Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells.

Over-consumption of fructose in adults and children has been linked to increased risk of non-alcoholic fatty liver disease (NAFLD). Recent studies have highlighted the effect of fructose on liver inflammation, fibrosis, and immune cell activation. However, little work summarizes the direct impact of fructose on macrophage infiltration, phenotype, and function within the liver. We demonstrate that chronic fructose diet decreased Kupffer cell populations while increasing transitioning monocytes. In addition, fructose increased fibrotic gene expression of collagen 1 alpha 1 (Col1a1) and tissue metallopeptidase inhibitor 1 (Timp1) as well as inflammatory gene expression of tumor necrosis factor alpha (Tnfa) and expression of transmembrane glycoprotein NMB (Gpnmb) in liver tissue compared to glucose and control diets. Single cell RNA sequencing (scRNAseq) revealed fructose elevated expression of matrix metallopeptidase 12 (Mmp12), interleukin 1 receptor antagonist (Il1rn), and radical S-adenosyl methionine domain (Rsad2) in liver and hepatic macrophages. In vitro studies using IMKC and J774.1 cells demonstrated decreased viability when exposed to fructose. Additionally, fructose increased Gpnmb, Tnfa, Mmp12, Il1rn, and Rsad2 in unpolarized IMKC. By mass spectrometry, C13 fructose tracing detected fructose metabolites in glycolysis and the pentose phosphate pathway (PPP). Inhibition of the PPP further increased fructose induced Il6, Gpnmb, Mmp12, Il1rn, and Rsad2 in nonpolarized IMKC. Taken together, fructose decreases cell viability while upregulating resolution and anti-inflammatory associated genes in Kupffer cells.

Assessment and Training of Perceptual-Motor Function: Performance of College Wrestlers Associated with History of Concussion.

Concussion may affect sport performance capabilities related to the visual perception of environmental events, rapid decision-making, and the generation of effective movement responses. Immersive virtual reality (VR) offers a means to quantify, and potentially enhance, the speed, accuracy, and consistency of responses generated by integrated neural processes. A cohort of 24 NCAA Division I male wrestlers completed VR assessments before and after a 3-week VR training program designed to improve their perceptual-motor performance. Prior to training, the intra-individual variability (IIV) among 40 successive task trials for perceptual latency (i.e., time elapsed between visual stimulus presentation and the initiation of movement response) demonstrated strong discrimination between 10 wrestlers who self-reported a history of concussion from 14 wrestlers who denied ever having sustained a concussion (Area Under Curve ≥ 0.750 for neck, arm, and step movements). Natural log transformation improved the distribution normality of the IIV values for both perceptual latency and response time (i.e., time elapsed between visual stimulus presentation and the completion of movement response). The repeated measures ANOVA results demonstrated statistically significant (p < 0.05) pre- and post-training differences between groups for the IIV in perceptual latency and the IIV in response time for neck, arm, and step movements. Five of the six IIV metrics demonstrated a statistically significant magnitude of change for both groups, with large effect sizes. We conclude that a VR assessment can detect impairments in perceptual-motor performance among college wrestlers with a history of concussion. Although significant post-training group differences were evident, VR training can yield significant performance improvements in both groups.

Myeloid cell MHC I expression drives CD8+ T cell activation in nonalcoholic steatohepatitis.

Background & aims: Activated CD8+ T cells are elevated in Nonalcoholic steatohepatitis (NASH) and are important for driving fibrosis and inflammation. Despite this, mechanisms of CD8+ T cell activation in NASH are largely limited. Specific CD8+ T cell subsets may become activated through metabolic signals or cytokines. However, studies in NASH have not evaluated the impact of antigen presentation or the involvement of specific antigens. Therefore, we determined if activated CD8+ T cells are dependent on MHC class I expression in NASH to regulate fibrosis and inflammation. Methods: We used H2Kb and H2Db deficient (MHC I KO), Kb transgenic mice, and myeloid cell Kb deficient mice (LysM Kb KO) to investigate how MHC class I impacts CD8+ T cell function and NASH. Flow cytometry, gene expression, and histology were used to examine hepatic inflammation and fibrosis. The hepatic class I immunopeptidome was evaluated by mass spectrometry. Results: In NASH, MHC class I isoform H2Kb was upregulated in myeloid cells. MHC I KO demonstrated protective effects against NASH-induced inflammation and fibrosis. Kb mice exhibited increased fibrosis in the absence of H2Db while LysM Kb KO mice showed protection against fibrosis but not inflammation. H2Kb restricted peptides identified a unique NASH peptide Ncf2 capable of CD8+ T cell activation in vitro. The Ncf2 peptide was not detected during fibrosis resolution. Conclusion: These results suggest that activated hepatic CD8+ T cells are dependent on myeloid cell MHC class I expression in diet induced NASH to promote inflammation and fibrosis. Additionally, our studies suggest a role of NADPH oxidase in the production of Ncf2 peptide generation.

An appraisal of the contextual drivers of successful antimicrobial stewardship implementation in Nigerian health care facilities.

OBJECTIVES: Antimicrobial resistance (AMR) is a consequence of inappropriate actions, including irrational antimicrobial prescribing and use. Antimicrobial resistance remains an emergent and significant public health threat, particularly in low and middle-income countries (LMICs), including Nigeria. Optimizing antimicrobial (AM) use through functional hospital antimicrobial stewardship (AMS) programs is one of the strategies to control the spread of AMR. Literature is replete with evidence, but few studies examined the contextual factors limiting AMS functionality at the facility levels. This study explored the intrinsic contextual factors shaping AMS practice at the three-tiered levels of care. METHODS: This was a qualitative case study with a purposeful sample size of 30 participants drawn from two primary, two secondary, and two tertiary health facilities in Nigeria. Data were coded and categorized for thematic analysis. RESULTS: Emergent themes include lack of AMS programs, inadequate guidelines, lack of modern equipment and incorrect diagnosis, absence of continuous medical education, imbalance of power among professionals, and pervasive external influence of pharmaceutical marketing companies. These findings demonstrate that the AMS program is lacking or poorly implemented at the three-tiered level of care. CONCLUSION: We recommended that health facilities establish AMS programs in line with the World Health Organization's stepwise approach. These challenges, if addressed, will promote the successful performance of the AMS program, contributing to rational AM use at all levels of care. Since primary health centres constitute 85.4% of all health facilities, customizing the AMS core elements at this level will contribute to achieving the goals of universal health coverage.

Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents.

Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area. We performed genome, and drug-resistance analysis of C. auris isolates from a patient who underwent multi-visceral transplantation. Whole-genome comparisons of 19 isolates, collected over 72 days, revealed closed similarity (Average Nucleotide Identity > 0.9996; Aligned Percentage > 0.9764) and a distinct subcluster of NY C. auris South Asia Clade I. All isolates had azole-linked resistance in ERG11(K143R) and CDR1(V704L). Echinocandin resistance first appeared with FKS1(S639Y) mutation and then a unique FKS1(F635C) mutation. Flucytosine-resistant isolates had mutations in FCY1, FUR1, and ADE17. Two pan-drug-resistant C. auris isolates had uracil phosphoribosyltransferase deletion (FUR1[1Δ33]) and the elimination of FUR1 expression, confirmed by a qPCR test developed in this study. Besides ERG11 mutations, four amphotericin B-resistant isolates showed no distinct nonsynonymous variants suggesting unknown genetic elements driving the resistance. Pan-drug-resistant C. auris isolates were not susceptible to two-drug antifungal combinations tested by checkerboard, Etest, and time-kill methods. The fungal population pattern, discerned from SNP phylogenetic analysis, was consistent with in-hospital or inpatient evolution of C. auris isolates circulating locally and not indicative of a recent introduction from elsewhere. The emergence of pan-drug-resistance to four major classes of antifungals in C. auris is alarming. Patients at high risk for drug-resistant C. auris might require novel therapeutic strategies and targeted pre-and/or posttransplant surveillance.

Detecting Language Associated With Home Healthcare Patient's Risk for Hospitalization and Emergency Department Visit.

BACKGROUND: About one in five patients receiving home healthcare (HHC) services are hospitalized or visit an emergency department (ED) during a home care episode. Early identification of at-risk patients can prevent these negative outcomes. However, risk indicators, including language in clinical notes that indicate a concern about a patient, are often hidden in narrative documentation throughout their HHC episode. OBJECTIVE: The aim of the study was to develop an automated natural language processing (NLP) algorithm to identify concerning language indicative of HHC patients' risk of hospitalizations or ED visits. METHODS: This study used the Omaha System-a standardized nursing terminology that describes problems/signs/symptoms that can occur in the community setting. First, five HHC experts iteratively reviewed the Omaha System and identified concerning concepts indicative of HHC patients' risk of hospitalizations or ED visits. Next, we developed and tested an NLP algorithm to identify these concerning concepts in HHC clinical notes automatically. The resulting NLP algorithm was applied on a large subset of narrative notes (2.3 million notes) documented for 66,317 unique patients ( n = 87,966 HHC episodes) admitted to one large HHC agency in the Northeast United States between 2015 and 2017. RESULTS: A total of 160 Omaha System signs/symptoms were identified as concerning concepts for hospitalizations or ED visits in HHC. These signs/symptoms belong to 31 of the 42 available Omaha System problems. Overall, the NLP algorithm showed good performance in identifying concerning concepts in clinical notes. More than 18% of clinical notes were detected as having at least one concerning concept, and more than 90% of HHC episodes included at least one Omaha System problem. The most frequently documented concerning concepts were pain, followed by issues related to neuromusculoskeletal function, circulation, mental health, and communicable/infectious conditions. CONCLUSION: Our findings suggest that concerning problems or symptoms that could increase the risk of hospitalization or ED visit were frequently documented in narrative clinical notes. NLP can automatically extract information from narrative clinical notes to improve our understanding of care needs in HHC. Next steps are to evaluate which concerning concepts identified in clinical notes predict hospitalization or ED visit.

Beneficial effects of eicosapentaenoic acid on the metabolic profile of obese female mice entails upregulation of HEPEs and increased abundance of enteric Akkermansia muciniphila.

Eicosapentaenoic acid (EPA) ethyl esters are of interest given their clinical approval for lowering circulating triglycerides and cardiometabolic disease risk. EPA ethyl esters prevent metabolic complications driven by a high fat diet in male mice; however, their impact on female mice is less studied. Herein, we first investigated how EPA influences the metabolic profile of female C57BL/6J mice consuming a high fat diet. EPA lowered murine fat mass accumulation, potentially through increased biosynthesis of 8-hydroxyeicosapentaenoic acid (HEPE), as revealed by mass spectrometry and cell culture studies. EPA also reversed the effects of a high fat diet on circulating levels of insulin, glucose, and select inflammatory/metabolic markers. Next, we studied if the improved metabolic profile of obese mice consuming EPA was associated with a reduction in the abundance of key gut Gram-negative bacteria that contribute toward impaired glucose metabolism. Using fecal 16S-ribosomal RNA gene sequencing, we found EPA restructured the gut microbiota in a time-dependent manner but did not lower the levels of key Gram-negative bacteria. Interestingly, EPA robustly increased the abundance of the Gram-negative Akkermansia muciniphila, which controls glucose homeostasis. Finally, predictive functional profiling of microbial communities revealed EPA-mediated reversal of high fat diet-associated changes in a wide range of genes related to pathways such as Th-17 cell differentiation and PI3K-Akt signaling. Collectively, these results show that EPA ethyl esters prevent some of the deleterious effects of a high fat diet in female mice, which may be mediated mechanistically through 8-HEPE and the upregulation of intestinal Akkermansia muciniphila.

Exploring prevalence of wound infections and related patient characteristics in homecare using natural language processing.

We aimed to create and validate a natural language processing algorithm to extract wound infection-related information from nursing notes. We also estimated wound infection prevalence in homecare settings and described related patient characteristics. In this retrospective cohort study, a natural language processing algorithm was developed and validated against a gold standard testing set. Cases with wound infection were identified using the algorithm and linked to Outcome and Assessment Information Set data to identify related patient characteristics. The final version of the natural language processing vocabulary contained 3914 terms and expressions related to the presence of wound infection. The natural language processing algorithm achieved overall good performance (F-measure = 0.88). The presence of wound infection was documented for 1.03% (n = 602) of patients without wounds, for 5.95% (n = 3232) of patients with wounds, and 19.19% (n = 152) of patients with wound-related hospitalisation or emergency department visits. Diabetes, peripheral vascular disease, and skin ulcer were significantly associated with wound infection among homecare patients. Our findings suggest that nurses frequently document wound infection-related information. The use of natural language processing demonstrated that valuable information can be extracted from nursing notes which can be used to improve our understanding of the care needs of people receiving homecare. By linking findings from clinical nursing notes with additional structured data, we can analyse related patients' characteristics and use them to develop a tailored intervention that may potentially lead to reduced wound infection-related hospitalizations.

Individual, social, and environmental factors for infection risk among home healthcare patients: A multi-method study.

There has been limited research into the individual, social, and environmental factors for infection risk among patients in the home healthcare (HHC) setting, where the infection is a leading cause of hospitalisation. The aims of this study were to (1) explore nurse perceptions of individual, social, and environmental factors for infection risk among HHC patients; and (2) identify the frequency of environmental barriers to infection prevention and control in HHC. Data were collected in 2017-2018 and included qualitative interviews with HHC nurses (n = 50) and structured observations of nurse visits to patients' homes (n = 400). Thematic analyses of interviews with nurses suggested they perceived infection risk among patients as being influenced by knowledge of and attitudes towards infection prevention and engagement in hygiene practices, receipt of support from informal caregivers and nurse interventions aimed at cultivating infection control knowledge and practices, and the home environment. Statistical analyses of observation checklists revealed nurses encountered an average of 1.7 environmental barriers upon each home visit. Frequent environmental barriers observed during visits to HHC patients included clutter (39.5%), poor lighting (38.8%), dirtiness (28.5%), and pets (17.2%). Additional research is needed to clarify inter-relationships among these factors and identify strategies for addressing each as part of a comprehensive infection control program in HHC.

Identifying Urinary Tract Infection-Related Information in Home Care Nursing Notes.

OBJECTIVES: Urinary tract infection (UTI) is common in home care but not easily captured with standard assessment. This study aimed to examine the value of nursing notes in detecting UTI signs and symptoms in home care. DESIGN: The study developed a natural language processing (NLP) algorithm to automatically identify UTI-related information in nursing notes. SETTING AND PARTICIPANTS: Home care visit notes (n = 1,149,586) and care coordination notes (n = 1,461,171) for 89,459 patients treated in the largest nonprofit home care agency in the United States during 2014. MEASURES: We generated 6 categories of UTI-related information from literature and used the Unified Medical Language System (UMLS) to identify a preliminary list of terms. The NLP algorithm was tested on a gold standard set of 300 clinical notes annotated by clinical experts. We used structured Outcome and Assessment Information Set data to extract the frequency of UTI-related emergency department (ED) visits or hospitalizations and explored time-patterns in documentation of UTI-related information. RESULTS: The NLP system achieved very good overall performance (F measure = 0.9, 95% CI: 0.87-0.93) based on the test results obtained by using the notes for patients admitted to the ED or hospital due to UTI. UTI-related information was significantly more prevalent (P < .01 for all the tests) in home care episodes with UTI-related ED admission or hospitalization vs the general patient population; 81% of home care episodes with UTI-related hospitalization or ED admission had at least 1 category of UTI-related information vs 21.6% among episodes without UTI-related hospitalization or ED admission. Frequency of UTI-related information documentation increased in advance of UTI-related hospitalization or ED admission, peaking within a few days before the event. CONCLUSIONS AND IMPLICATIONS: Information in nursing notes is often overlooked by stakeholders and not integrated into predictive modeling for decision-making support, but our findings highlight their value in early risk identification and care guidance. Health care administrators should consider using NLP to extract clinical data from nursing notes to improve early detection and treatment, which may lead to quality improvement and cost reduction.

Observation of Hand Hygiene Practices in Home Health Care.

OBJECTIVE: To describe nurse hand hygiene practices in the home health care (HHC) setting, nurse adherence to hand hygiene guidelines, and factors associated with hand hygiene opportunities during home care visits. DESIGN: Observational study of nurse hand hygiene practices. SETTING: and Participants: Licensed practical/vocational and registered nurses were observed in the homes of patients being served by a large nonprofit HHC agency. METHODS: Two researchers observed 400 home care visits conducted by 50 nurses. The World Health Organization's "5 Moments for Hand Hygiene" validated observation tool was used to record opportunities and actual practices of hand hygiene, with 3 additional opportunities specific to the HHC setting. Patient assessment data available in the agency electronic health record and a nurse demographic questionnaire were also collected to describe patients and nurse participants. RESULTS: A total of 2014 opportunities were observed. On arrival in the home was the most frequent opportunity (n = 384), the least frequent was after touching a patient's surroundings (n = 43). The average hand hygiene adherence rate was 45.6% after adjusting for clustering at the nurse level. Adherence was highest after contact with body fluid (65.1%) and lowest after touching a patient (29.5%). The number of hand hygiene opportunities was higher when patients being served were at increased risk of an infection-related emergency department visit or hospitalization and when the home environment was observed to be "dirty." No nurse or patient demographic characteristics were associated with the rate of nurse hand hygiene adherence. CONCLUSIONS AND IMPLICATIONS: Hand hygiene adherence in HHC is suboptimal, with rates mirroring those reported in hospital and outpatient settings. The connection between poor hand hygiene and infection transmission has been well studied, and it has received widespread attention with the outbreak of SARS-CoV-2. Agencies can use results found in this study to better inform quality improvement initiatives.

Infection prevention and control practices in the home environment: Examining enablers and barriers to adherence among home health care nurses.

BACKGROUND: Infection Prevention and Control (IPC) practices have been established in home health care. Adherence to IPC practices has been suboptimal with limited available evidence. The study aim was to examine the impact of individual, home environment, and organizational factors on IPC practices using human factors model. METHODS: Three hundred and fifty-three nurses were surveyed across two large home care agencies to examine the relationship between IPC adherence and individual, home environment, and organizational factors. RESULTS: Nurses reported multiple barriers to IPC practices in patients' homes (mean = 4.34, standard deviation = 2.53). Frequent barriers included clutter (reported by 74.5% of nurses) and a dirty environment (70.3%). Nurses also reported limited availability of some IPC supplies (mean = 7.76, standard deviation = 2.44), including personal protective equipment. Home environment factors were significant barriers, and availability of IPC supplies were significant enablers of IPC adherence. Agency-provided training and decision-making resources were not significant factors for IPC adherence in the presence of home environment barriers and IPC supplies. CONCLUSIONS: This study findings suggest that IPC adherence strategies point to addressing barriers in the home environment and increasing availability of IPC supplies. The relationship between the patient's home environment, organizational factors, and IPC practices among home health care nurses warrants further study.

Free-Text Documentation of Dementia Symptoms in Home Healthcare: A Natural Language Processing Study.

BACKGROUND: Little is known about symptom documentation related to Alzheimer's disease and related dementias (ADRD) by home healthcare (HHC) clinicians. OBJECTIVE: This study: (1) developed a natural language processing (NLP) algorithm that identifies common neuropsychiatric symptoms of ADRD in HHC free-text clinical notes; (2) described symptom clusters and hospitalization or emergency department (ED) visit rates for patients with and without these symptoms. METHOD: We examined a corpus of -2.6 million free-text notes for 112,237 HHC episodes among 89,459 patients admitted to a non-profit HHC agency for post-acute care with any diagnosis. We used NLP software (NimbleMiner) to construct indicators of six neuropsychiatric symptoms. Structured HHC assessment data were used to identify known ADRD diagnoses and construct measures of hospitalization/ED use during HHC. RESULTS: Neuropsychiatric symptoms were documented for 40% of episodes. Common clusters included impaired memory, anxiety and/or depressed mood. One in three episodes without an ADRD diagnosis had documented symptoms. Hospitalization/ED rates increased with one or more symptoms present. CONCLUSION: HHC providers should examine episodes with neuropsychiatric symptoms but no ADRD diagnoses to determine whether ADRD diagnosis was missed or to recommend ADRD evaluation. NLP-generated symptom indicators can help to identify high-risk patients for targeted interventions.

Risk factors for infection in home health care: Analysis of national Outcome and Assessment Information Set data.

Patients in home health care (HHC), a rapidly growing healthcare sector, are at high risk for infections. This study aimed to identify risk factors for infections among HHC patients using the Outcome and Assessment Information Set (OASIS) data. We used a 5% random sample of the 2013 national OASIS data. Infections were identified if records indicated that patients were hospitalized or received emergency care for one of three types of infections (respiratory, wound site, and urinary tract infection). Multivariate logistic regression models were used to identify risk factors for each individual infection type. The final analysis included 128,163 patients from 8,255 HHC agencies nationwide. Approximately 3.2% of the patients developed infections during their HHC stay that led to hospitalization or emergency care treatment. We found that associations between demographics and infection risk are specific to the type of infection. In general, a history of multiple hospitalizations in past 6 months, comorbidity, having a severe condition at HHC admission, and impaired physical functioning increased HHC patients' risk of infections. We also identified that HHC patients with caregivers who needed training in providing medical procedure or treatment are at higher risk for wound-site infections. Our findings suggest that patients with underlying medical conditions and limited physical function status are more likely to develop infection. The caregiver's lack of training in providing needed care at home also places HHC patients at high risk for infection. Education for patients and caregivers should be tailored based on their health literacy level to ensure complete understanding.

Mechanoresponsive Self-Assembled Perylene Bisimide Films.

In this work, self-assembled amino-acid appended perylene bisimides (PBIs) have been studied that when processed into thin films change their resistivity in response to being bent. The PBIs assemble into structures in water and form thin films upon drying. These normally delicate thin films can be tolerant to bending, depending on the aggregates they form. Furthermore, the films then reversibly change their resistivity in response to this mechanical stimulus. This change is proportional to the degree of bending of the film giving them the potential to be used quantitatively to measure mechanical movement, such as in wearable devices.

Factors for compliance with infection control practices in home healthcare: findings from a survey of nurses' knowledge and attitudes toward infection control.

BACKGROUND: Infection is a leading cause of hospitalization among home healthcare patients. Nurses play an important role in reducing infection among home healthcare patients by complying with infection control procedures. However, few studies have examined the compliance of home healthcare nurses with infection control practices or the range of sociocultural and organizational factors that may be associated with compliance. METHODS: This study analyzed survey responses from nurses at 2 large, certified home healthcare agencies (n = 359), to explore levels of compliance with infection control practices and identify associated demographic, knowledge, and attitudinal correlates. RESULTS: Nurses reported a high level of infection control compliance (mean = 0.89, standard deviation [SD] = 0.16), correct knowledge (mean = 0.85, SD = 0.09), and favorable attitudes (mean = 0.81, SD = 0.14). Multivariate mixed regression analyses revealed significant positive associations of attitudinal scores with reported level of compliance (P < .001). However, knowledge of inflection control practices was not associated with compliance. Older (P < .05) and non-Hispanic black (P < .001) nurses reported higher compliance with infection control practices than younger and white non-Hispanic nurses. CONCLUSION: These findings suggest that efforts to improve compliance with infection control practices in home healthcare should focus on strategies to alter perceptions about infection risk and other attitudinal factors.

Procalcitonin-Guided Antibiotic Therapy Reduces Antibiotic Use for Lower Respiratory Tract Infections in a United States Medical Center: Results of a Clinical Trial.

BACKGROUND: European trials using procalcitonin (PCT)-guided antibiotic therapy for patients with lower respiratory tract infections (LRTIs) have demonstrated significant reductions in antibiotic use without increasing adverse outcomes. Few studies have examined PCT for LRTIs in the United States. METHODS: In this study, we evaluated whether a PCT algorithm would reduce antibiotic exposure in patients with LRTI in a US hospital. We conducted a controlled pre-post trial comparing an intervention group of PCT-guided antibiotic therapy to a control group of usual care. Consecutive patients admitted to medicine services and receiving antibiotics for LRTI were enrolled in the intervention. Providers were encouraged to discontinue antibiotics according to a PCT algorithm. Control patients were similar patients admitted before the intervention. RESULTS: The primary endpoint was median antibiotic duration. Overall adverse outcomes at 30 days comprised death, transfer to an intensive care unit, antibiotic side effects, Clostridium difficile infection, disease-specific complications, and post-discharge antibiotic prescription for LRTI. One hundred seventy-four intervention patients and 200 controls were enrolled. Providers complied with the PCT algorithm in 75% of encounters. Procalcitonin-guided therapy reduced median antibiotic duration for pneumonia from 7 days to 6 (P = .045) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from 4 days to 3 (P = .01). There was no difference in the rate of adverse outcomes in the PCT and control groups. CONCLUSIONS: A PCT-guided algorithm safely reduced the duration of antibiotics for treating LRTI. Utilization of a PCT algorithm may aid antibiotic stewardship efforts.This clinical trial was a single-center, controlled, pre-post study of PCT-guided antibiotic therapy for LRTI. The intervention (incorporation of PCT-guided algorithms) started on April 1, 2017: the preintervention (control group) comprised patients admitted from November 1, 2016 to April 16, 2017, and the postintervention group comprised patients admitted from April 17, 2017 to November 29, 2017 (Supplementary Figure 1). The study comprised patients admitted to the internal medicine services to a medical ward, the Medical Intensive Care Unit (MICU), the Cardiac Intensive Care Unit (CICU), or the Progressive Care Unit (PCU) "step down unit". The registration data for the trails are in the ClinicalTrials.gov database, number NCT0310910.

Impact of an electronic sepsis initiative on antibiotic use and health care facility-onset Clostridium difficile infection rates.

BACKGROUND: Although integrated, electronic sepsis screening and treatment protocols are thought to improve patient outcomes, less is known about their unintended consequences. We aimed to determine if the introduction of a sepsis initiative coincided with increases in broad-spectrum antibiotic use and health care facility-onset (HCFO) Clostridium difficile infection (CDI) rates. METHODS: We used interrupted time series data from a large, tertiary, urban academic medical center including all adult inpatients on 4 medicine wards (June 2011-July 2014). The main exposure was implementation of the sepsis screening program; the main outcomes were the use of broad-spectrum antibiotics (including 3 that were part of an order set designed for the sepsis initiative) and HCFO CDI rates. Segmented regression analyses compared outcomes in 3 time segments: before (11 months), during (14 months), and after (12 months) implementation of a sepsis initiative. RESULTS: Antibiotic use and HFCO CDI rates increased during the period of implementation and the period after implementation compared with baseline; these increases were highest in the period after implementation (level change, 50.4 days of therapy per 1,000 patient days for overall antibiotic use and 10.8 HCFO CDIs per 10,000 patient days; P < .05). Remarkably, the main drivers of overall antibiotic use were not those included in the sepsis order set. CONCLUSIONS: The implementation of an electronic sepsis screening and treatment protocol coincided with increased broad-spectrum antibiotic use and HCFO CDIs. Because these protocols are increasingly used, further study of their unintended consequences is warranted.

Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance.

Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy.

Cap-translation inhibitor, 4EGI-1, restores sensitivity to ABT-737 apoptosis through cap-dependent and -independent mechanisms in chronic lymphocytic leukemia.

PURPOSE: The lymph node microenvironment promotes resistance to chemotherapy in chronic lymphocytic leukemia (CLL), partly through induction of BCL2 family prosurvival proteins. Currently available inhibitors do not target all BCL2 family prosurvival proteins and their effectiveness is also modified by proapoptotic BCL2 homology domain 3 (BH3) only protein expression. The goal of this study was to evaluate synergy between the eIF4E/eIF4G interaction inhibitor, 4EGI-1, and the BH3 mimetic, ABT-737. EXPERIMENTAL DESIGN: CLL cells were cultured in conditions to mimic the lymph node microenvironment. Protein synthesis and cap-complex formation were determined. Polysome association of mRNAs from BCL2 family survival genes was analyzed by translational profiling. The effects of 4EGI-1 and the BCL2/BCL2L1 antagonist, ABT-737, on CLL cell apoptosis were determined. RESULTS: Protein synthesis was increased approximately 6-fold by stromal cell/CD154 culture in a phosphoinositide 3-kinase α (PI3Kα)-specific manner and was reduced by 4EGI-1. PI3K inhibitors and 4EGI-1 also reduced cap-complex formation but only 4EGI-1 consistently reduced BCL2L1 and BCL2A1 protein levels. 4EGI-1, but not PI3K inhibitors or rapamycin, induced an endoplasmic reticulum stress response including proapoptotic NOXA and the translation inhibitor phosphorylated eIF2α. 4EGI-1 and ABT-737 synergized to cause apoptosis, independent of levels of prosurvival protein expression in individual patients. CONCLUSIONS: Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in CLL. Inhibition of the cap-complex was not sufficient to repress BCL2 family prosurvival expression, but 4EGI-1 inhibited BCL2A1 and BCL2L1 while inducing NOXA through cap-dependent and -independent mechanisms. 4EGI-1 and ABT-737 synergized to produce apoptosis, and these agents may be the basis for a therapeutically useful combination.