Perspective: Limiting Antimicrobial Resistance with Artificial Intelligence/Machine Learning.

The author traces his experience with the application of computers in clinical microbiology over the past 60 years, specifically in directing clinicians to treat bacterial infections diagnosed by the laboratory and the antibacterial agent(s) that could be used to treat those infections. Appropriate use of antibiotics will result in reduced antimicrobial resistance, which is increasing worldwide. An early form of AI, Mycin (1976), a system based on rules provided by experts designed to propose antibiotic regimens for central nervous system infections, was never applied due to the limitations in the number of rules that could be incorporated into the clinical workflow. Machine learning (ML) was developed to overcome the limitations of expert systems. Several variables that influence the outcome bacteria/drug interaction, such as the source of the infection, absence of antimicrobial resistance markers, patients' health profile, and the historical susceptibility within the hospital and the local area are incorporated in the proposed comprehensive AI/ML program. The role of AI in the discovery of new antimicrobial agents is also addressed.

Interplay of Anti-Viral Vaccines with Biologic Agents and Immunomodulators in Individuals with Autoimmune and Autoinflammatory Diseases.

Vaccines are an essential part of a preventative healthcare strategy. However, response to vaccines may be less predictable in immunocompromised people. While outcomes for individuals with autoimmune and autoinflammatory diseases have dramatically improved with treatment using immunomodulating and biologic agents, infections have caused significant morbidity in these people today often more than due to their underlying diseases. Immune-based biologic therapies contribute to these infectious complications. This review addresses anti-viral vaccines, their effectiveness and safety in patients treated with approved biologic agents and immune targeted therapy with a focus on vaccines against influenza, human papillomavirus, hepatitis B virus and varicella zoster virus. Preliminary information regarding SARS-CoV-2 anti-viral vaccines is addressed. Additionally, we present recommendations regarding the safe use of vaccines in immunocompromised individuals with the goal to enhance awareness of the safety and efficacy of these anti-viral vaccines in these high-risk populations.

The Impact of the Microbiome on Immunosenescence.

Human microbiome investigations now provide evidence that changes in the microbiome over time and their interaction with the immune, endocrine, and nervous systems are associated with a wide array of disorders. Human immunological studies typically absent a microbiome consideration in their investigations. An area of recent exploration is the role of the microbiome as a critical partner in the development and function of the human immune system in aging. It is well known that immunologic maturation is influenced by a lifetime of interactions of the host with its companion microbiome. It is generally not well recognized that intestinal microbes play an essential role in the development and expansion of gut mucosal and systemic immune function. Gut microbial communities of elderly people have different composition and behavior compared to healthy younger adults. Comorbidities associated with microbial pathogens and an aberrant immune system tend to increase with aging. This review underscores the impact of the human-microbiome interface on the development and function of the immune system and on immunosenescence. These changes have important implications regarding health and health system utilization in the elderly population.

Immunomodulatory interplay of the microbiome and therapy of rheumatic diseases.

Modulation of the immune system by microbes, especially from the gastrointestinal tract, is increasingly considered a key factor in the onset, course and outcome of rheumatic diseases. The interplay of the microbiome, along with genetic predisposition and environmental exposure, is thought to be an important trigger for rheumatic diseases. Improved identification of the relationship of disease-specific genetic alterations and rheumatic diseases has potential diagnostic and therapeutic applications. Treatment of rheumatic disorders is influenced by microbial actions but this interplay can be challenging due to variable and unpredictable responses to therapies. Expanded knowledge of the microbiome now allows clinicians to more precisely select ideal medication regimens and to predict response to and toxicity from drugs. Rheumatic diseases and associated therapies were among the earliest microbiome interactions investigated, yet it is notable that current research is focused on clinical and immunological associations but, in comparison, a limited number of studies regarding the microbiome's impact on treatment for rheumatic diseases have been published. In the coming years, further knowledge of immunomodulating interactions between the microbiome and the immune system will aid our understanding of autoimmunity and will be increasingly important in selection of therapeutic agents for patients with autoimmune and rheumatic diseases. In this review, recent literature regarding the bidirectional immunomodulatory effects of the microbiome with rheumatic diseases and current understanding and gaps regarding the drug-microbiome interface in the management of these disorders is presented.

Immunotherapeutic Approaches for the Control and Eradication of HIV.

Since the onset of the AIDS epidemic over 35 years ago, attempts at immunologic manipulation to develop preventative and therapeutic approaches to HIV infection have been the subject of intense focus by the scientific community. New tactics such as latency reveal agents and immune interventions with engineered and directed monoclonal antibodies, as well as vaccines for prevention and treatment are among the strategies addressed in this review.

The interference of monoclonal antibodies with laboratory diagnosis: clinical and diagnostic implications.

Diagnostic test interference is due to the presence of material that falsely changes an analytic test result. The development of monoclonal antibodies is discussed with focus on their extensive use as both therapeutic and diagnostic agents. In this review the interference of monoclonal antibodies with laboratory test methods and the potential impact on clinical care is addressed. Recognition of the types of interference, endogenous and exogenous, and the varied mechanisms by which monoclonal antibodies may cause interference are discussed in this report. Review of the literature identifies cases which exemplify the issues facing laboratorians and clinicians and describe the impact on patients. Approaches to reducing and eliminating sources of interference are also addressed. Education of ordering clinicians concerning the possibility of interference in at-risk patients is key in limiting the impact on care. Laboratorians and medical practitioners should be cognizant of the risk of interference to avoid incorrect management of patients.

Matrix metalloproteases in bronchoalveolar lavage fluid of patients with type III Pseudomonas aeruginosa pneumonia.

OBJECTIVES: In patients with ventilator-associated pneumonia (VAP), Pseudomonas aeruginosa type III (TTSS) secreting isolates have been linked to poor clinical outcomes. Differential expression of matrix metalloproteinases (MMPs) induced by type III effector proteins may herald an irreversible lung injury. METHODS: Serial bronchoalveolar lavage fluids collected from 41 patients with P. aeruginosa at onset of VAP, day 4, and day 8 after antibiotic therapy were assayed for MMP-8, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and alpha-2 macroglobulin levels. RESULTS: At the onset of VAP, isolates secreting ExoU had the highest MMP-9 levels. The response to antimicrobial therapy showed a differential drop in MMPs with significant decrease in MMP-8 and MMP-9 levels on days 4 and 8 in patients with TTSS(-) compared to TTSS(+) phenotype. The ratio of MMP-9/TIMP-1 was significantly associated with alpha-2 macroglobulin at end of therapy (r=0.4, p=0.02). Patients who survived had a lower MMP-9/TIMP-1 ratio than those who died (p=0.003). CONCLUSIONS: VAP linked to P. aeruginosa Type III phenotype portrays a divergent antibiotic treatment response in regards to the concentrations of metalloproteinases in the alveolar space. The imbalance between MMP-9 and TIMP-1 may determine the intensity of alveolocapillary damage and ultimate outcome of P. aeruginosa VAP.

Preclinical and clinical performance of the Efoora test, a rapid test for detection of human immunodeficiency virus-specific antibodies.

Barriers to effective diagnostic testing for human immunodeficiency virus type 1 (HIV-1) infection can be reduced with simple, reliable, and rapid detection methods. Our objective was to determine the accuracy, sensitivity, and specificity of a new rapid, lateral-flow immunochromatographic HIV-1 antibody detection device. Preclinical studies were performed using seroconversion, cross-reaction, and interference panels, archived clinical specimens, and fresh whole blood. In a multicenter, prospective clinical trial, a four-sample matrix of capillary (fingerstick) whole-blood specimens and venous whole blood, plasma, and serum was tested for HIV-1 antibodies with the Efoora HIV rapid test (Efoora Inc., Buffalo Grove, IL) and compared with an enzyme immunoassay (EIA) (Abbott Laboratories) licensed by the Food and Drug Administration. Western blot and nucleic acid test supplemental assays were employed to adjudicate discordant samples. Preclinical testing of seroconversion panels showed that antibodies were often detected earlier by the rapid test than by a reference EIA. No significant interference or cross-reactions were observed. Testing of 4,984 archived specimens yielded a sensitivity of 99.2% and a specificity of 99.7%. A prospective multicenter clinical study with 2,954 adult volunteers demonstrated sensitivity and specificity for the Efoora HIV rapid test of 99.8% (95% confidence interval [CI], 99.3 and 99.98%) and 99.0% (95% CI, 98.5 and 99.4%), respectively. Reactive rapid HIV-1 antibody detection was confirmed in 99.6% of those with a known HIV infection (n = 939), 5.2% of those in the high-risk group (n = 1,003), and 0.1% of those in the low-risk group (n = 1,012). For 21 (0.71%) patients, there was discordance between the results of the rapid test and the confirmatory EIA/Western blot tests. We conclude that the Efoora HIV rapid test is a simple, rapid assay for detection of HIV-1 antibodies, with high sensitivity and specificity compared to a standardized HIV-1 EIA.

Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea.

STUDY OBJECTIVES: It has been suggested that obstructive sleep apnea (OSA)-induced hypoxic stress might contribute to cardiovascular disorders by promoting expression of soluble adhesion molecules. The reported increase of circulating adhesion molecules in patients with OSA remains controversial because confounders such as cardiovascular risk factors and left ventricular function have not been adequately controlled for. We hypothesized that soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, L-selectin, and E-selectin levels are correlated with OSA independent of coexisting coronary artery disease (CAD). SETTINGS: University-affiliated teaching hospitals. DESIGN AND PARTICIPANTS: A prospective study of 61 consecutive subjects with angiographically proven CAD deemed to have stable angina. INTERVENTIONS: Fifteen patients (mean +/- SD) 61.2 +/- 1.9 years old with moderate-to-severe OSA (apnea-hypopnea index [AHI] > or = 20/h) were matched to a control group (AHI < or = 5/h) for age, gender, body mass index, and severity of CAD. Venous blood samples were collected the morning of the sleep study and assayed for human ICAM-1, VCAM-1, L-selectin, and E-selectin with commercially available enzyme-linked immunosorbent assay kits. RESULTS: All but L-selectin were significantly increased in the OSA group compared to the control subjects (ICAM-1, 367.4 +/- 85.2 ng/mL vs 252.8 +/- 68.4 ng/mL, p = 0.008; VCAM-1, 961.5 +/- 281.7 ng/mL vs 639.1 +/- 294.4 ng/mL, p = 0.004; E-selectin, 81.0 +/- 30.4 ng/mL vs 58.1 +/- 23.2 ng/mL, p = 0.03, respectively). The increased levels of adhesion molecules correlated with the AHI and the oxygen desaturation index but not with the severity of hypoxemia or the frequency of arousals. CONCLUSIONS: These findings suggest that OSA modulates the expression of proinflammatory mediators. Further studies should evaluate the influence of adhesion molecules on cardiovascular outcome in CAD patients with OSA.