Antibiotic Susceptibility and Therapy in Central Line Infections in Pediatric Home Parenteral Nutrition Patients.

BACKGROUND: Patients receiving home parenteral nutrition (HPN) are at high-risk for central line-associated bloodstream infections (CLABSI). There are no published management guidelines, however, for the antibiotic treatment of suspected CLABSI in this population. Historical microbiology data may help inform empiric antimicrobial regimens in this population. OBJECTIVE: The aim of the study was to describe antimicrobial resistance patterns and determine the most appropriate empiric antibiotic therapy in HPN-dependent children experiencing a community-acquired CLABSI. METHODS: Single-center retrospective cohort study evaluating potential coverage of empiric antibiotic regimens in children on HPN who developed a community-acquired CLABSI. RESULTS: From October 1, 2011 to September 30, 2017, there were 309 CLABSI episodes among 90 HPN-dependent children with median age 3.8 years old.Fifty-nine percent of patients carried the diagnosis of surgical short bowel syndrome. Organisms isolated during these infections included 60% Gram-positive bacteria, 34% Gram-negative bacteria, and 6% fungi. Among all staphylococcal isolates, 51% were methicillin sensitive. Among enteric Gram-negative organisms, sensitivities were piperacillin-tazobactam 71%, cefepime 97%, and meropenem 99%. Organisms were sensitive to current institutional standard therapy with vancomycin and piperacillin-tazobactam in 69% of cases compared with vancomycin and cefepime or vancomycin an meropenem in 85% and 96% of cases (both P < 0.01). CONCLUSIONS: Empiric antimicrobial therapy for suspected CLABSI in HPN-dependent children should include therapy for methicillin-resistant staphylococci as well as enteric Gram-negative organisms. Future studies are needed to evaluate clinical outcomes based upon evidence-based antimicrobial regimens.

Effect of Instrument-Based Vision Screening for 3- to 5-Year-Old Children on Referrals to Eye Care Specialists.

Recently, several professional groups have recommended a change from chart-based to instrument-based screening for preschool-age children, but the effect of this change on health care utilization is unknown. We performed a secondary analysis of a site-randomized quality improvement project on transitioning from chart-based to instrument-based vision screening for 3- to 5-year-old children in primary care. We analyzed visit rates to ophthalmologists and optometrists and costs of such care before and after implementation of instrument-based vision screening with comparison to nonparticipating practices. The implementation of instrument-based vision screening resulted in a decrease in visits to eye care specialists from 83.1 visits per 1000 children per year to 55.0, a reduction of 33.8%; no comparable reduction was seen in nonparticipating practices. The cost of services by eye care specialists fell from $65 715 per 1000 children per year prior to $55 740, a decline of 15.2%; similar costs among control practices rose 13.4%.

Resource reduction in pediatric chest pain: Standardized clinical assessment and management plan.

OBJECTIVE: Using a Standardized Clinical Assessment and Management Plan (SCAMP) for pediatric patients presenting to clinic with chest pain, we evaluated the cost impact associated with implementation of the care algorithm. Prior to introduction of the SCAMP, we analyzed charges for 406 patients with chest pain, seen in 2009, and predicted 21% reduction of overall charges had the SCAMP methodology been used. The SCAMP recommended an echocardiogram for history, examination, or ECG findings suggestive of a cardiac etiology for chest pain. DESIGN: Resource utilization was reviewed for 1517 patients (7-21 years) enrolled in the SCAMP from July 2010 to April 2014. RESULTS: Compared to the 2009 historic cohort, patients evaluated by the SCAMP had higher rates of exertional chest pain (45% vs 37%) and positive family history (5% vs 1%). The SCAMP cohort had fewer abnormal physical examination findings (1% vs 6%) and abnormal electrocardiograms (3% vs 5%). Echocardiogram use increased in the SCAMP cohort compared to the 2009 historic cohort (45% vs 41%), whereas all other ancillary testing was reduced: exercise stress testing (4% SCAMP vs 28% historic), Holter (4% vs 7%), event monitors (3% vs 10%), and MRI (1% vs 2%). Total charges were reduced by 22% ($822 625) by use of the Chest Pain SCAMP, despite a higher percentage of patients for whom echocardiogram was recommended compared to the historic cohort. CONCLUSIONS: The Chest Pain SCAMP effectively streamlines cardiac testing and reduces resource utilization. Further reductions can be made by algorithm refinement regarding echocardiograms for exertional symptoms.

Implementation of Instrument-Based Vision Screening for Preschool-Age Children in Primary Care.

BACKGROUND: Vision screening is an essential element of well-child care for young children. Recently, several professional groups have recommended the use of instrument-based screening; however, studies demonstrating the effectiveness of this technique in pediatric primary care settings are lacking. METHODS: We designed a cluster randomized quality improvement project to test the implementation of instrument-based vision screening for 3- to 5-year-old children within a pediatric primary care network. The program consisted of 12 pediatric practices randomized into phase 1 and phase 2 groups. We evaluated the effect of the intervention on completed vision screening at well-child visits, family satisfaction, and referrals to eye care specialists. RESULTS: Instrument-based vision screening increased completed screening among 3- to 5-year-old children from 54% to 89% in the phase 1 group and from 65% to 92% in the phase 2 group. Improvement was most marked among 3-year-old children, with completed screening increasing from 39% with chart-based screening to 87% with instrument screening. Family satisfaction was higher with instrument screening. In addition, instrument screening was associated with a 15% reduction in referrals to eye care specialists. CONCLUSIONS: Instrument-based vision screening for preschool-aged children can be effectively implemented into primary care practice, results in substantially improved rates of completed vision screening at well-child visits, and may result in a reduction in unnecessary referrals to eye care specialists. Additional research is needed regarding how best to overcome barriers to the widespread use of this technology in pediatric primary care settings, as well as its longer-term effect on referrals and the prevalence of amblyopia.

A Decision-Making Algorithm for Initiation and Discontinuation of RRT in Severe AKI.

BACKGROUND AND OBJECTIVES: AKI is an increasingly common and devastating complication in hospitalized patients. Severe AKI requiring RRT is associated with in-hospital mortality rates exceeding 40%. Clinical decision making related to RRT initiation for patients with AKI in the medical intensive care unit is not standardized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a 13-month (November of 2013 to December of 2014) prospective cohort study in an academic medical intensive care unit involving the implementation of an AKI Standardized Clinical Assessment and Management Plan, a decision-making algorithm to assist front-line clinicians caring for patients with AKI. The Standardized Clinical Assessment and Management Plan algorithms provided recommendations about optimal indications for initiating and discontinuing RRT on the basis of various clinical parameters; 176 patients managed by nine nephrologists were included in the study. We captured reasons for deviation from the recommended algorithm as well as mortality data. RESULTS: Patients whose clinicians adhered to the Standardized Clinical Assessment and Management Plan recommendation to start RRT had lower in-hospital mortality (42% versus 63%; P<0.01) and 60-day mortality (46% and 68%; P<0.01), findings that were confirmed after multivariable adjustment for age, albumin, and disease severity. There was a differential effect of Standardized Clinical Assessment and Management Plan adherence in low (<50% mortality risk) versus high (≥50% mortality risk) disease severity on in-hospital mortality (interaction term P=0.02). In patients with low disease severity, Standardized Clinical Assessment and Management Plan adherence was associated with lower in-hospital mortality (odds ratio, 0.21; 95% confidence interval, 0.08 to 0.54; P=0.001), but no significant association was evident in patients with high disease severity. CONCLUSIONS: Physician adherence to an algorithm providing recommendations on RRT initiation was associated with lower in-hospital mortality.

A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis.

OBJECTIVE: To define a pharmacodynamic biomarker based on gene expression in skin that would provide a biologic measure of the extent of disease in patients with diffuse cutaneous systemic sclerosis (dcSSc) and could be used to monitor skin disease longitudinally. METHODS: Skin biopsy specimens obtained from a cohort of patients with dcSSc (including longitudinal specimens) were analyzed by microarray. Expression of genes correlating with the modified Rodnan skin thickness score (MRSS) were examined for change over time using a NanoString platform, and a generalized estimating equation (GEE) was used to define and validate longitudinally measured pharmacodynamic biomarkers composed of multiple genes. RESULTS: Microarray analysis of genes parsed to include only those correlating with the MRSS revealed prominent clusters of profibrotic/transforming growth factor ß-regulated, interferon-regulated/proteasome, macrophage, and vascular marker genes. Using genes changing longitudinally with the MRSS, we defined 2 multigene pharmacodynamic biomarkers. The first was defined mathematically by applying a GEE to longitudinal samples. This modeling method selected cross-sectional THBS1 and longitudinal THBS1 and MS4A4A. The second model was based on a weighted selection of genes, including additional genes that changed statistically significantly over time: CTGF, CD163, CCL2, and WIF1. In an independent validation data set, biomarker levels calculated using both models correlated highly with the MRSS. CONCLUSION: Skin gene expression can be used effectively to monitor changes in SSc skin disease over time. We implemented 2 relatively simple models on a NanoString platform permitting highly reproducible assays that can be applied directly to samples from patients or collected as part of clinical trials.

Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients.

BACKGROUND: TGF-ß has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-ß-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-ß may benefit these patients. METHODS: Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-ß isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-ß-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). RESULTS: In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-ß-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. CONCLUSION: The rapid inhibition of TGF-ß-regulated gene expression in response to fresolimumab strongly implicates TGF-ß in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov NCT01284322.

Small molecule inhibition of cytoskeletal dynamics in melanoma tumors results in altered transcriptional expression patterns of key genes involved in tumor initiation and progression.

BACKGROUND: Rho kinase signaling plays an important role in the oncogenic process largely through its regulation of F-actin dynamics, and inhibition of this pathway results in reduction in tumor volume and metastasis across a number of tumor types. While the cytoskeletal-regulatory role of Rho kinase has been a topic of in-depth study, the mechanisms linking Rho kinase to altered gene expression are largely unknown. MATERIALS AND METHODS: Global gene expression analysis was performed on melanoma tumors treated with sham or the small molecule inhibitor Y27632. RESULTS: Inhibition of Rho kinase activity in melanoma tumors results in a statistically significant change in gene transcription of 94 genes, many of which are critically involved in tumor initiation and progression. CONCLUSION: In addition to regulating tumorigenesis through modulation of the phosphoproteome, Rho kinase signaling also contributes to the regulation of the tumor transcriptome.