Cohort study of patients with advanced cancer: outcomes associated with duration of antibiotic therapy for non-ventilator hospital-acquired pneumonia.

In this single-center observational study of 118 older adults with advanced cancer who developed non-ventilator hospital-acquired pneumonia, prolonged antibiotic durations (8-14 and ≥15 vs ≤7 d) were not associated with reduced adjusted odds of 90-day all-cause readmission or death. These data may inform antimicrobial stewardship efforts in palliative care settings.

Role of Macrophage PIST Protein in Regulating Leishmania major Infection.

PDZ protein interacting specifically with Tc10 or PIST is a mammalian trans-Golgi resident protein that regulates subcellular sorting of plasma membrane receptors. PIST has recently emerged as a key player in regulating viral pathogenesis. Nevertheless, the involvement of PIST in parasitic infections remains unexplored. Leishmania parasites infiltrate their host macrophage cells through phagocytosis, where they subsequently multiply within the parasitophorous vacuole (PV). Host cell autophagy has been found to be important in regulating this parasite infection. Since PIST plays a pivotal role in triggering autophagy through the Beclin 1-PI3KC3 pathway, it becomes interesting to identify the status of PIST during Leishmania infection. We found that while macrophage cells are infected with Leishmania major (L. major), the expression of PIST protein remains unaltered; however, it traffics from the Golgi compartment to PV. Further, we identified that in L. major-infected macrophage cells, PIST associates with the autophagy regulatory protein Beclin 1 within the PVs; however, PIST does not interact with LC3. Reduction in PIST protein through siRNA silencing significantly increased parasite burden, whereas overexpression of PIST in macrophages restricted L. major infectivity. Together, our study reports that the macrophage PIST protein is essential in regulating L. major infectivity.

Antioxidant Polymers with Phenolic Pendants for the Mitigation of Cellular Oxidative Stress.

Overproduction of reactive oxygen species (ROS) in cells is a major health concern as it may lead to various diseases through oxidative damage of biomolecules. Commonly used traditional small molecular antioxidants (polyphenols, carotenoids, vitamins, etc.) have inadequate efficacy in lowering excessive levels of ROS due to their poor aqueous solubility and bioavailability. In response to the widespread occurrence of antioxidant polyphenols in various biorenewable resources, we aimed to develop water-soluble antioxidant polymers with side chain phenolic pendants. Four different types of copolymers (P1-P4) containing phenyl rings with different numbers of hydroxy (-OH) substituents (0: phenylalanine, 1: tyrosyl, 2: catechol, or 3: gallol) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization with a desired molar mass (8500-10000 g/mol) and a narrow dispersity (D ≤ 1.3). After successful characterizations of P1-P4, their in vitro antioxidant properties were analyzed by different methods, including 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+), 4,4'-diamino-3,3',5,5'-tetramethylbiphenyl (TMB), and ß-carotene (ßC) assays. Our results revealed that the gallol pendant polymers can effectively scavenge ROS. Furthermore, electron paramagnetic resonance (EPR) spectroscopy with DPPH• also confirmed the radical quenching ability of the synthesized polymers. The gallol pendant polymers, at a well-tolerated concentration, could effectively penetrate the macrophage cells and restore the H2O2-induced ROS to the basal level. Overall, the present approach demonstrates the efficacy of water-soluble antioxidant polymers with gallol pendants toward the mitigation of cellular oxidative stress.

Clinicians who primarily practice in nursing homes and outcomes among residents with urinary tract infection or pneumonia.

Objective: Assess the association between clinicians who primarily practice in nursing homes (NHs) and 14-day resident outcomes following initial antibiotic dispensing for pneumonia or urinary tract infection (UTI). Design: Retrospective cohort. Setting: U.S. NHs. Participants: NH residents aged ≥65 years who were prescribed antibiotics for pneumonia or UTI between 1 January 2016 and 30 November 2018. Methods: Medicare fee-for-service claims were linked to Minimum Data Set data. Clinicians who primarily practiced in NHs prescribed ≥90% of Part D dispensings to NH residents. Outcomes included death, all-cause and infection-specific hospitalization, and subsequent antibiotic dispensing. Adjusted risk ratios were estimated using inverse-probability-of-treatment-weighted (IPTW) modified Poisson regression models adjusting for 53 covariates. Results: The study population included 28,826 resident-years who were prescribed antibiotics for pneumonia and 106,354 resident-years who were prescribed antibiotics for UTI. Among the pneumonia group, clinicians who primarily practiced in NHs were associated with a greater risk of death (RR 1.3; 95%CLs 1.0, 1.6), lower risks of all-cause (RR 0.9; 95%CLs 0.8, 0.9) and infection-specific hospitalization (RR 0.8; 95%CLs 0.7, 0.9), and similar risk of subsequent antibiotic dispensing (RR 1.0; 95%CLs 1.0, 1.1) after IPTW. No meaningful associations were observed between clinicians who primarily practiced in NHs and outcomes among the UTI group. Conclusions: Clinicians who primarily practiced in NHs were associated with a lower risk of hospitalization but greater risk of mortality for NH residents with pneumonia. Further examination is needed to better understand drivers of differences in infection-related outcomes based on clinicians' training and primary practice setting.

Diagnostic uncertainty and decision-making in home-based primary care: A qualitative study of antibiotic prescribing.

BACKGROUND: Evaluating infection in home-based primary care is challenging, and these challenges may impact antibiotic prescribing. A refined understanding of antibiotic decision-making in this setting can inform strategies to promote antibiotic stewardship. This study investigated antibiotic decision-making by exploring the perspectives of clinicians in home-based primary care. METHODS: Clinicians from the Department of Veterans Affairs Home-Based Primary Care Program were recruited. Semi-structured interviews were conducted from June 2022 through September 2022 using a discussion guide. Transcripts were analyzed using grounded theory. The constant comparative method was used to develop a coding structure and to identify themes. RESULTS: Theoretical saturation was reached after 22 clinicians (physicians, n = 7; physician assistants, n = 2, advanced practice registered nurses, n = 13) from 19 programs were interviewed. Mean age was 48.5 ± 9.3 years, 91% were female, and 59% had ≥6 years of experience in home-based primary care. Participants reported uncertainty about the diagnosis of infection due to the characteristics of homebound patients (atypical presentations of disease, presence of multiple chronic conditions, presence of cognitive impairment) and the challenges of delivering medical care in the home (limited access to diagnostic testing, suboptimal quality of microbiological specimens, barriers to establishing remote access to the electronic health record). When faced with diagnostic uncertainty about infection, participants described many factors that influenced the decision to prescribe antibiotics, including those that promoted prescribing (desire to avoid hospitalization, pressure from caregivers, unreliable plans for follow-up) and those that inhibited prescribing (perceptions of antibiotic-associated harms, willingness to trial non-pharmacological interventions first, presence of caregivers who were trusted by clinicians to monitor symptoms). CONCLUSIONS: Clinicians face the difficult task of balancing diagnostic uncertainty with many competing considerations during the treatment of infection in home-based primary care. Recognizing these issues provides insight into strategies to promote antibiotic stewardship in home care settings.

Career development in pragmatic clinical trials to improve care for people living with dementia.

The growing number of people living with dementia (PLWD) requires a coordinated clinical response to deliver pragmatic, evidence-based interventions in frontline care settings. However, infrastructure to support such a response is lacking. Moreover, there are too few researchers conducting rigorous embedded pragmatic clinical trials (ePCTs) to make the vision of high quality, widely accessible dementia care a reality. National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer's disease and Related Dementias Clinical Trials (IMPACT) Collaboratory seeks to improve the pipeline of early career researchers qualified to lead ePCTs by funding career development awards. Even with support from the Collaboratory, awardees face practical and methodological challenges to success, recently exacerbated by the COVID-19 pandemic. We first describe the training opportunities and support network for the IMPACT CDA recipients. This report then describes the unique career development challenges faced by early-career researchers involved in ePCTs for dementia care. Topics addressed include challenges in establishing a laboratory, academic promotion, mentoring and professional development, and work-life balance. Concrete suggestions to address these challenges are offered for early-career investigators, their mentors, and their supporting institutions. While some of these challenges are faced by researchers in other fields, this report seeks to provide a roadmap for expanding the work of the IMPACT Collaboratory and initiating future efforts to recruit, train, and retain talented early-career researchers involved in ePCTs for dementia care.

An AI-powered patient triage platform for future viral outbreaks using COVID-19 as a disease model.

Over the last century, outbreaks and pandemics have occurred with disturbing regularity, necessitating advance preparation and large-scale, coordinated response. Here, we developed a machine learning predictive model of disease severity and length of hospitalization for COVID-19, which can be utilized as a platform for future unknown viral outbreaks. We combined untargeted metabolomics on plasma data obtained from COVID-19 patients (n = 111) during hospitalization and healthy controls (n = 342), clinical and comorbidity data (n = 508) to build this patient triage platform, which consists of three parts: (i) the clinical decision tree, which amongst other biomarkers showed that patients with increased eosinophils have worse disease prognosis and can serve as a new potential biomarker with high accuracy (AUC = 0.974), (ii) the estimation of patient hospitalization length with ± 5 days error (R2 = 0.9765) and (iii) the prediction of the disease severity and the need of patient transfer to the intensive care unit. We report a significant decrease in serotonin levels in patients who needed positive airway pressure oxygen and/or were intubated. Furthermore, 5-hydroxy tryptophan, allantoin, and glucuronic acid metabolites were increased in COVID-19 patients and collectively they can serve as biomarkers to predict disease progression. The ability to quickly identify which patients will develop life-threatening illness would allow the efficient allocation of medical resources and implementation of the most effective medical interventions. We would advocate that the same approach could be utilized in future viral outbreaks to help hospitals triage patients more effectively and improve patient outcomes while optimizing healthcare resources.

Localized Leishmania major infection disrupts systemic iron homeostasis that can be controlled by oral iron supplementation.

Leishmania parasites are heavily dependent on efficient iron acquisition from a tightly regulated host iron pool for survival and virulence. Prior studies uncovered multiple strategies adopted by the parasite to hijack the iron-regulatory network of macrophages. Despite these extensive studies with infected macrophages, there is limited knowledge of the effect of Leishmania infection on systemic iron homeostasis. This issue is particularly relevant for Leishmania major, which causes localized skin infection with minimal lymphatic spread. We show for the first time that L. major infection in the mouse footpad induced influx of iron at the site of infection through blood with simultaneous upregulation of transferrin receptor 1 and downregulation of phagolysosomal iron exporter Nramp1 expression in the footpad tissue. Interestingly, localized L. major infection had far-reaching effects beyond the infection site triggering anemia-like symptoms. This was evident from depleted physiological iron stores from the liver and bone marrow as well as reduced hemoglobin levels and deformed erythrocytes. The infected mice also developed splenomegaly with signs of splenic stress erythropoiesis as indicated by upregulation of several erythroid-related genes. These observations prompted us to provide oral iron supplementations to the L. major-infected mice, which resulted in a drastic reduction of the parasite load and restoration of iron homeostasis.

Antimicrobial resistance in Escherichia coli and Klebsiella pneumoniae urine isolates from a national sample of home-based primary care patients with dementia.

Annual prevalences of antimicrobial resistance among urine isolates (3,913 Escherichia coli isolates and 1,736 Klebsiella pneumoniae isolates) from home-based primary care patients with dementia were high between 2014 and 2018 (ciprofloxacin, 18%-23% and 5%-7%, respectively; multidrug resistance, 9%-11% and 5%-6%, respectively). Multidrug resistance varied by region. Additional studies of antimicrobial resistance in home-care settings are needed.

Antibiotic therapy is associated with adverse drug events among older adults with advanced cancer: A cohort study.

BACKGROUND: Older adults with advanced cancer are exposed to antibiotics but estimates of adverse drug events associated with antibiotic therapy are lacking. AIM: Evaluate the association of antibiotic therapy with adverse drug events in older adults with advanced cancer. DESIGN: Cohort study where the exposure was the ratio of days of therapy of an oral or intravenous antibiotic per patient-day and the outcome was an adverse drug event, defined as cardiotoxicity, hepatotoxicity, nephrotoxicity, Clostridioides difficile infection, or new detection of a multidrug-resistant organism. SETTING/PARTICIPANTS: Patients aged ⩾65 years with solid tumors from a tertiary care center who received palliative chemotherapy (n = 914). RESULTS: Mean age was 75 ± 6.6 years, and 52% were female. Common tumors were lung (31%, n = 284) and gastrointestinal (26%, n = 234). Mean time from first course of palliative chemotherapy to index admission was 128 days. Five-hundred thirty (58%) patients were exposed to antibiotics during the index admission; of these, 27% (n = 143) met standardized criteria for infection. Patients were commonly exposed to cephalosporins (33%, n = 298) and vancomycin (30%, n = 276). Among patients exposed to antibiotics, 35% (n = 183/530) developed an adverse drug event. In multivariable testing, antibiotic therapy was associated with development of an adverse drug event (>0 to <1 vs 0 days of therapy/patient-day: adjusted odds ratio [aOR] = 1.9; 95% confidence interval [CI], 1.2-2.8; ⩾1 vs 0 days of therapy/patient-day: aOR = 2.1, 95% CI, 1.4-3.0). CONCLUSION: Antibiotic therapy was independently associated with adverse drug events in hospitalized older adults with advanced cancer. These findings may inform antibiotic decision-making among palliative care providers.

Nonutility of procalcitonin for diagnosing bacterial pneumonia in patients with severe COVID-19.

Background: Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. Methods: We retrospectively identified 185 patients hospitalized with severe COVID-19 who underwent lower respiratory culture; 85 had evidence of bacterial superinfection. Receiver operating characteristic curve and area under the curve (AUC) analyses were performed to assess the utility of procalcitonin for diagnosing superinfection. Results: This approach demonstrated that procalcitonin measured at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). The AUC not affected by exposure to antibiotics, treatment with immunomodulatory agents, or timing of procalcitonin measurement. Conclusion: Static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

Clinical outcomes following dalbavancin administration in patients with barriers to outpatient parenteral antimicrobial therapy.

Between 2016 and 2021, we retrospectively identified 42 patients receiving ≥1 dose of dalbavancin for osteomyelitis, skin and soft-tissue infection, endocarditis or bacteremia, or septic arthritis. Median antibiotic duration prior to dalbavancin administration was 7 days. Within 90 days, 93% achieved clinical cure, 12% were readmitted, 12% developed hepatotoxicity, and 5% died.

Prevalence and treatment of postobstructive pneumonia among older adults with advanced cancer.

Among 124 older adults with advanced cancer who were hospitalized with pneumonia, 7.3% met criteria for postobstructive pneumonia. There were no differences in antibiotic duration, antibiotic spectrum, 30-day and 90-day readmissions, or mortality between those with and without postobstructive pneumonia. Bacteria were identified in 5 patients with postobstructive pneumonia.

National Cohort Study of Homebound Persons Living With Dementia: Antibiotic Prescribing Trends and Opportunities for Antibiotic Stewardship.

Background: Over 7 million older Americans are homebound. Managing infections in homebound persons presents unique challenges that are magnified among persons living with dementia (PLWD). This work sought to characterize antibiotic use in a national cohort of PLWD who received home-based primary care (HBPC) through the Veterans Health Administration. Methods: Administrative data identified veterans aged ≥65 years with ≥2 physician home visits in a year between 2014 and 2018 and a dementia diagnosis 3 years before through 1 year after their initial HBPC visit. Antibiotics prescribed orally, intravenously, intramuscularly, or by enema within 3 days of an HBPC visit were assessed from the initial HBPC visit to death or December 31, 2018. Prescription fills and days of therapy (DOT) per 1000 days of home care (DOHC) were calculated. Results: Among 39 861 PLWD, the median age (interquartile range [IQR]) was 85 (78-90) years, and 15.0% were Black. Overall, 16 956 (42.5%) PLWD received 45 122 prescription fills. The antibiotic use rate was 20.7 DOT per 1000 DOHC. Telephone visits and advanced practice provider visits were associated with 30.9% and 42.0% of fills, respectively. Sixty-seven percent of fills were associated with diagnoses for conditions where antibiotics are not indicated. Quinolones were the most prescribed class (24.3% of fills). The overall median length of therapy (IQR) was 7 (7-10) days. Antibiotic use rates varied across regions. Within regions, the median annual antibiotic use rate decreased from 2014 to 2018. Conclusions: Antibiotic prescriptions were prevalent in HBPC. The scope, appropriateness, and harms of antibiotic use in homebound PLWD need further investigation.

Comparison of traditional instruction versus nontraditional learning to improve trainee knowledge of urine culture practices in catheterized patients.

We surveyed trainees about their urine culture practices and assessed the impact of an educational intervention delivered electronically and in-person. Trainee scores improved across all levels of training and across all questions on the post-intervention survey, but there was no difference in scores by mode of education (P=0.91).

Nonutility of procalcitonin for diagnosing bacterial pneumonia in COVID-19.

Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. To do so, we identified 185 patients with severe COVID-19 who underwent lower respiratory culture; 85 had superinfection. Receiver operating characteristic curve analysis showed that procalcitonin at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). We conclude that static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR.

Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to ß-glucuronidase (ß-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or ß-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135-/- fly), which also exhibited a significant loss of body fat. We report here that the lean phenotype of the CG2135-/- larvae is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135-/- larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135-/- larvae. Interestingly, treatment of the CG2135-/- larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.