Developing Parametric and Nonparametric Models for Model-Informed Precision Dosing: A Quality Improvement Effort in Vancomycin for Patients With Obesity.

BACKGROUND: Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity. METHODS: Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using metrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset. RESULTS: In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24-89 years), and a median BMI of 46.3 kg/m2 (range: 40-70.3 kg/m2). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to c clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were -6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients). CONCLUSIONS: Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.

Inflammatory potential of diet and mortality in Australian adults.

OBJECTIVE: Inflammation is implicated in chronic diseases including cancer and CVD, which are major causes of mortality. Diet can influence inflammation status. We therefore examined whether the inflammatory potential of a person's diet is associated with mortality. DESIGN: The inflammatory potential of the usual diet was assessed by calculating Dietary Inflammatory Index (DII) scores from repeated FFQ data (collected in 1992, 1994 and 1996), placing each participant's diet on a continuum from anti- to pro-inflammatory. DII scores were analysed as a continuous variable and as categories by creating quartile groups. Death registry data were used to ascertain all-cause mortality and separately mortality from CVD, cancers and other causes between 1992 and 2022. Cox proportional hazard regression analysis was used to calculate adjusted hazard ratios (HR) with 95 % CI, comparing higher and lowest quartile groups, or HR change per one DII unit increase. SETTING: Nambour, Australia. PARTICIPANTS: A community-based sample of 1440 adults aged 25-75 years. RESULTS: During follow-up, 488 participants died, including 188 from CVD, 151 from cancer and 170 from other causes. Participants in the most pro-inflammatory diet group were at increased risk of all-cause mortality (HRQ4 v. Q1 = 1·55; 95 % CI 1·19, 2·03; P < 0·001) and other-cause mortality (HRQ4 v. Q1 = 1·69; 95 % CI 1·12, 2·54; P 0·01). A one-unit increase in DII score was associated with a 36 % increased risk of CVD among those younger than 55 years of age (HR for a one-unit increase in DII score 1·36, 95 % CI 1·04, 1·78). The risk of cancer mortality was also increased for those with a more pro-inflammatory diet in age ≤ 55 years (HR for a one-unit increase in DII score 1·20, 95 % CI 1·02, 1·40) and age 56-65 years (HR for a one-unit increase in DII score 1·11, 95 % CI 1·00, 1·23). CONCLUSIONS: A pro-inflammatory diet increases the risk of all-cause mortality. Our results support the promotion of anti-inflammatory diets to help promote longevity.

Prognosis of naevoid melanomas.

INTRODUCTION: There appear to be several variants of naevoid melanoma suspected as having different outcomes, but follow-up studies have been few. We aimed to assess the prognosis of naevoid melanomas in a multi-centre study. MATERIAL AND METHODS: From histopathology records we ascertained patients in the UK, Australia and Italy diagnosed with maturing naevoid melanoma (n = 65; 14; 7 respectively) and nodular/papillomatous naevoid melanoma (12; 6; 0), and patients with superficial spreading melanoma (SSM) from UK (73) and Australia (26). Melanoma deaths in UK patients were obtained from NHS Digital; in Australia, via the National Death Index and cancer registry; and in Italy, through clinical records. For maturing naevoid vs. SSM, we used Cox-proportional hazard regression models to compare survival adjusted for age, sex, tumour thickness, and ulceration, and additionally Fine-Gray regression analysis, to calculate sub-hazard ratios (SHR) in the UK cohort, accounting for competing causes of death. RESULTS: Among UK patients, there was a non-significantly lower risk of melanoma death in maturing naevoid vs SSM, including after accounting for competing causes of death (SHR 0.40, 95% confidence interval (CI) 0.12-1.31), while among nodular/papillomatous naevoid melanoma patients, there were no melanoma deaths on follow-up. Two melanoma deaths occurred in Australian SSM patients, and none in maturing or nodular/papillomatous naevoid melanoma patients, after 5 years' minimum follow-up. None of the 7 Italian patients with maturing naevoid melanoma died of melanoma after nearly 12 years' average follow-up. CONCLUSIONS: There was no significant difference in risk of death from melanomas with naevoid features, and SSM. Nodular/ papillomatous naevoid melanoma patients did not carry higher risk of death than SSM patients though the very few cases of the papillomatous naevoid variant limited our assessment.

Associations of keratinocyte cancers with snp variants in the sonic hedgehog pathway.

BACKGROUND: Sonic Hedgehog (SHH) pathway dysregulation is implicated in basal cell carcinoma (BCC) development. To evaluate the possible wider role of SHH gene variants in skin carcinogenesis, we assessed associations of genes in the SHH pathway with lifetime development of any keratinocyte cancer (KC), and with developing either BCCs or squamous cell carcinomas (SCCs) exclusively, in a 25-year prospective, population-based study of 1,621 Australians. METHODS: We genotyped 795 unrelated adults with available blood samples: 311 cases with any KC (186 developing BCCs-only, 55 SCCs-only, 70 BCCs and SCCs) and 484 controls. We compared allele frequencies of 158 independent SNPs across 43 SHH genes between cases and controls, and performed a gene-based analysis. RESULTS: We found associations between SNP rs4848627 (GLI2) (related to DNA synthesis in keratinocytes) and development of any KC (OR = 1.53; 95% CI = 1.06-2.13, P < 0.01) and SCCs exclusively (OR = 2.12; 95%CI = 1.39-3.23, P < 0.01). SNP rs3217882 located in CCND2 was associated with exclusive BCC development (OR = 1.43, CI = 1.12-1.82, P < 0.01). The gene-based analysis suggested an association of PRKACG (protein kinase cAMP-activated catalytic subunit gamma) with any KC (P = 0.013). CONCLUSION: We conclude that variants located in genes in the SHH pathway may are involved in SCC as well as BCC development.

Hypothesised cutaneous sites of origin of stage III melanomas with unknown primary: A multicentre study.

Based on molecular evidence that melanomas with unknown primary (MUPs) arise from the skin, we hypothesised that sites of MUPs are disproportionately on trunk and lower limbs, sites that are not readily visible to patients and clinicians. We tested this hypothesis by inferring the anatomic site of origin of MUPs from the corresponding known cutaneous sites of melanoma patients with known primary tumours (MKPs). We analysed data from three separate cohorts of patients from Brisbane, Australia (n = 236); Manchester, UK (n = 51) and Padova, Italy (n = 33), respectively, who first presented with stage III melanoma with lymph node metastases. We matched two MKP patients to each MUP patient based on lymph node dissection (LND) site, age and sex, and imputed cutaneous sites of origin of MUPs from their two matched MKPs for study countries, giving two possible sites for each MUP per centre. Overall, results showed that MUP patients were predominantly male, and trunk was the most likely origin, comprising around a third to a half of MUPs across the three cohorts. The remaining MUP inferred sites varied by country. In the Australian cohort, the legs accounted for a third of imputed sites of MUPs, while in the UK and Italian cohorts, the most frequent site was the arms followed by the legs. Our findings suggest the need for regular and thorough skin examination on trunk and limbs, especially in males, to improve early detection of cutaneous melanoma and reduce the risk of metastatic disease at the time of presentation.

A generalist-specialist trade-off between switchgrass cytotypes impacts climate adaptation and geographic range.

Polyploidy results from whole-genome duplication and is a unique form of heritable variation with pronounced evolutionary implications. Different ploidy levels, or cytotypes, can exist within a single species, and such systems provide an opportunity to assess how ploidy variation alters phenotypic novelty, adaptability, and fitness, which can, in turn, drive the development of unique ecological niches that promote the coexistence of multiple cytotypes. Switchgrass, Panicum virgatum, is a widespread, perennial C4 grass in North America with multiple naturally occurring cytotypes, primarily tetraploids (4×) and octoploids (8×). Using a combination of genomic, quantitative genetic, landscape, and niche modeling approaches, we detect divergent levels of genetic admixture, evidence of niche differentiation, and differential environmental sensitivity between switchgrass cytotypes. Taken together, these findings support a generalist (8×)­specialist (4×) trade-off. Our results indicate that the 8× represent a unique combination of genetic variation that has allowed the expansion of switchgrass' ecological niche and thus putatively represents a valuable breeding resource.

Dark Green Leafy Vegetable Intake, MTHFR Genotype, and Risk of Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Evidence suggests that consumption of dark green leafy vegetables may influence the decrease in the risk of cutaneous squamous cell carcinoma (SCC). Dark green leafy vegetables contain folate as a main component among other nutrients; thus, we hypothesised that their possible observed protective effect on SCC, observed in previous studies, would be more evident in persons with specific genotypes related to folate metabolism. METHODS: Genotyping of methylenetetrahydrofolate reductase (MTHFR) gene variants rs1801133 (C677T) and rs1801131 (A1298C) was carried out for 1,128 participants in an Australian community-based longitudinal study of skin cancer. Dietary intakes were assessed through repeated Food Frequency Questionnaires (1992-1996), and all incident skin cancers were recorded in 1992-2007 and histologically confirmed. We assessed associations between intake of dark green leafy vegetables and SCC development in strata defined by genotype, by calculating relative risks (RRs) with 95% confidence intervals (CIs) using generalised linear models with negative binomial distribution and person-years of follow-up as offset. RESULTS: High versus low intake of dark green leafy vegetables was associated with a lower risk of SCC tumours in carriers of the C677T variant allele (RR = 0.42, 95% CI = 0.23-0.75), and within wild-type A1298C homozygotes (RR = 0.43, 95% CI = 0.22-0.85). CONCLUSION: The protective effect of dark green leafy vegetables on cutaneous SCC may be genotype-dependent. Folate metabolism-related gene polymorphisms should be considered when assessing the relation of green leafy vegetables to cancer risk.

Host genetic polymorphisms associated with beta human papillomavirus seropositivity.

Human papillomaviruses (HPVs) cause superficial epidermal infections and are only cleared if they trigger an immunological response. We analysed SNPs that had previously been investigated for association with HPV infection to determine whether they play a role in the serological response to cutaneous beta-HPVs in an Australian population. Serum samples from 1,142 participants were analysed for seropositivity against the L1 protein of 21 beta-HPV types. Associations between seropositivity to beta-HPV types and the SNPs rs9264942 (HLA-C; HPV-9, p = 0.022, HPV-15, p = 0.043 and HPV-17, p = 0.004), rs12449858 (EVER1; HPV-23, p = 0.029), and rs2981451 (FGFR2; HPV-22, p = 0.049) were identified. We found that certain SNPs could be involved in the serological response to beta-HPVs.

Discriminating Dietary Responses by Combining Transcriptomics and Metabolomics Data in Nutrition Intervention Studies.

SCOPE: Combining different "omics" data types in a single, integrated analysis may better characterize the effects of diet on human health. METHODS AND RESULTS: The performance of two data integration tools, similarity network fusion tool (SNFtool) and Data Integration Analysis for Biomarker discovery using Latent variable approaches for "Omics" (DIABLO; MixOmics), in discriminating responses to diet and metabolic phenotypes is investigated by combining transcriptomics and metabolomics datasets from three human intervention studies: a postprandial crossover study testing dairy foods (n = 7; study 1), a postprandial challenge study comparing obese and non-obese subjects (n = 13; study 2); and an 8-week parallel intervention study that assessed three diets with variable lipid content on fasting parameters (n = 39; study 3). In study 1, combining datasets using SNF or DIABLO significantly improve sample classification. For studies 2 and 3, the value of SNF integration depends on the dietary groups being compared, while DIABLO discriminates samples well but does not perform better than transcriptomic data alone. CONCLUSION: The integration of associated "omics" datasets can help clarify the subtle signals observed in nutritional interventions. The performance of each integration tool is differently influenced by study design, size of the datasets, and sample size.

Dietary Antioxidant Capacity and Skin Photoaging: A 15-Year Longitudinal Study.

The long-term effect of diet on skin aging is largely unknown, but evidence suggests that the antioxidants from foods may mitigate the main component of skin aging caused by sun exposure. We assessed the association between the total antioxidant capacity of foods people eat and the photoaging of their skin. In a community-based, prospective study among 777 Australian adults aged <55 years at baseline, we estimated the total dietary antioxidant capacity of participants' diets in 1992, 1994, and 1996 and graded photoaging severity using microtopography in 1992, 1996, and 2007. We used ordinal logistic regression and applied generalized estimating equations to estimate change in the degree of photoaging associated with increasing total antioxidant capacity compared with the group with the lowest antioxidant capacity, separately in younger (≤45 years) and older (>45 years) adults. In the 15-year study period, the overall prevalence of severe skin photoaging increased from 42% at baseline to 88%. Adults aged >45 years who consumed foods with high antioxidant capacity experienced approximately 10% less photoaging over 15 years than those who ate foods with low antioxidant capacity. No association was found among adults aged ≤45 years. Foods rich in antioxidants as measured by antioxidant capacity may retard skin aging among healthy men and women aged >45 years.

Anxiety and depression after diagnosis of high-risk primary cutaneous melanoma: a 4-year longitudinal study.

PURPOSE: To quantify the prevalence of anxiety or depression (overall; melanoma-related) among people with high-risk primary melanoma, their related use of mental health services and medications, and factors associated with persistent new-onset symptoms across 4 years post-diagnosis. METHODS: A longitudinal study of 675 patients newly diagnosed with tumor-stage 1b-4b melanoma. Participants completed the Hospital Anxiety and Depression Scale and answered questions about fear of cancer recurrence, use of medication, and support, serially over 4 years. We identified anxiety and depression trajectories with group-based trajectories models and factors associated with persistent symptoms with logistic regression. RESULTS: At diagnosis, 93 participants (14%) had melanoma-related anxiety or depression, and 136 (20%) were affected by anxiety and/or depression unrelated to melanoma. After 6 months, no more than 27 (5%) reported melanoma-related anxiety or depression at any time, while the point prevalence of anxiety and depression unrelated to melanoma was unchanged (16-21%) among the disease-free. Of 272 participants reporting clinical symptoms of any cause, 34% were taking medication and/or seeing a psychologist or psychiatrist. Of the participants, 11% (n = 59) had new-onset symptoms that persisted; these participants were more likely aged < 70. CONCLUSIONS: Melanoma-related anxiety or depression quickly resolves in high-risk primary melanoma patients after melanoma excision, while prevalence of anxiety or depression from other sources remains constant among the disease-free. However, one-in-ten develop new anxiety or depression symptoms (one-in-twenty melanoma-related) that persist. IMPLICATIONS FOR CANCER SURVIVORS: Chronic stress has been linked to melanoma progression. Survivors with anxiety and depression should be treated early to improve patient and, potentially, disease outcomes.

Comparison of Cardiovascular Risk Factors in European Population Cohorts for Predicting Atrial Fibrillation and Heart Failure, Their Subsequent Onset, and Death.

Background Differences in risk factors for atrial fibrillation (AF) and heart failure (HF) are incompletely understood. Aim of this study was to understand whether risk factors and biomarkers show different associations with incident AF and HF and to investigate predictors of subsequent onset and mortality. Methods and Results In N=58 693 individuals free of AF/HF from 5 population-based European cohorts, Cox regressions were used to find predictors for AF, HF, subsequent onset, and mortality. Differences between associations were estimated using bootstrapping. Median follow-up time was 13.8 years, with a mortality of 15.7%. AF and HF occurred in 5.0% and 5.4% of the participants, respectively, with 1.8% showing subsequent onset. Age, male sex, myocardial infarction, body mass index, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) showed similar associations with both diseases. Antihypertensive medication and smoking were stronger predictors of HF than AF. Cholesterol, diabetes mellitus, and hsCRP (high-sensitivity C-reactive protein) were associated with HF, but not with AF. No variable was exclusively associated with AF. Population-attributable risks were higher for HF (75.6%) than for AF (30.9%). Age, male sex, body mass index, diabetes mellitus, and NT-proBNP were associated with subsequent onset, which was associated with the highest all-cause mortality risk. Conclusions Common risk factors and biomarkers showed different associations with AF and HF, and explained a higher proportion of HF than AF risk. As the subsequent onset of both diseases was strongly associated with mortality, prevention needs to be rigorously addressed and remains challenging, as conventional risk factors explained only 31% of AF risk.

Patterns of Omega-3 and Omega-6 Fatty Acid Dietary Intake and Melanoma Thickness at Diagnosis.

BACKGROUND: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking. METHODS: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression. RESULTS: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: "meat, fish, and fat," positively correlated with intakes of all fatty acids; and "fish, low-meat, and low-fat," positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the "meat, fish, and fat" pattern (PR, 1.40; 95% CI, 1.01-1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15-2.92) or a family history (PR, 2.32; 95% CI, 1.00-5.35). The "fish, low-meat, and low-fat" pattern was not associated with melanoma thickness. CONCLUSIONS: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas. IMPACT: High omega-3 and omega-6 fatty acid intakes may contribute to patients' presentation with thick melanomas.

Antibiograms Cannot Be Used Interchangeably Between Acute Care Medical Centers and Affiliated Nursing Homes.

OBJECTIVE: To determine whether antibiograms for Veterans Affairs (VA) nursing homes (NHs), termed Community Living Centers, are similar to those from their affiliated acute care medical centers. DESIGN: Descriptive study. SETTING AND PARTICIPANTS: We compared the 2017 antibiograms for VA NHs to their affiliated VA medical centers (VAMCs). Antibiograms included antibiotic susceptibility rates for commonly observed bacteria in this setting (Staphylococcus aureus, Enterococcus spp, Escherichia coli, Klebsiella spp, Proteus mirabilis, and Pseudomonas aeruginosa). METHODS: Antibiograms were considered to be in complete agreement when the overall susceptibility rate between the NH and affiliated VAMC was either at or above 80% or below 80% across all bacteria and antibiotics. Average percentage of bacteria-antibiotic comparisons in disagreement per facility pair, and number of facilities with agreement for specific bacteria-antibiotic comparisons were also assessed. The chi-square test was used to compare disagreement between NH-VAMC facilities based on geographic proximity of the NH to the VAMC, culture source, and bed size. RESULTS: A total of 119 NH-VAMC affiliate pairs were included in this analysis, with 71% (84/119) on the same campus and 29% (35/119) on geographically distinct campuses. None of the NH-VAMC pairs demonstrated complete agreement (all bacteria vs all antibiotics) between their antibiograms. On average, 20% of the bacteria-antibiotic comparisons from the antibiogram disagreed clinically per NH-VAMC pair, and almost twice as often the nursing home had lower susceptibility (higher resistance) than the acute care facility. Some bacteria-antibiotic comparisons agreed in all facilities (eg, E coli-imipenem; S aureus-linezolid; S aureus-vancomycin), while others showed greater disagreement (eg, Klebsiella spp-cefazolin; Klebsiella spp-ampicillin-sulbactam; P aeruginosa-ciprofloxacin). Rates of clinical disagreement were similar by geographic proximity of the NH to the VAMC, culture source, and bed size. CONCLUSIONS AND IMPLICATIONS: Overall, this study showed a moderate lack of agreement between VA NH antibiograms and their affiliate VAMC antibiograms. Our data suggest that antibiograms of acute care facilities are often not accurate approximations of the nursing home resistance patterns and therefore should be used with caution (if at all) in guiding empiric antibiotic therapy.

A Review of Nonantibiotic Agents to Prevent Urinary Tract Infections in Older Women.

OBJECTIVE: This article provides a comprehensive literature review on nonantibiotic agents used for the prevention of urinary tract infections (UTIs) in women ≥45 years of age. DESIGN: A structured review was performed by conducting a literature search to identify relevant studies pertaining to the use of nonantibiotic agents to prevent UTIs in women who were perimenopausal through postmenopausal. Recommendations were made for or against the use of each nonantibiotic agent, unless data were unavailable. Levels of evidence were assigned to each recommendation made. SETTING AND PARTICIPANTS: Studies on the prevention of UTIs with women subjects ≥45 years of age in the community, inpatient, and long-term care settings were considered for inclusion. MEASURE: The efficacy and safety of using ascorbic acid, cranberry products, d-mannose, estrogens, lactobacilli, and methenamine hippurate for prevention of UTIs was assessed. RESULTS: There is evidence to support use of estrogens (A-I) in postmenopausal women, and cranberry capsules (C-I) in women ≥45 years of age for the prevention of UTIs. There was a lack of evidence to make recommendations for or against the use of ascorbic acid, cranberry juice, cranberry capsules with high proanthocyanidin (PAC) content, d-mannose, lactobacillus, and methenamine hippurate in this population. CONCLUSIONS/IMPLICATIONS: Current studies support that estrogens and cranberry capsules may have a role in preventing UTIs in women ≥45 years of age. Further research is needed to elucidate the role of these nonantibiotic agents and how they may be used to decrease antibiotic use.

Trends in Collection of Microbiological Cultures Across Veterans Affairs Community Living Centers in the United States Over 8 Years.

OBJECTIVES: To describe and evaluate changes in the collection of microbiological cultures across Veterans Affairs (VA) Community Living Centers (CLCs) nationally. DESIGN: Descriptive study. SETTING: 146 VA CLCs. PARTICIPANTS: We identified both positive and negative microbiological cultures collected during VA CLC admissions from January 2010 through December 2017. MEASURES: We measured the average annual percentage change (AAPC) in the rate of cultures collected per 1000 bed days and per admission, overall and stratified by culture type (ie, urine, blood, skin and soft tissue, and respiratory tract). AAPCs were also calculated for the proportion and rate of positive cultures collected, overall and stratified by culture type and organism (ie, Escherichia coli, Proteus mirabilis, Staphylococcus aureus, Enterococcus spp, Pseudomonas aeruginosa, Klebsiella spp, Enterobacter spp, Morganella morganii, Citrobacter spp, Serratia marcescens, and Streptococcus pneumoniae). Joinpoint regression software was used to assess trends and estimate AAPCs and 95% confidence intervals (CIs). RESULTS: Over 8 years, 355,329 cultures were collected. The rate of cultures collected per 1000 bed days of care decreased significantly by 6.0% per year (95% CI -8.7%, -3.2%). The proportion of positive cultures decreased by 0.9% (95% CI -1.4%, -0.4%). The most common culture types were urine (48.4%), followed by blood (27.7%). The rate of cultures collected per 1000 bed days of care decreased per year by 6.3% for urine, 5.0% for blood, 4.4% for skin and soft tissue, and 4.9% for respiratory tract. In 2010, S aureus was the most common organism identified, and in all subsequent years E coli was the most common. CONCLUSION AND IMPLICATIONS: We identified a significant reduction in the number of cultures collected over time among VA CLCs. Our findings may be explained by decreases in the collection of unnecessary cultures in VA CLCs nationally due to increased antibiotic stewardship efforts targeting unnecessary culturing and antibiotic treatment.