Combinations of Antibiotics Effective against Extensively- and Pandrug-Resistant Acinetobacter baumannii Patient Isolates.

Infections due to drug-resistant Acinetobacter baumannii strains are increasing and cause significant morbidity and mortality, especially in hospitalized and critically ill patients. A. baumannii rapidly develops resistance to numerous antibiotics, and antibiotics traditionally used against this deadly pathogen have been failing in recent years, highlighting the need to identify new treatment strategies. Treatment options that have shown promise include revisiting common antibiotics not typically used against A. baumannii, evaluating new antibiotics recently introduced to market, and identifying combinations of antibiotics that display synergistic interactions. In this study, we characterized the antibiotic susceptibility profiles of extensively (XDR) and pandrug-resistant (PDR) A. baumannii patient isolates. We examined the potency of 22 standard-of-care antibiotics and the newer antibiotics eravacycline, omadacycline, and plazomicin against these strains. Furthermore, we examined combinations of these antibiotics against our collection to identify synergistic effects. We found that this collection is highly resistant to most or all standard-of-care antibiotics, except for minocycline and rifampin. We show that eravacycline and omadacycline are effective against these strains based on minimum inhibitory concentrations. We also identified two highly effective combinations, cefepime and amikacin and cefepime and ampicillin-sulbactam, which exhibited high rates of synergy against this collection. This information is valuable in our battle against highly drug resistant and virtually untreatable A. baumannii infections.

Comparing Rates of Radiographic Baseplate Loosening Between Cement and Cementless INFINITY Total Ankle Prostheses.

INTRODUCTION: Total ankle replacement is indicated for end-stage ankle osteoarthritis. Periprosthetic radiolucency, from separation between the bone and implant, is suggested to be indicative of potential prosthesis failure risk. Anchoring implants with cement may mitigate this. This study aimed to compare rates of periprosthetic radiolucency between patients with cement-affixed and cementless implants. METHODS: A retrospective analysis was performed on 28 patients who underwent total ankle replacement with the INFINITY Total Ankle System (Wright Medical, Memphis, Tennessee) implant between January 2016 and May 2022. Anteroposterior, mortise, and lateral ankle X-rays were reviewed by 2 independent reviewers for tibiotalar angle, talar tilt, and periprosthetic radiolucency. The Wilcoxon rank-sum test and chi-square test were performed. RESULTS: The incidence of periprosthetic radiolucency at the most recent follow-up did not significantly differ between cement and cementless groups (57.1% in both groups, P = 1.0). Follow-up tibiotalar and talar tilt angles were not significantly different (P > .51 for all comparisons). CONCLUSIONS: Patients with cemented implants had a similar incidence of periprosthetic radiolucency compared with patients with cementless prostheses. Understanding of long-term clinical outcomes will help inform optimal operative approaches for ankle prostheses. LEVELS OF EVIDENCE: Therapeutic, Level III, Retrospective cohort study.

Association of Risk Factors and Comorbidities With Chronic Pain in the Elderly Population.

INTRODUCTION/OBJECTIVE: Chronic pain disorders affect about 20% of adults in the United States, and it disproportionately affects individuals living in the neighborhoods of extreme socioeconomic disadvantage. In many instances, chronic pain has been noted to arise from an aggregation of multiple risk factors and events. Therefore, it is of importance to recognize the modifiable risk factors. The aim of this study was to investigate the comorbid medical conditions and risk factors associated with chronic pain disorders in patients aged 65 years and older. METHODS: Our team retrospectively reviewed medical records of elderly patients (65 years and older) who were evaluated in our outpatient medicine office between July 1, 2020 and June 30, 2021 for acute problems, management of chronic medical problems, or well visits. We divided our patients into a group who suffered from chronic pain disorder, and another group who did not have chronic pain disorder. The association of variables were compared between those groups. RESULTS: Of the 2431 patients, 493 (20.3%) had a chronic pain disorder. A higher frequency of females in the group with chronic pain disorder was found compared to the group without a chronic pain disorder (60.6% vs 55.2%; P = .033). The mean ages between the two groups were similar in the group with a chronic pain disorder compared to the group without (76.35 ± 7.5 year vs 76.81 ± 7.59 year; P = .228). There were significant associations of certain comorbidities in the group with a chronic pain disorder compared to the group without a chronic pain disorder, such as depression (21.9% vs 15.2%; P < .001), anxiety (27.0% vs 17.1%; P < .001), chronic obstructive pulmonary disease (8.7% vs 6.1%; P = .036), obstructive sleep apnea (16.8% vs 11.6%; P = .002), gastroesophageal reflux disease (40.8% vs 29.0%; P < .001), osteoarthritis (49.3% vs 26.1%; P < .001), other rheumatologic diseases (24.9% vs 19.4%; P = .006), and peripheral neuropathy (14.4% vs 5.3%; P < .001). CONCLUSION: Female sex, depression, anxiety, chronic obstructive pulmonary disease, obstructive sleep apnea, gastroesophageal reflux disease, osteoarthritis, other rheumatologic diseases, and peripheral neuropathy were significantly associated with chronic pain disorder in elderly patients, while BMI was not associated with chronic pain disorder.

Comorbidities and Risk Factors Associated With Insomnia in the Elderly Population.

INTRODUCTION/OBJECTIVES: Sleep disorders affect around 50 to 70 million Americans, with chronic insomnia being the most common, especially in the elderly population. With an 11-fold increase in the US office visits due to insomnia, from 0.8 to 9.4 million, between 1993 and 2015, it is imperative to identify the modifiable risk factors. The aim of our study was to examine the association of risk factors and comorbid medical conditions with insomnia in patients 65 years, and older. METHODS: We performed a retrospective electronic medical record review of the patients aged 65 years and older, who visited our suburban internal medicine office between July 1, 2020 and June 30, 2021. Patients were divided into insomnia group, and the group without insomnia. The associated variables were compared. RESULTS: Among 2431 patients, 247 patients (10.2%) had insomnia. Mean ages of the patients in the insomnia group and the group without insomnia were comparable (77 ± 8.1 year vs 76 ± 7.5 year; P = .211). There was a significantly greater frequency of women in the insomnia group compared to the group without insomnia (63.2% vs 55.5%; P = .022). In the insomnia group, there were significantly higher frequencies of association of certain comorbidities compared to the group without insomnia, such as dementia (6.5% vs 3.4%; P = .015), depression (30.8% vs 14.9%; P < 0.001), anxiety disorder (34.4% vs 17.4%; P < .001), atrial fibrillation (19.4% vs 13.4%; P = .01), and chronic pain disorders (32.8% vs 18.9%; P < .001). Logistic regression analysis showed significantly greater odds of insomnia in patients who had depression (OR = 1.860, 95% CI 1.342-2.576; P < .001), anxiety (OR = 1.845, 95% CI 1.342-2.537; P < .001), and chronic pain disorders (OR = 1.901, 95% CI 1.417-2.549; P < .001). CONCLUSIONS: Female sex, dementia, depression, anxiety, chronic pain disorders, and atrial fibrillation are associated with insomnia in the elderly patients. Presence of depression, anxiety, and chronic pain disorders are associated with greater odds of having insomnia in the elderly patients.

MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma.

The degree of metastatic disease varies widely among patients with cancer and affects clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC)-a tumor type in which most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor-associated macrophages, leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. SIGNIFICANCE: Here, we investigate metastatic variation seen clinically in patients with PDAC and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.This article is highlighted in the In This Issue feature, p. 275.

Calcium signaling induces a partial EMT.

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.