SUMMARY Sepsis is a life-threatening inflammatory syndrome accompanying a bloodstream infection. Frequently secondary to pathogenic bacterial infections, sepsis remains difficult to treat as a singular disease mechanism. We compared the pathogenesis of murine sepsis experimentally elicited by five bacterial pathogens and report similarities among host responses to Gram-negative Salmonella and E. coli. We observed that a host protective mechanism involving de-toxification of lipopolysaccharide by circulating alkaline phosphatase (AP) isozymes was incapacitated during sepsis caused by Salmonella or E. coli through activation of host Toll-like receptor 4, which triggered Neu1 and Neu3 neuraminidase induction. Elevated neuraminidase activity accelerated the molecular aging and clearance of AP isozymes, thereby intensifying disease. Mice deficient in the sialyltransferase ST3Gal6 displayed increased disease severity, while deficiency of the endocytic lectin hepatic Ashwell-Morell receptor was protective. AP augmentation or neuraminidase inhibition diminished inflammation and promoted host survival. This study illuminates distinct routes of sepsis pathogenesis, which may inform therapeutic development.

No abstract

Background The opioid epidemic is a rapidly growing public health concern in the USA, as the number of overdose deaths continues to increase each year. One strategy for combating the rising number of overdoses is through opioid overdose prevention programs (OOPPs). Objective To evaluate the effectiveness of an innovative OOPP, with changes in knowledge and attitudes serving as the primary outcome measures. Methods The OOPP was developed by a group of medical students under guidance from faculty advisors. Training sessions focused on understanding stigmatizing factors of opioid use disorder (OUD), as well as protocols for opioid overdose reversal through naloxone administration. Pre- and post-surveys were partially adapted from the opioid overdose attitudes and knowledge scales and administered to all participants. Paired t-tests were conducted to assess differences between pre- and post-surveys. Results A total of 440 individuals participated in the training; 381 completed all or the majority of the survey. Participants came from a diverse set of backgrounds, ages, and experiences. All three knowledge questions showed significant improvements. For attitude questions, significant improvements were found in all three questions evaluating confidence, two of three questions assessing attitudes towards overdose reversal, and four of five questions evaluating stigma and attitudes towards individuals with OUD. Conclusions Our innovative OOPP was effective not only in increasing knowledge but also in improving attitudes towards overdose reversal and reducing stigma towards individuals with OUD. Given the strong improvements in attitudes towards those with OUD, efforts should be made to incorporate the unique focus on biopsychosocial and sociohistorical components into future OOPPs.

Background The opioid epidemic is a progressively worsening public health crisis that continues to impact healthcare system strategies such as overdose reversal and destigmatization. Even among healthcare professionals, there remains a lack of confidence in naloxone administration and a prevalence of stigma. While training can play a major impact in reducing these shortcomings, the long-term effectiveness has yet to be characterized in training healthcare professionals. This study examined the long-term retention of opioid overdose awareness and reversal training (OOART) by evaluating performance at two-time intervals, immediately post-training and at a 3-month follow-up. Methods Voluntary training was offered to first-year (M1) medical students at the Drexel University College of Medicine in 2021. At this training, 118 students completed training, 95 completed the post-training survey, and 42 completed the 3-month follow-up. Results Opioid reversal knowledge questions assessed significantly increased scores post-training and at the 3-month follow-up. In three of the attitude questions, scores were improved at both follow-up timepoints. In addition, three attitude questions indicating a participant’s confidence to respond to an opioid overdose situation increased directly after the training, but regressed at the 3-month follow-up. The remaining questions did not show any statistical difference across the survey intervals. Conclusions This study establishes that while OOART provides participants with the knowledge of how to respond to an opioid overdose, the retention of this knowledge at a 3-month interval is reduced. The results were mixed for longitudinal assessment of participant’s attitudes toward people with opioid use disorder. Some positive increases in attitudes were retained at the 3-month interval, while others trended back toward pre-training levels. These results support the effectiveness of the training but also provide evidence that OOART must be reinforced often.

Lyme disease (LD) infection is caused by Borrelia burgdorferi sensu lato (Bb). Due to the limited presence of this pathogen in the bloodstream in humans, diagnosis of LD relies on seroconversion. Immunoglobulins produced in response to infection are differentially glycosylated to promote or inhibit downstream inflammatory responses by the immune system. Immunoglobulin G (IgG) N-glycan responses to LD have not been characterized. In this study, we analyzed IgG N-glycans from cohorts of healthy controls, acute LD patient serum, and serum collected after acute LD patients completed a 2- to 3-week course of antibiotics and convalesced for 70-90 days. Results indicate that during the acute phase of Bb infection, IgG shifts its glycosylation profile to include structures that are not associated with the classic proinflammatory IgG N-glycan signature. This unexpected result is in direct contrast to what is reported for other inflammatory diseases. Furthermore, IgG N-glycans detected during acute LD infection discriminated between control, acute, and treated cohorts with a sensitivity of 75-100% and specificity of 94.7-100%.

The acceleration of climate change has been associated with an alarming increase in the prevalence and geographic range of tick-borne diseases (TBD), many of which have severe and long-lasting effects—particularly when treatment is delayed principally due to inadequate diagnostics and lack of physician suspicion. Moreover, there is a paucity of treatment options for many TBDs that are complicated by diagnostic limitations for correctly identifying the offending pathogens. This review will focus on the biology, disease pathology, and detection methodologies used for the Borreliaceae family which includes the Lyme disease agent Borreliella burgdorferi. Previous work revealed that Borreliaceae genomes differ from most bacteria in that they are composed of large numbers of replicons, both linear and circular, with the main chromosome being the linear with telomeric-like termini. While these findings are novel, additional gene-specific analyses of each class of these multiple replicons are needed to better understand their respective roles in metabolism and pathogenesis of these enigmatic spirochetes. Historically, such studies were challenging due to a dearth of both analytic tools and a sufficient number of high-fidelity genomes among the various taxa within this family as a whole to provide for discriminative and functional genomic studies. Recent advances in long-read whole-genome sequencing, comparative genomics, and machine-learning have provided the tools to better understand the fundamental biology and phylogeny of these genomically-complex pathogens while also providing the data for the development of improved diagnostics and therapeutics.

Glycosidases are hydrolytic enzymes studied principally in the context of intracellular catabolism within the lysosome. Therefore, glycosidase activities are classically measured in experimentally acidified assay conditions reflecting their low pH optima. However, glycosidases are also present the bloodstream where they may retain sufficient activity to participate in functions including the regulation of glycoprotein half-lives, proteostasis, and disease pathogenesis. We have herein established at physiological pH 7.4 in blood plasma and sera the normal ranges of four major glycosidase activities essential for blood glycoprotein remodeling in healthy mice and humans. These activities included β-galactosidase, β-N-acetylglucosaminidase, α-mannosidase, and α-fucosidase. We have identified their origins to include the mammalian genes Glb1, HexB, Man2a1, and FucA1. In experimental sepsis, excursions of glycosidase activities occurred with differences in host responses to discrete bacterial pathogens. Among similar excursions in human sepsis, the elevation of β-galactosidase activity was a prognostic indicator of increased likelihood of patient death.

IgG N-glycans are an emerging source of disease-specific biomarkers. Over the last decade, the continued development of glycomic databases and the evolution of glyco-analytic methods have resulted in increased throughput, resolution, and sensitivity. IgG N-glycans promote adaptive immune responses through antibody-dependent cellular cytotoxicity (ADCC) and complement activation to combat infection or cancer and promote autoimmunity. In addition to the functional assays, researchers are examining the ability of protein-specific glycosylation to serve as biomarkers of disease. This literature review demonstrates that IgG N-glycans can discriminate between healthy controls, autoimmune disease, infectious disease, and cancer with high sensitivity. The literature also indicates that the IgG glycosylation patterns vary across disease state, thereby supporting their role as specific biomarkers. In addition, IgG N-glycans can be collected longitudinally from patients to track treatment responses or predict disease reoccurrence. This review focuses on IgG N-glycan profiles applied as diagnostics, cohort discriminators, and prognostics. Recent successes, remaining challenges, and upcoming approaches are critically discussed.