Impact of the COVID-19 Pandemic on Inpatient Antibiotic Use in the United States, January 2019 Through July 2022.

Antimicrobial use data reported to the National Healthcare Safety Network's Antimicrobial Use and Resistance Module between January 2019 and July 2022 were analyzed to assess the impact of the COVID-19 pandemic on inpatient antimicrobial use.

Vital Signs: Health Disparities in Hemodialysis-Associated Staphylococcus aureus Bloodstream Infections - United States, 2017-2020.

INTRODUCTION: Racial and ethnic minorities are disproportionately affected by end-stage kidney disease (ESKD). ESKD patients on dialysis are at increased risk for Staphylococcus aureus bloodstream infections, but racial, ethnic, and socioeconomic disparities associated with this outcome are not well described. METHODS: Surveillance data from the 2020 National Healthcare Safety Network (NHSN) and the 2017-2020 Emerging Infections Program (EIP) were used to describe bloodstream infections among patients on hemodialysis (hemodialysis patients) and were linked to population-based data sources (CDC/Agency for Toxic Substances and Disease Registry [ATSDR] Social Vulnerability Index [SVI], United States Renal Data System [USRDS], and U.S. Census Bureau) to examine associations with race, ethnicity, and social determinants of health. RESULTS: In 2020, 4,840 dialysis facilities reported 14,822 bloodstream infections to NHSN; 34.2% were attributable to S. aureus . Among seven EIP sites, the S. aureus bloodstream infection rate during 2017-2020 was 100 times higher among hemodialysis patients (4,248 of 100,000 person-years) than among adults not on hemodialysis (42 of 100,000 person-years). Unadjusted S. aureus bloodstream infection rates were highest among non-Hispanic Black or African American (Black) and Hispanic or Latino (Hispanic) hemodialysis patients. Vascular access via central venous catheter was strongly associated with S. aureus bloodstream infections (NHSN: adjusted rate ratio [aRR] = 6.2; 95% CI = 5.7-6.7 versus fistula; EIP: aRR = 4.3; 95% CI = 3.9-4.8 versus fistula or graft). Adjusting for EIP site of residence, sex, and vascular access type, S. aureus bloodstream infection risk in EIP was highest in Hispanic patients (aRR = 1.4; 95% CI = 1.2-1.7 versus non-Hispanic White [White] patients), and patients aged 18-49 years (aRR = 1.7; 95% CI = 1.5-1.9 versus patients aged ≥65 years). Areas with higher poverty levels, crowding, and lower education levels accounted for disproportionately higher proportions of hemodialysis-associated S. aureus bloodstream infections. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Disparities exist in hemodialysis-associated S. aureus infections. Health care providers and public health professionals should prioritize prevention and optimized treatment of ESKD, identify and address barriers to lower-risk vascular access placement, and implement established best practices to prevent bloodstream infections.

Vital Signs: Health Disparities in Hemodialysis-Associated Staphylococcus aureus Bloodstream Infections - United States, 2017-2020.

Introduction: Racial and ethnic minorities are disproportionately affected by end-stage kidney disease (ESKD). ESKD patients on dialysis are at increased risk for Staphylococcus aureus bloodstream infections, but racial, ethnic, and socioeconomic disparities associated with this outcome are not well described. Methods: Surveillance data from the 2020 National Healthcare Safety Network (NHSN) and the 2017-2020 Emerging Infections Program (EIP) were used to describe bloodstream infections among patients on hemodialysis (hemodialysis patients) and were linked to population-based data sources (CDC/Agency for Toxic Substances and Disease Registry [ATSDR] Social Vulnerability Index [SVI], United States Renal Data System [USRDS], and U.S. Census Bureau) to examine associations with race, ethnicity, and social determinants of health. Results: In 2020, 4,840 dialysis facilities reported 14,822 bloodstream infections to NHSN; 34.2% were attributable to S. aureus. Among seven EIP sites, the S. aureus bloodstream infection rate during 2017-2020 was 100 times higher among hemodialysis patients (4,248 of 100,000 person-years) than among adults not on hemodialysis (42 of 100,000 person-years). Unadjusted S. aureus bloodstream infection rates were highest among non-Hispanic Black or African American (Black) and Hispanic or Latino (Hispanic) hemodialysis patients. Vascular access via central venous catheter was strongly associated with S. aureus bloodstream infections (NHSN: adjusted rate ratio [aRR] = 6.2; 95% CI = 5.7-6.7 versus fistula; EIP: aRR = 4.3; 95% CI = 3.9-4.8 versus fistula or graft). Adjusting for EIP site of residence, sex, and vascular access type, S. aureus bloodstream infection risk in EIP was highest in Hispanic patients (aRR = 1.4; 95% CI = 1.2-1.7 versus non-Hispanic White [White] patients), and patients aged 18-49 years (aRR = 1.7; 95% CI = 1.5-1.9 versus patients aged ≥65 years). Areas with higher poverty levels, crowding, and lower education levels accounted for disproportionately higher proportions of hemodialysis-associated S. aureus bloodstream infections. Conclusions and implications for public health practice: Disparities exist in hemodialysis-associated S. aureus infections. Health care providers and public health professionals should prioritize prevention and optimized treatment of ESKD, identify and address barriers to lower-risk vascular access placement, and implement established best practices to prevent bloodstream infections.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

The impact of preoperative imaging on wait times, surgical approach and overall survival in endometrioid endometrial cancers.

OBJECTIVES: Routine preoperative axial imaging studies (CT/MRI) are not recommended for endometrioid endometrial cancer as they are unlikely to change management and may delay surgery. This study evaluated the association of receiving preoperative imaging on various outcomes. METHODS: A population-based cohort of Endometrioid Endometrial Cancer cases from 2006 to 2016 were identified from the Cancer Registry in Ontario, Canada. Wait time to surgery, type of surgery and overall survival were evaluated in patients with and without preoperative imaging. Predictive factors for wait time > 56 days and aggressive surgery (radical hysterectomy / lymphadenectomy) were determined using multivariable regression analysis. RESULTS: 13,050 cases were included. 22.6% of patients received preoperative imaging, mainly CT scans. Most patients (95.9%) received no neoadjuvant treatment. Patients with preoperative imaging were more likely to have neoadjuvant treatment (11.7% vs. 1.8%) and less likely to have surgery at 180 days post diagnosis (87.9% vs 94.6%). Patients with preoperative imaging had median wait time to surgery of 64 days (47-87), compared to 53 days (36-74) than those without imaging (p < 0.001). Multivariable modeling showed preoperative imaging was associated with decreased odds of having surgery within 56 days (OR = 0.68, 95% CI = 0.62-0.75), and increased odds (OR = 1.73, 95% CI = 1.53-1.95) of having aggressive surgery. The 5-year overall survival for patients with imaging was 84.8% versus 91.1% for patients without preoperative imaging. CONCLUSIONS: Preoperative imaging was associated with longer wait times to surgery, more aggressive surgery, surgery with a gynecologic oncologist and increased use of neoadjuvant and adjuvant treatment. In early-stage disease there was no observed improvement in overall survival for patients with preoperative imaging. Further research on potential benefits of preoperative imaging in higher risk patients is required.

Antimicrobial Use in US Hospitals: Comparison of Results From Emerging Infections Program Prevalence Surveys, 2015 and 2011.

BACKGROUND: In the 2011 US hospital prevalence survey of healthcare-associated infections and antimicrobial use 50% of patients received antimicrobial medications on the survey date or day before. More hospitals have since established antimicrobial stewardship programs. We repeated the survey in 2015 to determine antimicrobial use prevalence and describe changes since 2011. METHODS: The Centers for Disease Control and Prevention's Emerging Infections Program sites in 10 states each recruited ≤25 general and women's and children's hospitals. Hospitals selected a survey date from May-September 2015. Medical records for a random patient sample on the survey date were reviewed to collect data on antimicrobial medications administered on the survey date or day before. Percentages of patients on antimicrobial medications were compared; multivariable log-binomial regression modeling was used to evaluate factors associated with antimicrobial use. RESULTS: Of 12 299 patients in 199 hospitals, 6084 (49.5%; 95% CI, 48.6-50.4%) received antimicrobials. Among 148 hospitals in both surveys, overall antimicrobial use prevalence was similar in 2011 and 2015, although the percentage of neonatal critical care patients on antimicrobials was lower in 2015 (22.8% vs 32.0% [2011]; P = .006). Fluoroquinolone use was lower in 2015 (10.1% of patients vs 11.9% [2011]; P < .001). Third- or fourth-generation cephalosporin use was higher (12.2% vs 10.7% [2011]; P = .002), as was carbapenem use (3.7% vs 2.7% [2011]; P < .001). CONCLUSIONS: Overall hospital antimicrobial use prevalence was not different in 2011 and 2015; however, differences observed in selected patient or antimicrobial groups may provide evidence of stewardship impact.

Changes in Prevalence of Health Care-Associated Infections in U.S. Hospitals.

BACKGROUND: A point-prevalence survey that was conducted in the United States in 2011 showed that 4% of hospitalized patients had a health care-associated infection. We repeated the survey in 2015 to assess changes in the prevalence of health care-associated infections during a period of national attention to the prevention of such infections. METHODS: At Emerging Infections Program sites in 10 states, we recruited up to 25 hospitals in each site area, prioritizing hospitals that had participated in the 2011 survey. Each hospital selected 1 day on which a random sample of patients was identified for assessment. Trained staff reviewed medical records using the 2011 definitions of health care-associated infections. We compared the percentages of patients with health care-associated infections and performed multivariable log-binomial regression modeling to evaluate the association of survey year with the risk of health care-associated infections. RESULTS: In 2015, a total of 12,299 patients in 199 hospitals were surveyed, as compared with 11,282 patients in 183 hospitals in 2011. Fewer patients had health care-associated infections in 2015 (394 patients [3.2%; 95% confidence interval {CI}, 2.9 to 3.5]) than in 2011 (452 [4.0%; 95% CI, 3.7 to 4.4]) (P<0.001), largely owing to reductions in the prevalence of surgical-site and urinary tract infections. Pneumonia, gastrointestinal infections (most of which were due to Clostridium difficile [now Clostridioides difficile]), and surgical-site infections were the most common health care-associated infections. Patients' risk of having a health care-associated infection was 16% lower in 2015 than in 2011 (risk ratio, 0.84; 95% CI, 0.74 to 0.95; P=0.005), after adjustment for age, presence of devices, days from admission to survey, and status of being in a large hospital. CONCLUSIONS: The prevalence of health care-associated infections was lower in 2015 than in 2011. To continue to make progress in the prevention of such infections, prevention strategies against C. difficile infection and pneumonia should be augmented. (Funded by the Centers for Disease Control and Prevention.).

The use of imaging in endometrial cancer prior to potential surgery: Are guidelines being followed?

OBJECTIVES: Clinical practice guidelines recommend against routine preoperative axial imaging studies (CT/MRI) for endometrial cancer, except for cases of locally advanced disease or aggressive histologies. This study utilized population-based data to evaluate the use of preoperative imaging and factors associated with its use. METHODS: A population-based cohort of women diagnosed with endometrial cancer from 2006 to 2016 were identified from the Ontario Cancer Registry in Ontario, Canada. Patients were excluded if they had: hysterectomy prior to the date of diagnosis, non-epithelial histology or a prior cancer diagnosis within 5 years. Preoperative imaging (CT or MRI) rates were calculated over time. Predictive factors for preoperative imaging use were determined using multi-variable regression analysis. RESULTS: 17,718 cases were eligible for analysis. From 2006 to 2016, the proportion of patients receiving preoperative imaging increased from 22.2% to 39.3%. In a subgroup of patients with low-risk disease (stage 1, endometrioid adenocarcinoma), imaging increased from 16.3% to 29.5%. Multivariate analysis showed an association between preoperative imaging and advanced stage, advanced grade, non-endometrioid morphology, surgery with a gynecologic oncologist, surgery at a teaching hospital and a later year of diagnosis. From 2006 to 2016, the yearly incidence of endometrial cancer increased from 22.3/100,000 to 36.1/100,000, representing a mean annual increase of 3.6% per year. CONCLUSIONS: Endometrial cancer incidence and the use of preoperative imaging are increasing. Factors most associated with preoperative imaging are high-risk features. However, preoperative imaging is still being performed in low-risk patients, indicating non-adherence to guidelines, which has implications for constrained healthcare resources.

Long-Term Effectiveness of a Drug-Eluting Stent for Femoropopliteal In-Stent Restenosis: Subanalysis of the Zilver PTX Japan Post-Market Surveillance Study.

PURPOSE: To present a subgroup analysis of patients from a large real-world study evaluating the safety and effectiveness of the Zilver PTX drug-eluting stent (DES) for treating femoropopliteal in-stent restenosis (ISR). MATERIALS AND METHODS: This study examined patients enrolled in the Zilver PTX Japan Post-Market Surveillance Study (ClinicalTrials.gov identifier NCT02254837), a prospective, multicenter registry of 904 symptomatic patients with 1082 femoropopliteal lesions treated with the DES at 95 institutions in Japan. Five-year outcomes, including mortality, stent radiography, freedom from target lesion revascularization (TLR), and clinical benefit, were evaluated for 177 patients (mean age 74.2±8.3 years; 118 men) with 204 ISR lesions treated with the Zilver DES. Over half of the patients (108, 61.0%) were diabetic. Mean lesion length was 17.8±10.4 cm, and a third (72, 35.3%) were total occlusions. Outcome measures were all-cause mortality, thrombosis, freedom from TLR, and clinical benefit, defined as freedom from persistent or deteriorating ischemic symptoms. RESULTS: No device-related or procedure-related deaths or paclitaxel-related adverse events were reported. All-cause mortality was 25.1% at 5 years. Stent fracture was observed in 5 stents through 5 years. The 5-year rate of freedom from clinically-driven TLR was 73.4%, and the rate of clinical benefit was 63.6%. Improvement in Rutherford category and ankle-brachial index was sustained through 5 years. CONCLUSION: The safety and effectiveness of the Zilver PTX stent for the treatment of femoropopliteal ISR lesions demonstrated that this device provides a favorable treatment option in this difficult-to-treat subgroup.

Tissue-Resident Alveolar Macrophages Do Not Rely on Glycolysis for LPS-induced Inflammation.

Macrophage effector function is dynamic in nature and largely dependent on not only the type of immunological challenge but also the tissue-specific environment and developmental origin of a given macrophage population. Recent research has highlighted the importance of glycolytic metabolism in the regulation of effector function as a common feature associated with macrophage activation. Yet, most research has used macrophage cell lines and bone marrow-derived macrophages, which do not account for the diversity of macrophage populations and the role of tissue specificity in macrophage immunometabolism. Tissue-resident alveolar macrophages (TR-AMs) reside in an environment characterized by remarkably low glucose concentrations, making glycolysis-linked immunometabolism an inefficient and unlikely means of immune activation. In this study, we show that TR-AMs rely on oxidative phosphorylation to meet their energy demands and maintain extremely low levels of glycolysis under steady-state conditions. Unlike bone marrow-derived macrophages, TR-AMs did not experience enhanced glycolysis in response to LPS, and glycolytic inhibition had no effect on their proinflammatory cytokine production. Hypoxia-inducible factor 1α stabilization promoted glycolysis in TR-AMs and shifted energy production away from oxidative metabolism at baseline, but it was not sufficient for TR-AMs to mount further increases in glycolysis or enhance immune function in response to LPS. Importantly, we confirmed these findings in an in vivo influenza model in which infiltrating macrophages had significantly higher glycolytic and proinflammatory gene expression than TR-AMs. These findings demonstrate that glycolysis is dispensable for macrophage effector function in TR-AM and highlight the importance of macrophage tissue origin (tissue resident vs. recruited) in immunometabolism.

TGF-ß Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-ß (transforming growth factor-ß)-dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-ß upregulates the expression of the enzymes of the de novo serine-glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here, we demonstrate that TGF-ß promotes accumulation of ATF4 (activating transcription factor 4), which is required for increased expression of the serine-glycine synthesis pathway enzymes in response to TGF-ß. We found that induction of the integrated stress response (ISR) contributes to TGF-ß-induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-ß is activation of mTORC1 (mTOR Complex 1). TGF-ß activates the PI3K-Akt-mTOR pathway, and inhibition of PI3K prevents activation of downstream signaling and induction of ATF4. Using a panel of mTOR inhibitors, we found that ATF4 activation is dependent on mTORC1, independent of mTORC2. Rapamycin, which incompletely and allosterically inhibits mTORC1, had no effect on TGF-ß-mediated induction of ATF4; however, Rapalink-1, which specifically targets the kinase domain of mTORC1, completely inhibited ATF4 induction and metabolic reprogramming downstream of TGF-ß. Our results provide insight into the mechanisms of metabolic reprogramming in myofibroblasts and clarify contradictory published findings on the role of mTOR inhibition in myofibroblast differentiation.

National Healthcare Safety Network Standardized Antimicrobial Administration Ratios (SAARs): A Progress Report and Risk Modeling Update Using 2017 Data.

BACKGROUND: The Standardized Antimicrobial Administration Ratio (SAAR) is a risk-adjusted metric of antimicrobial use (AU) developed by the Centers for Disease Control and Prevention (CDC) in 2015 as a tool for hospital antimicrobial stewardship programs (ASPs) to track and compare AU with a national benchmark. In 2018, CDC updated the SAAR by expanding the locations and antimicrobial categories for which SAARs can be calculated and by modeling adult and pediatric locations separately. METHODS: We identified eligible patient-care locations and defined SAAR antimicrobial categories. Predictive models were developed for eligible adult and pediatric patient-care locations using negative binomial regression applied to nationally aggregated AU data from locations reporting ≥9 months of 2017 data to the National Healthcare Safety Network (NHSN). RESULTS: 2017 Baseline SAAR models were developed for 7 adult and 8 pediatric SAAR antimicrobial categories using data reported from 2156 adult and 170 pediatric locations across 457 hospitals. The inclusion of step-down units and general hematology-oncology units in adult 2017 baseline SAAR models and the addition of SAARs for narrow-spectrum B-lactam agents, antifungals predominantly used for invasive candidiasis, antibacterial agents posing the highest risk for Clostridioides difficile infection, and azithromycin (pediatrics only) expand the role SAARs can play in ASP efforts. Final risk-adjusted models are used to calculate predicted antimicrobial days, the denominator of the SAAR, for 40 SAAR types displayed in NHSN. CONCLUSIONS: SAARs can be used as a metric to prompt investigation into potential overuse or underuse of antimicrobials and to evaluate the effectiveness of ASP interventions.

Glutamine Metabolism Is Required for Collagen Protein Synthesis in Lung Fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is characterized by the transforming growth factor (TGF)-ß-dependent differentiation of lung fibroblasts into myofibroblasts, leading to excessive deposition of extracellular matrix proteins, which distort lung architecture and function. Metabolic reprogramming in myofibroblasts is emerging as an important mechanism in the pathogenesis of IPF, and recent evidence suggests that glutamine metabolism is required in myofibroblasts, although the exact role of glutamine in myofibroblasts is unclear. In the present study, we demonstrate that glutamine and its conversion to glutamate by glutaminase are required for TGF-ß-induced collagen protein production in lung fibroblasts. We found that metabolism of glutamate to α-ketoglutarate by glutamate dehydrogenase or the glutamate-pyruvate or glutamate-oxaloacetate transaminases is not required for collagen protein production. Instead, we discovered that the glutamate-consuming enzymes phosphoserine aminotransferase 1 (PSAT1) and aldehyde dehydrogenase 18A1 (ALDH18A1)/Δ1-pyrroline-5-carboxylate synthetase (P5CS) are required for collagen protein production by lung fibroblasts. PSAT1 is required for de novo glycine production, whereas ALDH18A1/P5CS is required for de novo proline production. Consistent with this, we found that TGF-ß treatment increased cellular concentrations of glycine and proline in lung fibroblasts. Our results suggest that glutamine metabolism is required to promote amino acid biosynthesis and not to provide intermediates such as α-ketoglutarate for oxidation in mitochondria. In support of this, we found that inhibition of glutaminolysis has no effect on cellular oxygen consumption and that knockdown of oxoglutarate dehydrogenase has no effect on the ability of fibroblasts to produce collagen protein. Our results suggest that amino acid biosynthesis pathways may represent novel therapeutic targets for treatment of fibrotic diseases, including IPF.

Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing.

BACKGROUND: Genetic testing capability and guidelines are rapidly expanding to assess inherited prostate cancer (PCA). Clinical genetic data from multigene testing can provide insights into the germline pathogenic variant (PV) spectrum and correlates in men with PCA unselected for metastatic disease to optimize identification of men for genetic evaluation and management. METHODS: A retrospective cross-sectional analysis was conducted of de-identified clinical genetic testing data from a large commercial genetic testing laboratory in the US. ICD-10 claims codes were used to identify men with PCA, along with family history data. Gleason score was abstracted from test request forms. Overall PV rate among men with PCA was estimated, along with PVs in DNA repair genes. Family history and Gleason score association to germline DNA repair PVs was assessed using Fisher's exact test with correction for false-discovery. RESULTS: As of August 2017, genetic results were available on 1328 men with PCA. Overall PV rate was 15.6%, with 10.9% of PV in DNA repair genes. PVs were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%). Breast cancer family history was significantly associated with germline DNA repair PVs (OR 1.89, [95%CI 1.33, 2.68], P = 0.003). Among men with Gleason score>= 6 (n = 706), Gleason> = 8 was significantly associated with DNA repair PVs (OR 1.85 [95%CI 1.22, 2.80], P = 0.004). CONCLUSIONS: A substantial proportion of men with PCA unselected for metastatic disease carry germline DNA repair PVs. Breast cancer family history and high Gleason score are important predictors to identify men with PCA who may carry germline DNA repair PVs. Our findings support current NCCN guidelines and have implications for genetic assessment, therapeutic management, and cascade testing for men with PCA and their families.

Inhibition of Phosphoglycerate Dehydrogenase Attenuates Bleomycin-induced Pulmonary Fibrosis.

Organ fibrosis, including idiopathic pulmonary fibrosis, is associated with significant morbidity and mortality. Because currently available therapies have limited effect, there is a need to better understand the mechanisms by which organ fibrosis occurs. We have recently reported that transforming growth factor (TGF)-ß, a key cytokine that promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts, and that phosphoglycerate dehydrogenase (PHGDH; the first and rate-limiting enzyme of the pathway) is required to promote collagen protein synthesis downstream of TGF-ß. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung fibrosis in vivo. We found that TGF-ß induces mRNA and protein expression of PHGDH in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of PHGDH in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of PHGDH (NCT-503), we tested whether pharmacologic inhibition of PHGDH could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-ß-induced collagen protein synthesis. Mice treated with the PHGDH inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis. These results indicate that the de novo serine and glycine synthesis pathway is necessary for TGF-ß-induced collagen synthesis and bleomycin-induced pulmonary fibrosis. PHGDH and other enzymes in the de novo serine and glycine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including idiopathic pulmonary fibrosis.

The Standardized Antimicrobial Administration Ratio: A New Metric for Measuring and Comparing Antibiotic Use.

Background: To provide a standardized, risk-adjusted method for summarizing antibiotic use (AU), enable hospitals to track their AU over time and compare their AU data to national benchmarks, the Centers for Disease Control and Prevention developed the Standardized Antimicrobial Administration Ratio (SAAR). Methods: Hospitals reporting to the National Healthcare Safety Network (NHSN) AU Option collect and submit aggregated AU data electronically as antimicrobial days of therapy per patient days present. SAARs were developed for specific NHSN adult and pediatric patient care locations and cover five antimicrobial agent categories: (1) broad-spectrum agents predominantly used for hospital-onset/multi-drug resistant bacteria; (2) broad-spectrum agents predominantly used for community-acquired infections; (3) anti-methicillin-resistant Staphylococcus aureus agents; (4) agents predominantly used for surgical site infection prophylaxis; and (5) all antibiotic agents. The SAAR is an observed-to-predicted use ratio where predicted use is estimated from a statistical model; a SAAR of 1 indicates that observed use and predicted use are equal. Results: Most location-level SAARs were statistically significantly different than 1: adult locations up to 52% lower than 1 and up to 41% higher than 1. Median SAARs in adult and pediatric ICUs had a range of 0.667-1.119. SAAR distributions serve as an external comparison to national SAARs. Conclusions: This is the first aggregate AU metric that uses point-of-care, antimicrobial administration data electronically reported to a national surveillance system to enable risk-adjusted, AU comparisons across multiple hospitals. Endorsed by the National Quality Forum, SAARs provide AU benchmarks that stewardship programs can use to help drive improvements.

Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark.

BACKGROUND: An estimated 5-10% of breast and ovarian cancers are due to hereditary causes such as hereditary breast and ovarian cancer (HBOC) syndrome. Medicare, the third-party payer that covers 44 million patients in the United States, has implemented a set of clinical criteria to determine coverage for the testing of the BRCA1 and BRCA2 genes. These criteria, developed to identify carriers of BRCA1/2 variants, have not been evaluated in the panel testing era. This study investigated a series of Medicare patients undergoing genetic testing for HBOC to determine the efficacy of genetic testing criteria in identifying patients with hereditary risk. METHODS: This study retrospectively examined de-identified data from a consecutive series of Medicare patients undergoing genetic testing based on personal and family history of breast and gynecologic cancer. Ordering clinicians indicated whether patients did or did not meet established criteria for BRCA1/2 genetic testing. The genetic test results were compared between the group that met the criteria and the group that did not. Patients in families with known pathogenic (P) or likely pathogenic (LP) variants were excluded from the primary analysis. RESULTS: Among 4196 unique Medicare patients, the rate of P/LP variants for the patients who met the criteria for genetic testing was 10.5%, and for those who did not, the rate was 9% (p = 0.26). CONCLUSIONS: The results of this study indicate that a substantial number of Medicare patients with clinically actionable genetic variants are being missed by current testing criteria and suggest the need for significant expansion and simplification of the testing criteria for HBOC.

Dilation or biodegradable stent placement for recurrent benign esophageal strictures: a randomized controlled trial.

BACKGROUND: Dilation is the standard of care for recurrent benign esophageal strictures (BES). Biodegradable stents may prolong the effect of dilation and reduce recurrences. Efficacy and safety of dilation and biodegradable stent placement early in the treatment algorithm of recurrent BES were compared. METHODS: This multicenter, randomized study enrolled patients with BES treated with previous dilations to ≥ 16 mm. The primary end point was number of repeat endoscopic dilations for recurrent stricture within 3 and 6 months. Secondary outcomes through 12 months included safety, time to first dilation for recurrent stricture, dysphagia, and level of activity. RESULTS: At 3 months, the biodegradable stent group (n = 32) underwent significantly fewer endoscopic dilations for recurrent stricture compared with the dilation group (n = 34; P < 0.001). By 6 months, the groups were similar. The number of patients experiencing adverse events was similar between the groups. Two patients in the biodegradable stent group died after developing tracheoesophageal fistulas at 95 and 96 days post-placement; no deaths were attributed to the stent. Median time to first dilation of recurrent stricture for the biodegradable stent group was significantly longer (106 vs. 41.5 days; P = 0.003). Dysphagia scores improved for both groups. Patients in the biodegradable stent group had a significantly higher level of activity through 12 months (P < 0.001). CONCLUSION: Biodegradable stent placement is associated with temporary reduction in number of repeat dilations and prolonged time to recurrent dysphagia compared with dilation. Additional studies are needed to better define the exact role of biodegradable stent placement to treat recurrent BES.

Long-Term Effectiveness of the Zilver PTX Drug-Eluting Stent for Femoropopliteal Peripheral Artery Disease in Patients with No Patent Tibial Runoff Vessels-Results from the Zilver PTX Japan Post-Market Surveillance Study.

PURPOSE: To evaluate 2-year results of the Zilver PTX (Cook Medical, Bloomington, Indiana) drug-eluting stent (DES) for femoropopliteal peripheral artery disease (PAD) in patients with no continuous patent infrapopliteal runoff arteries compared with patients with ≥ 1 continuous patent runoff vessels. MATERIALS AND METHODS: A retrospective analysis of patients with femoropopliteal PAD enrolled in the Zilver PTX Post-Market Surveillance Study in Japan was performed. There were no exclusion criteria. Outcomes, including freedom from target lesion revascularization (TLR), patency, and clinical benefit, for the no-runoff group (n = 54) were compared with the runoff group (n = 846). RESULTS: The 2 groups were similar in terms of demographics, lesion characteristics, and comorbidities (P > .05). There was a higher incidence of critical limb ischemia in the no-runoff group compared with the runoff group (44.8% vs 19.7%; P < .01). There were 3 amputations (5.6%) in the no-runoff group versus 7 amputations (0.8%) in the runoff group (P = .02). At 2 years, freedom from TLR rates were 81.3% versus 83.8% (P = .87), patency rates were 68.4% versus 70.7% (P = .95), and clinical benefit rates were 73.7% versus 80.0% (P = .16) in the no-runoff versus runoff group, respectively. CONCLUSIONS: Results in patients with no continuous patent tibial runoff were favorable through 2 years and similar to results for patients with ≥ 1 continuous patent runoff vessels, indicating that the Zilver PTX DES may be a valid treatment option for patients with these difficult-to-treat lesions.

Transforming Growth Factor (TGF)-ß Promotes de Novo Serine Synthesis for Collagen Production.

TGF-ß promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. Here, we report that TGF-ß induces expression of glycolytic genes and increases glycolytic flux. TGF-ß also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-ß-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.