grown on medium with BCS or fetal bovine serum showed some conditioning in their selection for different media, but the outcome in choice experiments indicated that the ciliate was attracted to BCS and not seawater. Our findings indicate that O. stellarum is a facultative parasite of blue crabs. It can cause infections in exposed crabs at 10-15°C, but it requires a portal of entry for successful host invasion, and it may find injured hosts using chemotaxis.

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Invasive fusariosis (IF) is an infection with Fusarium spp. fungi that primarily affects patients with hematologic malignancies and hematopoietic cell transplant recipients. A cutaneous portal of entry is occasionally reported. We reviewed all cases of IF in Brazil during 2000-2010, divided into 2 periods: 2000-2005 (period 1) and 2006-2010 (period 2). We calculated incidence rates of IF and of superficial infections with Fusarium spp. fungi identified in patients at a dermatology outpatient unit. IF incidence for periods 1 and 2 was 0.86 cases versus 10.23 cases per 1,000 admissions (p<0.001), respectively; superficial fusarial infection incidence was 7.23 versus 16.26 positive cultures per 1,000 superficial cultures (p<0.001), respectively. Of 21 cases of IF, 14 showed a primary cutaneous portal of entry. Further studies are needed to identify reservoirs of these fungi in the community and to implement preventive measures for patients at risk.

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The portal of entry of Escherichia coli bacteremia, a frequent and severe disease, is most commonly the urinary tract followed by the digestive tract. Recent reports have evidenced the presence of several distinct E. coli clones within a single patient suffering of extra-intestinal infection. To explore the relationships between the blood and portal of entry strains, we thoroughly studied 98 bacteremic patients from the French prospective COLIBAFI cohort. In these patients, we compared genotypically and phenotypically E. coli strains isolated from the blood and the suspected portal of entry [non-urinary pus (n=52) and urine (n=52)]. We found genetically distinct strains exhibiting distinct antibiotypes in the blood and pus samples (8 patients; 15%) and the blood and urine samples (2 patients; 3.8%) (p=0.09). These data highlight the complexity of pathophysiology of E. coli bacteremia and should be taken into consideration when strain antibiotic susceptibility is tested, especially in bacteremia of pus origin.

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