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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial use during end-of-life care of older adults with advanced cancer is prevalent. Factors influencing the decision to prescribe antimicrobials during end-of-life care are not well defined. Aim: To evaluate factors influencing medicine subspecialists to prescribe intravenous and oral antimicrobials during end-of-life care of older adults with advanced cancer to guide an educational intervention. Design: 18-item single-center cross-sectional survey. Setting/participants: Inpatient medicine subspecialists in 2018. Results: Of 186 subspecialists surveyed, 67 (36%) responded. Most considered withholding antimicrobials at the time of clinical deterioration during hospitalization (n = 54/67, 81%), viewed the initiation of additional intravenous antimicrobials as escalation of care (n = 44/67, 66%), and believed decision-making should involve patients or surrogates and providers (n = 64/67, 96%). Fifty-one percent (n = 30/59) of respondents who conducted advance care planning did not discuss antimicrobials. Barriers to discussing end-of-life antimicrobials included the potential to overwhelm patients or families, challenges of withdrawing antimicrobials, and insufficient training. Conclusions: Although the initiation of additional intravenous antimicrobials was viewed as escalation of care, antimicrobials were not routinely discussed during advance care planning. Educational interventions that promote recognition of antimicrobial-associated adverse events, incorporate antimicrobial use into advance care plans, and offer communication simulation training around the role of antimicrobials during end-of-life care are warranted. [ABSTRACT FROM AUTHOR]

Natural resistance–associated macrophage protein 1 (Nramp1) was originally discovered as a genetic determinant of resistance against multiple intracellular pathogens, including Leishmania. It encodes a transmembrane protein of the phago‐endosomal compartments, where it functions as an iron transporter. But the mechanism by which Nramp1 controls host–pathogen dynamics and determines final outcome of an infection is yet to be fully deciphered. Whether the expression of Nramp1 is altered in response to a pathogen attack is also unknown. To address these, Nramp1 status was examined in Leishmania major–infected murine macrophages. We observed that at 12 hrs post infection, there was drastic lowering of Nramp1 level accompanied by increased phagolysosomal iron content and enhanced intracellular parasite growth. Leishmania infection–induced Nramp1 downregulation was caused by ubiquitin‐proteasome degradation pathway, which in turn was found to be mediated by the iron‐regulatory peptide hormone hepcidin. Blocking of Nramp1 degradation with proteasome inhibitor or transcriptional agonist of hepcidin resulted in depletion of phagolysosomal iron pool that led to significant reduction of intracellular parasite burden. Interestingly, Nramp1 level was restored to normalcy after 30 hrs of infection with a concomitant drop in phagolysosomal iron, which is suggestive of a host counteractive response to deprive the pathogen of this essential micronutrient. Taken together, our study implicates Nramp1 as a central player in the host–pathogen battle for phagolysosomal iron. We also report Nramp1 as a novel target for hepcidin, and this 'hepcidin‐Nramp1' axis may have a broader role in regulating macrophage iron homeostasis. [ABSTRACT FROM AUTHOR]

Among older (n = 204) versus younger (n = 253) adults, there was no difference in adverse events (adjusted odds ratio [aOR] = 0.98; 95% confidence interval [CI] = 0.6–1.6) or healthcare utilization (incidence rate ratio = 1.09; 95% CI = 0.9–1.3) within 30 days after discontinuing outpatient parenteral antimicrobial therapy. Vancomycin (aOR = 1.92) and oxacillin (aOR = 3.12) were independently associated with adverse events. [ABSTRACT FROM AUTHOR]

This paper deals with global delay-range-dependent (DRD) stability analysis for Takagi–Sugeno (T–S) fuzzy Hopfield neural network with time-varying delays. First, we proposes a new Lyapunov-Krasovskii functional (LKF) by incorporating the information of activation function, the lower and upper bound of time delay. Further, to achieve the larger delay bound results and approximating the derivatives of LKFs, Wirtinger based inequality (WBI) together with reciprocal convex lemma (RCL) is being utilized. As a result some DRD global stability conditions for the system under consideration with less conservatism are derived in an linear matrix inequality (LMI) framework. Three numerical examples are presented in this work to exhibit the efficacy of the proposed stability criterion over the recent existing results. [ABSTRACT FROM AUTHOR]

This paper presents the development of a new double integral inequality (II) with the motivation of yielding quadratic approximation. It is well known that approximating integral quadratic terms with quadratic terms involves a certain degree of conservatism. In this paper, a sufficient gap has been identified in the approximation of two recent IIs reported in the literature, thereby leading to the new double II. The developed inequality has been applied to access the stability of a linear retarded system to estimate a maximum delay upper‐bound. Furthermore, a mathematical relationship of the new double II with existing inequalities is discussed to show that the developed inequality is more general, effective and bears less computational burden. Four numerical examples are given to validate the authors' claim with regard to the effective estimate of delay bound results for a linear retarded system. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Reducing hospital readmissions, including preventable healthcare-associated infections, is a national priority. The proportion of readmissions due to infections is not well-understood. Better understanding of hospital risk factors for readmissions and infection-related readmissions may help optimize interventions to prevent readmissions. Methods: Retrospective cohort study of California acute care hospitals and their patient populations discharged between 2009 and 2011. Demographics, comorbidities, and socioeconomic status were entered into a hierarchical generalized linear mixed model predicting all-cause and infection-related readmissions. Crude verses adjusted hospital rankings were compared using Cohen's kappa. Results: We assessed 30-day readmission rates from 323 hospitals, accounting for 213 879 194 post-discharge person-days of follow-up. Infection-related readmissions represented 28% of all readmissions and were associated with discharging a high proportion of patients to skilled nursing facilities. Hospitals serving populations with high proportions of males, comorbidities, prolonged length of stay, and populations living in a federal poverty area, had higher all-cause and infection-related readmission rates. Academic hospitals had higher all-cause and infectionrelated readmission rates (odds ratio 1.24 and 1.15, respectively). When comparing adjusted vs crude hospital rankings for infection-related readmission rates, adjustment revealed 31% of hospitals changed performance category for infection-related readmissions. Conclusions: Infection-related readmissions accounted for nearly 30% of all-cause readmissions. High hospital infection-related readmissions were associated with serving a high proportion of patients with comorbidities, long lengths of stay, discharge to skilled nursing facility, and those living in federal poverty areas. Preventability of these infections needs to be assessed. [ABSTRACT FROM AUTHOR]

The article focuses on a retrospective cohort study which investigated the effect of environmental cleaning intervention on the risk of acquiring vancomycin-resistant enteroccocci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) from prior hospital room occupants. The study was conducted among patients admitted to several intensive care units. The environmental cleaning intervention is composed of targeted feedback using black-light market, cleaning cloths soaked in bucket with disinfectant solution, and increased informed education.

Mutations in the human carbonic anhydrase IV (hCAIV) have been associated with retinal degeneration in an áutosomal-dominant form of retinitis pigmentosa (RP17). Prior in vitro cell culture studies confirmed that all of the RP17-associated hCAIV mutations cause protein misfolding, leading to endoplasmic reticulum (ER) stressinduced apoptosis in cells expressing the mutant proteins. To evaluate the physiological impacts of these folding mutants in other carbonic anhydrase IV-producing tissues, we generated two transgenic mouse lines expressing R219S or R14W hCAIV under control of the endogenous hCAIV promoter. Expression of either of these mutant proteins in kidneys caused progressive renal injury in male transgenic mice as evidenced by an age-dependent increase in the tubule cell apoptosis starting at approximately 20 weeks of age and vacuolization throughout the renal cortex in older mice. Up-regulation of the ER chaperone, BiP, was observed in the cells of the renal cortex of the male transgenic mice, suggesting ER stress as a causal factor for the renal injury. The renal injury inflicted by expression of the folding mutants was markedly enhanced by haploinsufficiency of the ER cochaperone pS8lM(. The transgenic mice expressing the hCAIV folding mutants on a p58IPK heterozygous background showed. extensive renal tubular apoptosis by approximately 10 weeks of age in both male and female mice. These data indicate that expression of the RP17-associated folding mutants of hCAIV can adversely affect tissues beyond the retina and their in vivo proteotoxicity is sensitive to modulation of the protein folding environment of the ER. [ABSTRACT FROM AUTHOR]

Missense mutations in the carbonic anhydrase IV (CA IV) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP17). We used two transient, expression systems to investigate the molecular mechanism by which the newly identified CA IV mutations, R69H and R219S, contribute to retinal pathogenesis. Although the R219S mutation drastically reduced the activity of the enzyme, the R69H mutation had a minimal effect, suggesting that loss of CA activity is not the molecular basis for their pathogenesis. Defective processing was apparent for both mutant proteins. Cell surface-labeling techniques showed that the R69H and R219S mutations both impaired the trafficking of CA IV to the cell surface, resulting in their abnormal intracellular retention. Expression of both CA IV mutants induced elevated levels of the endoplasmic reticulum (ER) stress markers, BiP and CHOP, and led to cell death by apoptosis. They also had a dominant-negative effect on the secretory function of the ER. These properties are similar to those of R14W CA IV, the signal sequence variant found in the original patients with RP17. These findings suggest that toxic gain of function involving ER stress-induced apoptosis is the common mechanism for pathogenesis of this autosomal-dominant disease. Apoptosis induced by the CA IV mutants could be prevented, at least partially, by treating the cells with dorzolamide, a CA inhibitor. Thus, the use of a CA inhibitor as a chemical chaperone to reduce ER stress may delay or prevent the onset of blindness in RP17. [ABSTRACT FROM AUTHOR]

Background. Patients with newly acquired methicillin-resistant Staphylococcus aureus (MRSA) have significant risks of short-term morbidity and mortality due to this pathogen. We were interested in assessing whether longterm carriers have persistent risks of disease and whether all carriers, regardless of the duration of carriage, should be considered to be reasonable candidates for interventions to reduce the risk of infection. Methods. We conducted a single-center retrospective cohort study to evaluate the risk of subsequent MRSA infection and death among patients known to have harbored MRSA for at least 1 year (i.e., prevalent carriers). Results. Among 281 prevalent carriers, 65 (23%) developed a total of 96 discrete and unrelated MRSA infections in the year after their identification as prevalent carriers. The most common infections were pneumonia (accounting for 39% of MRSA infections), soft-tissue infection (14%), and central venous catheter infection (14%). Twenty-four percent of all infections involved bacteremia. Thirty-eight MRSA infections occurred during a new hospitalization, and 32 (84%) of these infections were the reason for admission to the hospital. MRSA contributed to 14 deaths, with 6 of these deaths deemed to be attributable to MRSA. Harboring MRSA for <2 years and MRSA colonization at the time of detection as a prevalent carrier were predictive of subsequent infection with MRSA. Conclusions. Individuals who are known to have harbored MRSA for >1 year are at high risk for subsequent MRSA morbidity and mortality and should be considered to be targets for intervention, in addition to individuals who have newly acquired this pathogen. [ABSTRACT FROM AUTHOR]

Autosomal dominant familial isolated hypoparathyroidism (AD- FIH) is caused by a Cys → Arg mutation (C18R) in the hydrophobic core of the signal peptide of human preproparathyroid hormone (PPTH). Although this mutation impairs secretion of the hormone, the mechanism by which one mutant allele produces the autoso- mal-dominant disease is unexplained. Using transfected HEK293 cells, we demonstrate that the expressed mutant hormone is trapped intracellularly, predominantly in the endoplasmic reticu- lum (ER). This ER retention was found to be toxic for the cells, which underwent apoptosis, as evident from the marked increase in the number of cells staining positive for Annexin V binding and for the TUNEL reaction. The cells producing mutant hormone also had marked up-regulation of the ER stress-responsive proteins, BiP and PERK, as well as the proapoptotic transcription factor, CHOP. Up-regulation of these markers of the unfolded protein response supported a causal link between the ER stress and the cell death cascade. When the C18R PPTH was expressed in the presence of 4-phenylbutyric acid, which is a pharmacological chaperone, intra- cellular accumulation was reduced and normal secretion was re- stored. This treatment also produced remarkable reduction of ER stress signals and protection against cell death. These data impli- cate ER stress-induced cell death as the underlying mechanism for AD-FIH and suggest that the pharmacological manipulation of this pathway by using chemical chaperones offers a therapeutic option for treating this disease. [ABSTRACT FROM AUTHOR]

The article investigates on the danger of acquiring antibiotic-resistant bacteria from previous hospital room occupants. The study found that a room previously occupied by patients infected with methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) increases the risks of succeeding room occupants in acquiring the said pathogens. The study also showed that environmental contamination played a key role in MRSA and VRE transmission.

Background As cancer survivorship improves, the number of patients with hematologic malignancies receiving palliative chemotherapy will grow. Older adults with hematologic malignancies often carry poor prognoses and experience high risks of infection. We evaluated the frequency of CDC criteria confirmed infection and antimicrobial use during hospitalizations following initiation of palliative chemotherapy. Methods We conducted a cohort study of patients aged ≥65 years who received non-curative palliative chemotherapy between January 1, 2016 and September 30, 2017 and were subsequently hospitalized by January 31, 2018. Hematologic malignancies were verified with medical record review. Infections were identified using CDC criteria, and antimicrobials were categorized by indication for use. Results We identified 268 patients receiving palliative chemotherapy for hematologic malignancies (Table 1) who had a total 591 hospitalizations (Table 2) during follow-up. There were 162 readmissions (27%) among 92 patients. Among all patients, 128 (48%) died during follow-up. Forty-one (15%) deaths were within 30 days of discharge. The most common site of death was hospice, in and outpatient (27%). Two hundred forty-nine (42%) admissions were for infectious causes; of the 34 patients who died inpatient (non hospice), 56% had been admitted for infectious causes. Antimicrobials were prescribed for prophylaxis in 57% (n = 337/591) of hospitalizations. Antimicrobials were prescribed for suspected infection in 48% (n = 282/591) of hospitalizations. Only 30% (n = 178/591) of hospitalizations had antimicrobials given for CDC confirmed infections. Figure 1 shows the most common indications for antimicrobial use. Conclusion Infections are an important cause of the morbidity and mortality in older adults receiving palliative chemotherapy for hematology malignancies. Hospitalizations for infectious causes were frequent in our cohort. Nearly half of hospitalizations involved antimicrobial use for suspected infection, but CDC confirmed infections were less common. This population warrants further investigation to improve antimicrobial use. Future studies should identify the subset of patients at high risk for recurrent admissions to optimize medical care. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

The article discusses a randomized clinical trial involving women with acute uncomplicated urinary tract infection (UTI) or cystitis to compare the clinical efficacy of nitrofurantoin and oral fosfomycin. Topics discussed include days of clinical cure after completion of therapy, no significant difference in the duration of symptoms despite the clinical efficacy of nitrofurantoin and microbiologic and clinical responses.

Case Presentation: A 62-year-old nonsmoking woman with no medical history initially presented with a 3-month history of rash. A painful, erythematous exanthem had progressed from her forehead, cheeks, and upper chest to her eyes (heliotrope rash) and hands, primarily involving the extensor surface finger joints with prominent digital ulceration. [ABSTRACT FROM AUTHOR]

Administering and monitoring intravenous antimicrobials may cause discomfort in patients at the end of life and delay transition to hospice. We describe 3 patients with terminal cancer with methicillin-resistant Staphylococcus aureus, Streptococcus gallolyticus, and Granulicatella adiacens bacteremia who were managed with the long-acting lipoglycopeptide oritavancin to facilitate discharge to hospice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Copper (Cu) is essential for all life forms; however, in excess, it becomes toxic. Toxic properties of Cu are known to be utilized by host species against various pathogenic invasions. Leishmania, in both free-living and intracellular forms, exhibits appreciable tolerance toward Cu stress. While determining the mechanism of Cu-stress evasion employed by Leishmania, we identified and characterized a hitherto unknown Cu-ATPase in Leishmania major and established its role in parasite survival in host macrophages. This novel L. major Cu-ATPase, LmATP7, exhibits homology with its orthologs at multiple motifs. In promastigotes, LmATP7 primarily localized at the plasma membrane. We also show that LmATP7 exhibits Cu-dependent expression patterns and complements Cu transport in a Cu-ATPase-deficient yeast strain. Promastigotes overexpressing LmATP7 exhibited higher survival upon Cu stress, indicating efficacious Cu export compared with Wt and heterozygous LmATP7 knockout parasites. We further explored macrophage-Leishmania interactions with respect to Cu stress. We found that Leishmania infection triggers upregulation of major mammalian Cu exporter, ATP7A, in macrophages, and trafficking of ATP7A from the trans-Golgi network to endolysosomes in macrophages harboring amastigotes. Simultaneously, in Leishmania, we observed a multifold increase in LmATP7 transcripts as the promastigote becomes established in macrophages and morphs to the amastigote form. Finally, overexpressing LmATP7 in parasites increases amastigote survivability within macrophages, whereas knocking it down reduces survivability drastically. Mice injected in their footpads with an LmATP7-overexpressing strain showed significantly larger lesions and higher amastigote loads as compared with controls and knockouts. These data establish the role of LmATP7 in parasite infectivity and intra-macrophagic survivability. [ABSTRACT FROM AUTHOR]

Background: Many studies have evaluated methicillin-resistant Staphylococcus aureus (MRSA) infections during single hospitalizations and subsequent readmissions to the same institution. None have assessed the comprehensive burden of MRSA infection in the period after hospital discharge while accounting for healthcare utilization across institutions. Methodology/Principal Findings: We conducted a retrospective cohort study of adult patients insured by Harvard Pilgrim Health Care who were newly-detected to harbor MRSA between January 1991 and December 2003 at a tertiary care medical center. We evaluated all MRSA-attributable infections associated with hospitalization in the year following new detection, regardless of hospital location. Data were collected on comorbidities, healthcare utilization, mortality and MRSA outcomes. Of 591 newly-detected MRSA carriers, 23% were colonized and 77% were infected upon detection. In the year following detection, 196 (33%) patients developed 317 discrete and unrelated MRSA infections. The most common infections were pneumonia (34%), soft tissue (27%), and primary bloodstream (18%) infections. Infections occurred a median of 56 days post-detection. Of all infections, 26% involved bacteremia, and 17% caused MRSA-attributable death. During the admission where MRSA was newly-detected, 14% (82/576) developed subsequent infection. Of those surviving to discharge, 24% (114/ 482) developed post-discharge infections in the year following detection. Half (99/185, 54%) of post-discharge infections caused readmission, and most (104/185, 55%) occurred over 90 days post-discharge. Conclusions/Significance: In high-risk tertiary care patients, newly-detected MRSA carriage confers large risks of infection and substantial attributable mortality in the year following acquisition. Most infections occur post-discharge, and 18% of infections associated with readmission occurred in hospitals other than the one where MRSA was newly-detected. Despite gains in reducing MRSA infections during hospitalization, the risk of MRSA infection among critically and chronically ill carriers persists after discharge and warrants targeted prevention strategies. [ABSTRACT FROM AUTHOR]

Cyclophilins have been implicated in several important cellular functions. Our earlier results showed that reactivation of adenosine kinase (AdK) by CyP (LdCyP) from the parasitic protozoa Leishmania donovani is accompanied with disaggregation of the enzyme [Chakraborty, A., et al. (2002) J. Biol. Chem. 277, 47451-47460; Chakraborty, A., et al. (2004) Biochemistry 43, 11862-11872]. However, it remained to be known why the enzyme displayed progressive inhibition during the time-dependent reaction and what LdCyP does to prevent and/or reverse the inhibition. Herein, we demonstrate that one of its reaction products, ADP but not AMP, facilitates the formation of AdK aggregates, leading to its inactivation. Further studies revealed that LdCyP reactivates the enzyme by withdrawing the ADP inhibition. To investigate the molecular mechanism, the intrinsic tryptophan fluorescence and polarization of AdK were monitored in the presence of either LdCyP or ADP and in combination thereof. Whereas in the presence of LdCyP the tryptophan fluorescence emission maxima of AdK exhibited a red shift, ADP had a quenching effect. However, both the red shift and quenching became less noticeable when one (W234) of the two tryptophan residues of AdK was altered, indicating W234 fluorescence is relatively more sensitive to both LdCyP and ADP binding. Kinetic measurements indicated that LdCyP-facilitated reactivation of AdK is accompanied with a concomitant increase in the KD of ADP but not of AMP. Interestingly, addition of myokinase (MK) and pyruvate kinase (PK) along with phosphoenolpyruvate, either singly or in conjunction, to the AdK reaction mixture led to its reactivation. The effect of PK but not of MK could be substituted by CyP and vice versa. Taken together, the results suggest that LdCyP-induced reactivation occurs due to conformational reorientation of AdK in a manner that decreases the affinity of the enzyme for ADP with consequent relief from the ADP-mediated aggregation. [ABSTRACT FROM AUTHOR]

Using inactive aggregates of adenosine kinase (AdK) from Leishmania donovani as the model substrate, we recently demonstrated that a cyclophilin (LdCyP) from the same source in an isomerase-independent fashion reactivated the enzyme in vitro by disaggregating its inactive oligomers [Chakraborty et al. (2002) J. Biol. Chem. 277, 47451-47460]. Besides disrupting preformed aggregates, LdCyP also prevents reaggregation of the newly formed active protein that is generated after productive refolding from its urea-denatured state. To investigate possible physiological implications of such phenomena, a unique expression system that simultaneously induces both AdK and LdCyP in naturally AdK-deficient Escherichia coli, was developed. Both in vitro and in vivo experiments revealed that oligomerization is an inherent property of this particular enzyme. In vivo protein cross-linking studies, activity determination analysis and Ado phosphorylation experiments carried out in cells coexpressing both the proteins unequivocally demonstrated that, similar to the phenomena observed in vitro, aggregates of the enzyme formed in vivo are able to interact with both LdCyP and its N-terminal truncated form (N22-88DEL LdCyP) in a crowded intracellular environment, resulting in aggregation prevention and reactivation of the enzyme. Our results indicate that the isomerase-independent chaperone function of LdCyP, detected in vitro, participates in vivo as well to keep aggregation-prone proteins in a monomeric state. Furthermore, analogous to yeast/bacterial two-hybrid systems, development of this simple coexpression system may help in the confirmation of interaction of two proteins under simulated in vivo conditions. [ABSTRACT FROM AUTHOR]

Leishmania has a remarkable ability to proliferate under widely fluctuating levels of essential nutrients, such as glucose. For this, the parasite is heavily dependent on its gluconeogenic machinery. One perplexing aspect of gluconeogenesis in Leishmania is the lack of the crucial gene for pyruvate carboxylase (PC). PC‐catalyzed conversion of pyruvate to oxaloacetate is a key entry point through which gluconeogenic amino acids are funneled into this pathway. The absence of PC in Leishmania thus raises question about the mechanism of pyruvate entry into the gluconeogenic route. In the present study, we report that this task is accomplished in Leishmania major through a novel functional partnership between its mitochondrial malic enzyme (LmME) and carbonic anhydrase 1 (LmCA1). Using a combination of pharmacological inhibition studies with genetic manipulation, we show that both of these enzymes are necessary for promoting gluconeogenesis and supporting parasite growth under glucose‐limiting conditions. Functional cross‐talk between LmME and LmCA1 was evident when it was observed that the growth retardation caused by inhibition of any one of these enzymes could be protected to a significant extent by overexpressing the other enzyme. We also found that, although LmCA1 exhibited constitutive expression, the LmME protein level was strongly upregulated under low glucose conditions. Notably, both LmME and LmCA1 were found to be important for survival of Leishmania amastigotes within host macrophages. Taken together, our results indicate that LmCA1 by virtue of its CO2 concentrating ability stimulates LmME‐catalyzed pyruvate carboxylation, thereby driving gluconeogenesis through the pyruvate–malate–oxaloacetate bypass pathway. Additionally, our study establishes LmCA1 and LmME as promising therapeutic targets. [ABSTRACT FROM AUTHOR]

We analyzed feasibility of pooling saliva samples for severe acute respiratory syndrome coronavirus 2 testing and found that sensitivity decreased according to pool size: 5 samples/pool, 7.4% reduction; 10 samples/pool, 11.1%; and 20 samples/pool, 14.8%. When virus prevalence is >2.6%, pools of 5 require fewer tests; when <0.6%, pools of 20 support screening strategies. [ABSTRACT FROM AUTHOR]

The expense of saliva collection devices designed to stabilize severe acute respiratory syndrome coronavirus 2 RNA is prohibitive to mass testing. However, virus RNA in nonsupplemented saliva is stable for extended periods and at elevated temperatures. Simple plastic tubes for saliva collection will make large-scale testing and continued surveillance easier. [ABSTRACT FROM AUTHOR]

Introduction: Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW. Methods and findings: We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV-2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P <.01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P <.01). Conclusions: In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms. [ABSTRACT FROM AUTHOR]

Background A positive urine culture often drives initiation of antimicrobials even in the absence of symptoms. Our objectives were to evaluate the knowledge and practice patterns related to ordering urine cultures in patients with indwelling urinary catheters. Methods We performed chart reviews of catheter-associated urinary tract infections (CAUTIs) at our academic health care system between October 1, 2015, and September 30, 2017, to assess practice patterns related to the assessment of potential CAUTIs. Following this, we surveyed physicians and nurses about indications for ordering urine cultures in catheterized patients between January 11, 2018, and April 17, 2018. The accuracy of these indications was assessed based on Infectious Diseases Society of America CAUTI and asymptomatic bacteriuria guidelines. Results On chart review, we identified 184 CAUTIs in 2 years. In 159 episodes (86%), urine cultures were ordered inappropriately. In 114 episodes (62%), CAUTI criteria were met by "pan-culturing" rather than symptom-directed testing. Twenty cases (11%) experienced partial or delayed management of other infections, drug adverse events, and Clostridioides difficile infections (CDIs). On our survey, we received 405 responses, for a response rate of 45.3%. Mean scores varied by occupation and level of training. Nurses were more likely than physicians to consider change in appearance (61% vs 23%; P <.05) and odor (74% vs 42%; P <.05) of urine as indications to order urine cultures. Conclusions Our data reveal specific knowledge gaps among physicians and nurses related to ordering urine cultures in catheterized patients. The practice of pan-culturing and inappropriate urine culture orders may contribute to overdiagnosis of surveillance CAUTIs, delay in diagnosis of alternative infections, and excess CDIs. [ABSTRACT FROM AUTHOR]

A series of peptides (1‐3) containing m‐nitrocinnamic acid, α‐aminoisobutyric acid (Aib) and L‐leucine has been synthesized and their antileishmanial propensities have been studied. The compound 1 was synthesized by condensation reaction of 3‐nitrobenzaldehyde and malonic acid. The compound 1 forms duplex by intermolecular hydrogen bonding interactions in solid state and finally self‐assemble to form supramolecular helix through C‐H⋅⋅⋅O hydrogen bonds. The peptide 2 shows antiparallel sheet‐like assembly through intermolecular N‐H⋅⋅⋅O and C‐H⋅⋅⋅O hydrogen bonding interactions. The peptide 3 adopts extended conformation and self‐assemble to form bowl‐like morphology. Moreover, the peptide 3 exhibits significant growth inhibition property on Leishmania major promastigotes with an IC50 value of 13 μg/ml. But compound 1 and peptide 2 have IC50 values 100 μg/ml and 41 μg/ml respectively. The higher lipophilicity of peptide 3 may increase the chances of reaching this intracellular parasite. Thus peptide 3 shows selective toxicity towards Leishmania (IC50=13 μg/ml) and compared to several existing standard antileishmanial drugs like pentastam (IC50 > 64 μg/ml), sodium stibogluconate (IC50 > 64 μg/ml) or ketoconazole (IC50=72 μg/ml), peptide 3 shows at least 2–6 times higher potency. Antileishmanial property: Lipophilic peptide containing m‐nitrocinnamic acid, α‐aminoisobutyric acid and L‐leucine shows selective toxicity towards Leishmania major parasite (IC50=13 μg/ml) and compared to several existing standard antileishmanial drugs like pentastam (IC50 > 64 μg/ml), sodium stibogluconate (IC50 > 64 μg/ml) or ketoconazole (IC50=72 μg/ml), shows at least 2–6 times higher potency. Also, the peptide does not have significant harmful effect on macrophage cell line. [ABSTRACT FROM AUTHOR]

Abstract: The dipeptides 1–4 with a triazole containing synthetic amino acid and Leu/ Phe/ Val/ Gly have been designed and synthesized as a potent antileishmanial agent. The 1‐(2‐Amino‐phenyl)‐1H‐[1, 2,3] triazole‐4‐carboxylic acid was synthesized using click chemistry approach. From X‐ray crystallography, the peptide 1 containing a Leu residue at C‐terminus adopts kink like structure but there is no intramolecular hydrogen bond. So, the hydrogen bonding sites are free and allowed for intermolecular interaction with the guests. The phenylalanine analogue 2 where the phenyl and triazole rings are perpendicular to each other also form supramolecular column‐like structure through π‐π stacking interaction. The incorporation of a triazole containing synthetic amino acid at the N‐terminus enhances its anti‐parasites activity. The properties such as lipophilicity and cytotoxicity, are relevant factors for the design of new antileishmanial agent. IC50 value were calculated for dipeptides 1–4 using normal growth inhibition strategy. For dipeptide 1, IC50 value is 11μg/ml and the Phe containing dipeptide 2 exhibits IC50 21.17μg/ml on Leishmania major promastigotes. But the Val and Gly containing dipeptides 3 and 4 have IC50 values 138.23 μg/ml and 21.75 μg/ml respectively. The higher lipophilicity of dipeptide 1 is likely to improve the chances of reaching this intracellular parasite. The experimental result show that the triazole‐based dipeptide 1 is promising as antileishmanial agent. [ABSTRACT FROM AUTHOR]

Leishmania parasites have evolved to endure the acidic phagolysosomal environment within host macrophages. How Leishmania cells maintain near-neutral intracellular pH and proliferate in such a proton-rich mileu remains poorly understood. We report here that, in order to thrive in acidic conditions, Leishmania major relies on a cytosolic and a cell surface carbonic anhydrase, LmCA1 and LmCA2, respectively. Upon exposure to acidic medium, the intracellular pH of the LmCA1+/-, LmCA2+/- and LmCA1+/-:LmCA2+/- mutant strains dropped by varying extents that led to cell cycle delay, growth retardation and morphological abnormalities. Intracellular acidosis and growth defects of the mutant strains could be reverted by genetic complementation or supplementation with bicarbonate. When J774A.1 macrophages were infected with the mutant strains, they exhibited much lower intracellular parasite burdens than their wild-type counterparts. However, these differences in intracellular parasite burden between the wild-type and mutant strains were abrogated if, before infection, the macrophages were treated with chloroquine to alkalize their phagolysosomes. Taken together, our results demonstrate that haploinsufficiency of LmCA1 and/or LmCA2 renders the parasite acid-susceptible, thereby unravelling a carbonic anhydrase-mediated pH homeostatic circuit in Leishmania cells. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-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 β-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. [Display omitted] • β-Glucuronidase (CG2135) loss of function in Drosophila perturbs adipogenesis and leads to a lean phenotype. • Impaired autophagosome-lysosome fusion in the CG2135−/− larval fat tissue results in aberrant accumulation of autophagosomes. • Stimulation of mTOR in the CG2135−/− larvae with glucose and 3-BDO rescued defective autophagy and adipose deficiency. [ABSTRACT FROM AUTHOR]

New prophylactic approaches are needed to control infection with the Gram-positive bacterium Staphylococcus aureus, which is a major cause of nosocomial and community-acquired infections. To develop these, greater understanding of protective immunity against S. aureus infection is needed. Human immunity to extracellular Gram-positive bacterial pathogens is primarily mediated by opsonic killing (OPK) via antibodies specific for surface polysaccharides. S. aureus expresses two such antigens, capsular polysaccharide (CP) and poly-N-acetyl glucosamine (PNAG). Here, we have shown that immunization-induced polyclonal animal antisera and monoclonal antibodies specific for either CP or PNAG antigens have excellent in vitro OPK activity in human blood but that when mixed together they show potent interference in OPK activity. In addition, reductions in antibody binding to the bacterial surface, complement deposition, and passive protection were seen in two mouse models of S. aureus infection. Electron microscopy, isothermal calorimetry, and surface plasmon resonance indicated that antibodies to CP and PNAG bound together via an apparent idiotype-anti-idiotype interaction. This interaction was also found in sera from humans with S. aureus bacteremia. These findings suggest that the lack of effective immunity to S. aureus infections in humans could be due, in part, to interference in OPK when antibodies to CP and PNAG antigens are both present. This information could be used to better design S. aureus vaccine components. [ABSTRACT FROM AUTHOR]

Invasive disease following methicillin-resistant Staphylococcus aureus (MRSA) detection is common, regardless of whether initial detection involves colonization or infection. We assessed the genetic relatedness of isolates obtained ⩾2 weeks apart representing either repeated infections or colonization-infection sets to determine if infections are likely to be caused by previously harbored strains. We found that MRSA infection following initial colonization or infection is caused by the same strain in most cases, suggesting that a single successful attempt at decolonization may prevent the majority of later infection. [ABSTRACT FROM AUTHOR]

Cyclophilins (CyPs), by interacting with a variety of proteins, often modulate their biological activities and thus have been implicated in several cellular functions. However, mechanisms that determine such interactions are poorly understood. We earlier reported that an endoplasmic reticulum (ER)-located cyclophilin (LdCyP) from the purine auxotrophic parasitic protozoan Leishmania donovani reactivated its adenosine kinase (AdK). The AdK-reactivating property of LdCyP was however abolished at high ionic strength but not by nonionic detergents. Modeling of LdCyP, based on its crystal structure solved at 1.97 Å resolution, revealed several solvent-exposed hydrophobic and charged residues. Mutagenesis of several of such solvent-exposed residues was performed and their corresponding activities with regard to their (i) AdK reactivation property, (ii) ability to form complex with the enzyme, (iii) capacity to induce red shift in the intrinsic tryptophan fluorescence maxima of AdK, and (iv) efficiency to withdraw the ADP inhibition from the AdK-mediated reaction were compared to the wild-type protein. Results indicated that while the replacement of R147 with either A or D severely impaired all of the above characteristics displayed by the wild-type LdCyP, the effect of mutating K114 and K153 was although relatively less but nevertheless noticeable. Alteration of other exposed hydrophobic and charged residues apparently did not have any discernible effect. Under the condition of cellular stress, the ER-located LdCyP is released into the cytoplasm with concomitant increase both in the specific activity of the cytosol-resident AdK and the uptake of radiolabeled Ado into the cells. These experiments, besides demonstrating the importance of the positive charge, identified R147 as the most crucial residue in the LdCyP—AdK interaction and provide evidence for the stress-induced retrograde translocation of LdCyP from the ER to the cytoplasm. A possible implication of this interaction in the life cycle of the parasite is proposed. [ABSTRACT FROM AUTHOR]

Background. Serial interventions are often used to reduce the risk of health care-associated methicillin-resistant Staphylococcus aureus (MRSA) infections. To our knowledge, the relative impact of these interventions has not previously been ascertained. Methods. We conducted a retrospective study of 4 major infection control interventions using an interrupted time series design to evaluate their impact on MRSA bacteremia in an 800-bed hospital with 8 intensive care units (ICUs). Interventions were introduced 1 at a time during a 9-year period and involved the promotion of compliance with maximal sterile barrier precautions during central venous catheter placement, the institution of alcohol-based hand rubs for hand disinfection, the introduction of a hand hygiene campaign, and the institution of routine nares surveillance cultures for MRSA in all ICUs for patients on ICU admission and weekly thereafter while in the ICU. Positive cultures resulted in the initiation of contact isolation precautions. Using segmented regression analyses, we evaluated changes in monthly incidence and prevalence of MRSA bacteremia from their predicted values. Methicillin-susceptible Staphylococcus aureus bacteremia was monitored as a control. Results. Routine surveillance cultures and subsequent contact isolation precautions resulted in substantial reductions in MRSA bacteremia in both ICUs and non-ICUs. In 16 months, the incidence density of MRSA bacteremia decreased by 75% in ICUs (P=.007) and by 40% in non-ICUs (P=.008), leading to a 67% hospital-wide reduction in the incidence density of MRSA bacteremia (P=.002). Methicillin-susceptible S. aureus bacteremia rates remained stable during this time. The other interventions were not associated with a statistically significant change in MRSA bacteremia. Conclusions. Routine surveillance for MRSA in ICUs allowed earlier initiation of contact isolation precautions and was associated with large and statistically significant reductions in the incidence of MRSA bacteremia in the ICUs and hospital wide. In contrast, no similar decrease was attributable to the other infection control interventions. [ABSTRACT FROM AUTHOR]

Rationale: Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear. Objective: We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801). Methods: In adult, male CFW mice, sensitization was induced by either ten daily injections of D-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined. Results: The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization. Conclusions: These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be. [ABSTRACT FROM AUTHOR]