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Sepsis has been around since the dawn of time, having been described for more than 2000 years, although clinical definitions are recent. The consensus sepsis definitions have permitted worldwide epidemiological studies of sepsis to be conducted. We now recognize the common nature of sepsis and the consistency of its disease - particularly severe sepsis and septic shock. The incidence of sepsis, severe sepsis and septic shock continues to increase, and although Gram-positive bacterial pathogens remain the most common cause of sepsis, fungal organisms are increasing rapidly. We have made progress over the past half-century in identifying and treating patients with sepsis, and decreasing fatality rates reflect this progress. However, owing to the increasing incidence of sepsis, the number of people who die each year continues to increase. The mortality with sepsis, particularly related to treating organ dysfunction, remains a priority to clinicians worldwide and is deserving of greater public health attention.

Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers. To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing. Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover. Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture. Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.

Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (<33 weeks) very low-birth-weight infants. Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks' completed gestation did not reduce the association of the nSOFA score with infection-related mortality. The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.

•The clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear.•EBV DNA in CSF is occasionally found in the immunocompetent population.•EBV was frequently found together with other microbes in CSF and associated with encephalitis and poor prognosis. Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.

Toll-like receptors (TLRs) on keratinocytes are important cell surface receptors involved in the innate and acquired immune response to invading microorganisms. In acne vulgaris, TLR2 activation by Propionibacterium acnes (P. acnes) may induce skin inflammation via induction of various proinflammatory molecules that stimulate the invasion of inflammatory cells. Although corticosteroids themselves exert immunosuppressive or anti-inflammatory effects, it is well known clinically that systemic or topical glucocorticoid treatment provokes an acneiform reaction. Nevertheless, the effect of steroids on TLR2 expression in human keratinocytes remains unknown. Here, we found that the addition of glucocorticoids, such as dexamethasone and cortisol, to cultured human keratinocytes increased their TLR2 gene expression. Moreover, these glucocorticoids markedly enhanced TLR2 gene expression, which was further stimulated by P. acnes, tumor necrosis factor-α, and IL-1α. Gene expression of mitogen-activated protein kinase (MAPK) phosphatase-1 was also increased by the addition of dexamethasone. By using several inhibitors and activators, we found that TLR2 gene induction by glucocorticoids was mediated by the suppression of p38 MAPK activity following induction of MAPK phosphatase-1. These findings strongly suggest that steroid-induced TLR2 together with P. acnes existing as normal resident flora plays an important role in the exacerbation of acne vulgaris as well as in possible induction of corticosteroid-induced acne or in that of rosacea-like dermatitis.

To investigate the rate of recovery from septic shock in patients with suspected left ventricular (LV) preload deficiency and LV systolic dysfunction. A monitoring period was defined by the need for inotropic/vasopressor support, and LV function was assessed daily during this period by bedside two-dimensional echocardiography (2D-ECHO). University hospital ICU. During a 5-year period, 90 patients with an episode of septic shock (60% with gram-positive bacteria as the causative agent) were consecutively enrolled in the study (mean age, 55 +/- 18 years). Standard volume resuscitation combined with inotropic/vasopressor support was used to maintain systolic arterial pressure > 90 mm Hg. All patients received mechanical ventilation because of associated respiratory failure. The average duration of hemodynamic support was 4.4 +/- 1.6 days. Thirty-four patients were weaned from hemodynamic support during the monitoring period and ultimately recovered (group I). Twenty-eight patients died from refractory circulatory failure during the monitoring period, and 28 died later from ARDS or multiple organ dysfunction syndrome, leading to a 62% overall mortality rate (group II). Daily bedside LV volumes and ejection fraction (LVEF) were recorded using 2D-ECHO. Data obtained at the start (day 1 and day 2) and end of the monitoring period (day n) were compared. LV end-diastolic volume was within the normal range of our laboratory values in all patients, but was initially smaller in group II than in group I, and remained so despite fluid loading. LVEF was significantly depressed in all patients, resulting in severe reduction in LV stroke volume (LVSV), which was initially more marked in group I. In group I patients, LVEF significantly improved during the monitoring period, resulting in an increase in LVSV. 2D-ECHO changes during hemodynamic support in 90 septic patients confirmed defective LV preload with a propensity to worsen despite fluid loading in nonsurvivors (62% in the present study). Our results are also in agreement with previous studies reporting depressed LV systolic function at the initial phase of septic shock. Since LV dysfunction was more marked in patients who recovered, we suggest that the exact significance of this finding should be reevaluated.

The clinical significance of intrinsically vancomycin-resistant enterococci is not yet fully established, as these organisms are infrequently recovered from clinical specimens. We report our experience with 20 cases of Enterococcus gallinarum and Enterococcus casseliflavus/flavescens bacteremia in humans from 1992 through 1998. Sixteen cases of bacteremia were caused by E. gallinarum. Underlying conditions were present in 19 (95%) of the patients and included malignancy, receipt of transplant, and Caroli's disease. Polymicrobial bacteremia was present in 9 patients (45%). E. gallinarum and E. casseliflavus/flavescens, although they are infrequently isolated from clinical specimens, may cause serious invasive infections.

Enterococcal prosthetic valve infective endocarditis (PVE) is an incompletely understood disease. In the present study, patients with enterococcal PVE were compared to patients with enterococcal native valve endocarditis (NVE) and other types of PVE to determine differences in basic clinical characteristics and outcomes using a large multicenter, international database of patients with definite endocarditis. Forty-five of 159 (29%) cases of definite enterococcal endocarditis were PVE. Patients with enterococcal PVE were demographically similar to patients with enterococcal NVE but had more intracardiac abscesses (20% vs. 6%; p=0.009), fewer valve vegetations (51% vs. 79%; p<0.001), and fewer cases of new valvular regurgitation (12% vs. 45%; p=0.01). Patients with either enterococcal PVE or NVE were elderly (median age, 73 vs. 69; p=0.06). Rates of in-hospital mortality, surgical intervention, heart failure, peripheral embolization, and stroke were similar in both groups. Patients with enterococcal PVE were also demographically similar to patients with other types of PVE, but mortality may be lower (14% vs. 26%; p=0.08). Notably, 93% of patients with enterococcal PVE came from European centers, as compared with only 79% of patients with enterococcal NVE (p=0.03). Thus, patients with enterococcal PVE have higher rates of myocardial abscess formation and lower rates of new regurgitation compared to patients with enterococcal NVE, but there are no differences between the groups with regard to surgical or mortality rates. In contrast, though patients with enterococcal PVE and patients with other types of PVE share similar characteristics, mortality is higher in the latter group. Importantly, the prevalence of enterococcal PVE was higher in the European centers in this study.

gls24 was previously identified as a general stress protein of Enterococcus faecalis. In the present study, we found that a gls24 disruption mutant (TX10100) of E. faecalis strain OG1RF showed a considerably increased 50% lethal dose in a mouse peritonitis model, and, at high inocula, TX10100 was either not lethal or was much less so than wild-type OG1RF (P < .001). TX10100 was also more sensitive to bile salts (mean±SD survival rate relative to wild-type OG1RF, 9.7%±2.0%) at late stationary phase, as previously found by Giard et al. with another strain. Inactivation of glsB, downstream of and cotranscribed with gls24, had no effect on E. faecalis virulence but resulted in reduced bile-salts resistance (to a mean±SD survival rate of 28.0%±5.1%) relative to wild-type OG1RF. Results of complementation of TX10100 with different combinations of gls24-glsB and 2 promoters—a remote promoter (P1) and an adjacent promoter (P2)—suggested that both genes and both promoters, especially P1, are important for bile-salts resistance. Anti-gls24 immune rabbit serum, which showed some Gls24 on the cell surface, protected mice against a lethal challenge of OG1RF in the peritonitis model (e.g., survival of 12/18 mice vs. 1/18 mice with preimmune rabbit serum; P = .008). In conclusion, the E. faecalis gls24 gene is important for virulence as well as stress response, and Anti-gls24 immune rabbit serum shows protection against E. faecalis infection in a mouse peritonitis model.