Increased Production of Outer Membrane Vesicles by Salmonella Interferes with Complement-Mediated Innate Immune Attack.

Bacterial outer membrane vesicles (OMVs) enriched with bioactive proteins, toxins, and virulence factors play a critical role in host-pathogen and microbial interactions. The two-component system PhoP-PhoQ (PhoPQ) of Salmonella enterica orchestrates the remodeling of outer membrane lipopolysaccharide (LPS) molecules and concomitantly upregulates OMV production. In this study, we document a novel use of nanoparticle tracking analysis to determine bacterial OMV size and number. Among the PhoPQ-activated genes tested, pagC expression had the most significant effect on the upregulation of OMV production. We provide the first evidence that PhoPQ-mediated upregulation of OMV production contributes to bacterial survival by interfering with complement activation. OMVs protected bacteria in a dose-dependent manner, and bacteria were highly susceptible to complement-mediated killing in their absence. OMVs from bacteria expressing PagC bound to complement component C3b in a dose-dependent manner and inactivated it by recruiting complement inhibitor Factor H. As we also found that Factor H binds to PagC, we propose that PagC interferes with complement-mediated killing of Salmonella in the following two steps: first by engaging Factor H, and second, through the production of PagC-enriched OMVs that divert and inactivate the complement away from the bacteria. Since PhoPQ activation occurs intracellularly, the resultant increase in PagC expression and OMV production is suggested to contribute to the local and systemic spread of Salmonella released from dying host cells that supports the infection of new cells. IMPORTANCE Bacterial outer membrane vesicles (OMVs) mediate critical bacterium-bacterium and host-microbial interactions that influence pathogenesis through multiple mechanisms, including the elicitation of inflammatory responses, delivery of virulence factors, and enhancement of biofilm formation. As such, there is a growing interest in understanding the underlying mechanisms of OMV production. Recent studies have revealed that OMV biogenesis is a finely tuned physiological process that requires structural organization and selective sorting of outer membrane components into the vesicles. In Salmonella, outer membrane remodeling and OMV production are tightly regulated by its PhoPQ system. In this study, we demonstrate that PhoPQ-regulated OMV production plays a significant role in defense against host innate immune attack. PhoPQ-activated PagC expression recruits the complement inhibitor Factor H and degrades the active C3 component of complement. Our results provide valuable insight into the combination of tools and environmental signals that Salmonella employs to evade complement-mediated lysis, thereby suggesting a strong evolutionary adaptation of this facultative intracellular pathogen to protect itself during its extracellular stage in the host.

Cost comparison of osteopathic manipulative treatment for patients with chronic low back pain.

CONTEXT: Chronic low back pain (cLBP) is the second leading cause of disability in the United States, with significant physical and financial implications. Development of a multifaceted treatment plan that is cost effective and optimizes patients' ability to function on a daily basis is critical. To date, there have been no published prospective studies comparing the cost of osteopathic manipulative treatment to that of standard care for patients with cLBP. OBJECTIVES: To contrast the cost for standard of care treatment (SCT) for cLBP with standard of care plus osteopathic manipulative treatment (SCT + OMT). METHODS: This prospective, observational study was conducted over the course of 4 months with two groups of patients with a diagnosis of cLBP. Once consent was obtained, patients were assigned to the SCT or the SCT + OMT group based on the specialty practice of their physician. At enrollment and after 4 months of treatment, all patients in both groups completed two questionnaires: the 11 point pain intensity numerical scale (PI-NRS) and the Roland Morris Disability Questionnaire (RMDQ). Cost data was collected from the electronic medical record of each patient enrolled in the study. Chi-square (χ2Yates) tests for independence using Yates' correction for continuity were performed to compare the results for each group. RESULTS: There was a total of 146 patients: 71 (48.6%) in the SCT + OMT group and 75 (51.4%) in the SCT group. The results showed no significant differences between the mean total costs for the SCT + OMT ($831.48 ± $553.59) and SCT ($997.90 ± $1,053.22) groups. However, the utilization of interventional therapies (2; 2.8%) and radiology (4; 5.6%) services were significantly less for the SCT + OMT group than the utilization of interventional (31; 41.3%) and radiology (17; 22.7%) therapies were for the SCT group (p<0.001). Additionally, the patients in the SCT + OMT group were prescribed fewer opioid medications (15; 21.1) than the SCT (37; 49.3%) patients (p.001). Patients in the SCT group were approximately 14.7 times more likely to have received interventional therapies than patients in the SCT + OMT group. Likewise, the patients in the SCT group were approximately four times more likely to have received radiological services. Paired t tests comparing the mean pre- and 4 month self reported pain severity scores on the RMDQ for 68 SCT + OMT patients (9.91 ± 5.88 vs. 6.40 ± 5.24) and 66 SCT patients (11.44 ± 6.10 vs. 8.52 ± 6.14) found highly significant decreases in pain for both group (<0.001). CONCLUSIONS: The mean total costs for the SCT and SCT + OMT patients were statistically comparable across 4 months of treatment. SCT + OMT was comparable to SCT alone in reducing pain and improving function in patients with chronic low back pain; however, there was less utilization of opioid analgesics, physical therapy, interventional therapies, radiologic, and diagnostic services for patients in the SCT + OMT group.

Transforming a clerkship with telemedicine.

The coronavirus disease 2019 (COVID-19) pandemic had an overwhelming impact on both clinical practices and learning environments. On March 17th, 2020, the American Association of Colleges of Osteopathic Medicine and Commission on Osteopathic College Accreditation issued a statement recommending a "pause" in medical student participation in-person at clinical sites. In response, the Family Medicine Department at the Rowan University School of Osteopathic Medicine recognized the need to evolve the traditional curriculum and quickly transitioned to an online format, incorporating telemedicine into the clerkship. This new model enabled 44 third-year medical students to obtain high-quality, offsite, virtual education and learn new skills.

Health-related Internet use among patients of osteopathic physicians.

CONTEXT: Using the Internet has transformed communication and improved access to health-related information for patients and physicians. OBJECTIVE: To determine why patients use the Internet for health-related information, where patients find answers to their questions, and whether patient use of the Internet impacts the patient-physician relationship. This study focused on patients of osteopathic physicians to confirm previously published data in a more specific population. METHODS: An anonymous 25-item survey was distributed to patients in a primary care setting. The survey elicited information regarding demographics, health-related Internet use, and discussion of Web-based health information during the clinical visit. RESULTS: Two hundred eighty-five patient surveys were collected. Data based on sex, age, education level, and ethnicity were evaluated. Two hundred fifty of 280 patients (89%) reported that they use the Internet to find health-related information, and 134 of 250 patients (54%) indicated that they changed their health-related behaviors based on information they found. Seventy-three of 133 patients (55%) who changed their behaviors reported these findings to their physicians. This finding differed by age and ethnicity. Patients aged 50 to 64 years (22 responses, 73%) were the most likely group to report behavioral changes to their physicians (P=.048). No patients who identified themselves as of Asian/Pacific Islander descent indicated that they reported behavioral changes to their physician (P=.043). Two hundred forty-two of 261 patients (93%) reported that their personal physician is the most reliable source for health information. CONCLUSION: Most patients use the Internet to find health-related information, but many of them are not reporting potentially important health-related behavioral changes to their physicians. However, most patients still consider their physician as the most reliable source for health-related information. Physicians should ask patients about Internet use and counsel them about where to find reliable, accurate, high-quality health information.