Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) ...domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.
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•Intermolecular β sheet hydrogen bonding and cation-π interactions drive FUS demixing•Cation-π interactions form between C-terminal arginines and N-terminal tyrosines•Cation-π strength is regulated by arginine methylation and interacting proteins•FUS hypomethylation in FTLD induces FUS gelation and impairs RNP granule function
Phase transition of the RNA-binding protein FUS is mediated by cation-π interactions between C-terminal arginines and N-terminal tyrosines and is modulated by arginine methlylation.
OBJECTIVETo characterize trends in outpatient antibiotic prescriptions in the United StatesDESIGNRetrospective ecological and temporal trend study evaluating outpatient antibiotic prescriptions from ...2013 to 2015SETTINGNational administrative claims data from a pharmacy benefits manager PARTICIPANTS. Prescription pharmacy beneficiaries from Express Scripts Holding CompanyMEASUREMENTSAnnual and seasonal percent change in antibiotic prescriptionsRESULTSApproximately 98 million outpatient antibiotic prescriptions were filled by 39 million insurance beneficiaries during the 3-year study period. The most commonly prescribed antibiotics were azithromycin, amoxicillin, amoxicillin/clavulanate, ciprofloxacin, and cephalexin. No significant changes in individual or overall annual antibiotic prescribing rates were found during the study period. Significant seasonal variation was observed, with antibiotics being 42% more likely to be prescribed during February than September (peak-to-trough ratio PTTR, 1.42; 95% confidence interval CI, 1.39-1.61). Similar seasonal trends were found for azithromycin (PTTR, 2.46; 95% CI, 2.44-3.47), amoxicillin (PTTR, 1.52; 95% CI, 1.42-1.89), and amoxicillin/clavulanate (PTTR, 1.78; 95% CI, 1.68-2.29).CONCLUSIONSThis study demonstrates that annual national outpatient antibiotic prescribing practices remained unchanged during our study period. Furthermore, seasonal peaks in antibiotics generally used to treat viral upper respiratory tract infections remained unchanged during cold and influenza season. These results suggest that inappropriate prescribing of antibiotics remains widespread, despite the concurrent release of several guideline-based best practices intended to reduce inappropriate antibiotic consumption; however, further research linking national outpatient antibiotic prescriptions to associated medical conditions is needed to confirm these findings.Infect Control Hosp Epidemiol 2018;39:584-589.
Both targeted decolonization and universal decolonization of patients in intensive care units (ICUs) are candidate strategies to prevent health care-associated infections, particularly those caused ...by methicillin-resistant Staphylococcus aureus (MRSA).
We conducted a pragmatic, cluster-randomized trial. Hospitals were randomly assigned to one of three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carriers); and group 3, universal decolonization (i.e., no screening, and decolonization of all patients). Proportional-hazards models were used to assess differences in infection reductions across the study groups, with clustering according to hospital.
A total of 43 hospitals (including 74 ICUs and 74,256 patients during the intervention period) underwent randomization. In the intervention period versus the baseline period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screening and isolation (crude rate, 3.2 vs. 3.4 isolates per 1000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1000 days), and 0.63 for universal decolonization (2.1 vs. 3.4 isolates per 1000 days) (P=0.01 for test of all groups being equal). In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1000 days), 0.78 (3.7 vs. 4.8 infections per 1000 days), and 0.56 (3.6 vs. 6.1 infections per 1000 days), respectively (P<0.001 for test of all groups being equal). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isolation. One bloodstream infection was prevented per 54 patients who underwent decolonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not significant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine.
In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infection from any pathogen. (Funded by the Agency for Healthcare Research and the Centers for Disease Control and Prevention; REDUCE MRSA ClinicalTrials.gov number, NCT00980980).
Background.Previous studies of risk factors for Clostridium difficile—associated disease (CDAD) have been limited by small sample sizes and case-control study designs. Many of these studies were ...performed during outbreaks of CDAD. Colonization pressure and use of fluoroquinolones, vancomycin, and gastric acid suppressors have not been fully evaluated as risk factors for CDAD. The purpose of this study was to determine risk factors for endemic CDAD, including CDAD pressure, a modified version of colonization pressure. Methods.We performed a retrospective cohort study of 36,086 patients admitted to Barnes-Jewish Hospital (St. Louis, MO) during the period from 1 January 2003 through 31 December 2003. Administrative, laboratory, and pharmacy data were collected from electronic hospital databases. Colonization pressure was measured through a surrogate variable (i.e., CDAD pressure). Multivariable pooled logistic regression models were used to evaluate independent risk factors for CDAD. Results.The analysis included 382 CDAD case patient admissions and 35,704 non—case patient admissions. Significant independent risk factors for CDAD included increasing age, admission(s) in the previous 60 days, hypoalbuminemia, leukemia and/or lymphoma, mechanical ventilation, and receipt of antimotility drugs, histamine-2 blockers, proton pump inhibitors, intravenous vancomycin, fluoroquinolones, and first-, third-, or fourth-generation cephalosporins. Increasing CDAD pressure was a strong risk factor for CDAD (for a CDAD pressure >1.4, the odds ratio was 4.0; 95% confidence interval, 2.9–5.6). Receipt of metronidazole was protective against CDAD (odds ratio, 0.5; 95% confidence interval, 0.3–0.6). Conclusions.This study identified the previously underrecognized CDAD risk factors of CDAD pressure and vancomycin. More studies are needed to evaluate the relationship between CDAD, these risk factors, and use of gastric acid suppressors and fluoroquinolones.
Background The National Healthcare Safety Network (NHSN) classifies surgical procedures into 40 categories. The objective of this study was to determine surgical site infection (SSI) incidence for ...clinically defined subgroups within 5 heterogeneous NHSN surgery categories. Methods This is a retrospective cohort study using the longitudinal State Inpatient Database. We identified 5 groups of surgical procedures (amputation; bile duct, liver or pancreas BILI; breast; colon; and hernia) using ICD-9-CM procedure codes in community hospitals in California, Florida, and New York from January 2009-September 2011 in persons aged ≥18 years. Each of these 5 categories was classified to more specific surgical procedures within the group. The 90-day SSI rates were calculated using ICD-9-CM diagnosis codes. Results There were 62,901 amputation surgeries, 33,358 BILI surgeries, 72,058 breast surgeries, 125,689 colon surgeries, and 85,745 hernia surgeries in 349,298 people. The 90-day SSI rates varied significantly within each of the 5 subgroups. Within the BILI category, bile duct, pancreas, and laparoscopic liver procedures had SSI rates of 7.2%, 17.2%, and 2.2%, respectively ( P < .0001 for each) compared with open liver procedures (11.1% SSI). Conclusion The 90-day SSI rates varied widely within certain NHSN categories. Risk adjustment for specific surgery type is needed to make valid comparisons between hospitals.
Background.. Herpes zoster occurs more commonly in patients taking immunosuppressive medications, although the risk associated with different medications is poorly understood. Methods.. We conducted ...a retrospective cohort study involving 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster and herpes zoster–free survival. Chart review was performed to validate the diagnosis of herpes zoster. Results.. The incidence of herpes zoster was 9.96 episodes per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (P<.001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor–α antagonists, etanercept (hazard ratio, 0.62) and adalimumab (hazard ratio, 0.53) were associated with a lower risk of herpes zoster. There was excellent agreement between the International Classification of Diseases, Version 9, Clinical Modification diagnosis of herpes zoster and diagnosis by chart review (k=0.92). Conclusions.. Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs' national administrative databases can be used to study rare adverse drug events.
Surgical site infections are not uncommon following spinal operations, and they can be associated with serious morbidity, mortality, and increased resource utilization. The accurate identification of ...risk factors is essential to develop strategies to prevent these potentially devastating infections. We conducted a case-control study to determine independent risk factors for surgical site infection following orthopaedic spinal operations.
We performed a retrospective case-control study of patients who had had an orthopaedic spinal operation performed at a university-affiliated tertiary-care hospital from 1998 to 2002. Forty-six patients with a superficial, deep, or organ-space surgical site infection were identified and compared with 227 uninfected control patients. Risk factors for surgical site infection were determined with univariate analyses and multivariate logistic regression.
The overall rate of spinal surgical site infection during the five years of the study was 2.0% (forty-six of 2316). Univariate analyses showed serum glucose levels, preoperatively and within five days after the operation, to be significantly higher in patients in whom surgical site infection developed than in uninfected control patients. Independent risk factors for surgical site infection that were identified by multivariate analysis were diabetes (odds ratio = 3.5, 95% confidence interval = 1.2, 10.0), suboptimal timing of prophylactic antibiotic therapy (odds ratio = 3.4, 95% confidence interval = 1.5, 7.9), a preoperative serum glucose level of >125 mg/dL (>6.9 mmol/L) or a postoperative serum glucose level of >200 mg/dL (>11.1 mmol/L) (odds ratio = 3.3, 95% confidence interval = 1.4, 7.5), obesity (odds ratio = 2.2, 95% confidence interval = 1.1, 4.7), and two or more surgical residents participating in the operative procedure (odds ratio = 2.2, 95% confidence interval = 1.0, 4.7). A decreased risk of surgical site infection was associated with operations involving the cervical spine (odds ratio = 0.3, 95% confidence interval = 0.1, 0.6).
Diabetes was associated with the highest independent risk of spinal surgical site infection, and an elevated preoperative or postoperative serum glucose level was also independently associated with an increased risk of surgical site infection. The role of hyperglycemia as a risk factor for surgical site infection in patients not previously diagnosed with diabetes should be investigated further. Administration of prophylactic antibiotics within one hour before the operation and increasing the antibiotic dosage to adjust for obesity are also important strategies to decrease the risk of surgical site infection after spinal operations.
OBJECTIVE To evaluate healthcare worker (HCW) risk of self-contamination when donning and doffing personal protective equipment (PPE) using fluorescence and MS2 bacteriophage. DESIGN Prospective ...pilot study. SETTING Tertiary-care hospital. PARTICIPANTS A total of 36 HCWs were included in this study: 18 donned/doffed contact precaution (CP) PPE and 18 donned/doffed Ebola virus disease (EVD) PPE. INTERVENTIONS HCWs donned PPE according to standard protocols. Fluorescent liquid and MS2 bacteriophage were applied to HCWs. HCWs then doffed their PPE. After doffing, HCWs were scanned for fluorescence and swabbed for MS2. MS2 detection was performed using reverse transcriptase PCR. The donning and doffing processes were videotaped, and protocol deviations were recorded. RESULTS Overall, 27% of EVD PPE HCWs and 50% of CP PPE HCWs made ≥1 protocol deviation while donning, and 100% of EVD PPE HCWs and 67% of CP PPE HCWs made ≥1 protocol deviation while doffing (P=.02). The median number of doffing protocol deviations among EVD PPE HCWs was 4, versus 1 among CP PPE HCWs. Also, 15 EVD PPE protocol deviations were committed by doffing assistants and/or trained observers. Fluorescence was detected on 8 EVD PPE HCWs (44%) and 5 CP PPE HCWs (28%), most commonly on hands. MS2 was recovered from 2 EVD PPE HCWs (11%) and 3 CP PPE HCWs (17%). CONCLUSIONS Protocol deviations were common during both EVD and CP PPE doffing, and some deviations during EVD PPE doffing were committed by the HCW doffing assistant and/or the trained observer. Self-contamination was common. PPE donning/doffing are complex and deserve additional study. Infect Control Hosp Epidemiol 2017;38:1077-1083.
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