Scope and Predictive Genetic/Phenotypic Signatures of Bicarbonate (NaHCO3) Responsiveness and β-Lactam Sensitization in Methicillin-Resistant Staphylococcus aureus.

Addition of sodium bicarbonate (NaHCO3) to standard antimicrobial susceptibility testing medium reveals certain methicillin-resistant Staphylococcus aureus (MRSA) strains to be highly susceptible to β-lactams. We investigated the prevalence of this phenotype (NaHCO3 responsiveness) to two β-lactams among 58 clinical MRSA bloodstream isolates. Of note, ∼75% and ∼36% of isolates displayed the NaHCO3 responsiveness phenotype to cefazolin (CFZ) and oxacillin (OXA), respectively. Neither intrinsic β-lactam MICs in standard Mueller-Hinton broth (MHB) nor population analysis profiles were predictive of this phenotype. Several genotypic markers (clonal complex 8 [CC8]; agr I and spa t008) were associated with NaHCO3 responsiveness for OXA

A Combined Phenotypic-Genotypic Predictive Algorithm for In Vitro Detection of Bicarbonate: β-Lactam Sensitization among Methicillin-Resistant Staphylococcus aureus (MRSA).

Antimicrobial susceptibility testing (AST) is routinely used to establish predictive antibiotic resistance metrics to guide the treatment of bacterial pathogens. Recently, a novel phenotype termed "bicarbonate (NaHCO3)-responsiveness" was identified in a relatively high frequency of clinical MRSA strains, wherein isolates demonstrate in vitro "susceptibility" to standard β-lactams (oxacillin [OXA]; cefazolin [CFZ]) in the presence of NaHCO3, and in vivo susceptibility to these β-lactams in experimental endocarditis models. We investigated whether a targeted phenotypic-genotypic screening of MRSA could rule in or rule out NaHCO3 susceptibility upfront. We studied 30 well-characterized clinical MRSA bloodstream isolates, including 15 MIC-susceptible to CFZ and OXA in NaHCO3-supplemented Mueller-Hinton Broth (MHB); and 15 MIC-resistant to both β-lactams in this media. Using a two-tiered strategy, isolates were first screened by standard disk diffusion for susceptibility to a combination of amoxicillin-clavulanate [AMC]. Isolates then underwent genomic sequence typing: MLST (clonal complex [CC]); agr; SCCmec; and mecA promoter and coding region. The combination of AMC disk susceptibility testing plus mecA and spa genotyping was able to predict MRSA strains that were more or less likely to be NaHCO3-responsive in vitro, with a high degree of sensitivity and specificity. Validation of this screening algorithm was performed in six strains from the overall cohort using an ex vivo model of endocarditis. This ex vivo model recapitulated the in vitro predictions of NaHCO3-responsiveness vs. nonresponsiveness above in five of the six strains

A new bronchodilator response grading strategy ıdentifies distinct patient populations

Rationale: A positive bronchodilator response (BDR) according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines require both 200 ml and 12% increase in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) after bronchodilator inhalation. This dual criterion is insensitive in those with high or low FEV1. Objectives: To establish BDR criteria with volume or percentage FEV1 change. Methods: The largest FEV1 and FVC were identified fromthree pre- and three post-bronchodilator maneuvers in COPDGene (Genetic Epidemiology of COPD) participants. A total of 7,741 individuals with coefficient of variation less than 15% for both FEV1 and FVC formed bronchodilator categories of FEV1 response: negative (0.00% to 0.00 L to 9.00% to 16.00% to 0.16 L to 26.00% or >0.26 L). These response size categories are based on empirical limits considering average FEV1 increase of approximately 160 ml and the clinically important difference for FEV1. To compare flow and volume response characteristics, BDR-FEV1 category assignments were applied for the BDR-FVC response. Results: Twenty percent met mild and 31% met moderate or marked BDR-FEV1 criteria, whereas 12% met mild and 33% met moderate or marked BDR-FVC criteria. In contrast, only 20.6% met ATS/ERS positive criteria. Compared with the negative BDR-FEV1 category, the minimal, mild, moderate, and marked BDR-FEV1 categories were associated with greater 6-minute-walk distance and lower St. George's Respiratory Questionnaire and modified Medical Research Council dyspnea scale scores. Compared with negative BDR, moderate and marked BDR-FEV1 categories were associated with fewer exacerbations, and minimal BDR was associated with lower computed tomography airway wall thickness. Compared with the negative category, all BDR-FVC categories were associated with increasing emphysema percentage and gas trapping percentage. Moderate and marked BDR-FVC categories were associated with higher St. George's Respiratory Questionnaire scores but fewer exacerbations and lower dyspnea scores. Conclusions: BDR grading by FEV1 volume or percentage response identified subjects otherwise missed by ATS/ERS criteria. BDR grades were associated with functional exercise performance, quality of life, exacerbation frequency, dyspnea, and radiological airway measures. BDR grades in FEV1 and FVC indicate different clinical and radiological characteristics.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI)National Center for Advancing Translational Sciences through UCLA CTSI Gran

A novel spirometric measure identifies mild COPD unidentified by standard criteria

BACKGROUND: In chronic obstructive pulmonary disease, both smaller and larger airways are affected. FEV1 mainly reflects large airways obstruction, while the later fraction of forced exhalation reflects reduction in terminal expiratory flow. In this study, the objective was to evaluate the relationship between spirometric ratios, including the ratio of forced expiratory volume in 3 and 6 seconds (FEV3/FEV6), and small airways measures and gas trapping at quantitative chest CT scanning, and clinical outcomes in the Genetic Epidemiology of COPD (COPDGene) cohort. METHODS: Seven thousand eight hundred fifty-three current and ex-smokers were evaluated for airflow obstruction by using recently defined linear iteratively derived equations of Hansen et al to determine lower limit of normal (LLN) equations for prebronchodilator FEV1/FVC, FEV1/FEV6, FEV3/FEV6, and FEV3/FVC. General linear and ordinal regression models were applied to the relationship between prebronchodilator spirometric and radiologic and clinical data. RESULTS: Of the 10,311 participants included in the COPDGene phase I study, participants with incomplete quantitative CT scanning or relevant spirometric data were excluded, resulting in 7,853 participants in the present study. Of 4,386 participants with FEV1/FVC greater than or equal to the LLN, 15.4% had abnormal FEV3/FEV6. Compared with normal FEV3/FEV6 and FEV1/FVC, abnormal FEV3/FEV6 was associated with significantly greater gas trapping; St. George's Respiratory Questionnaire score; modified Medical Research Council dyspnea score; and BMI, airflow obstruction, dyspnea, and exercise index and with shorter 6-min walking distance (all P < .0001) but not with CT scanning evidence of emphysema. CONCLUSIONS: Current and ex-smokers with prebronchodilator FEV3/FEV6 less than the LLN as the sole abnormality identifies a distinct population with evidence of small airways disease in quantitative CT scanning, impaired indexes of physical function and quality of life otherwise deemed normal by using the current spirometric definition.United States Department of Health & Human Services - R01 HL 08 9856 - R01 HL 08 9897National Institutes of Health (NIH) - USA - 1KL2TR001419NIH National Heart Lung & Blood Institute (NHLBI) - UL1TR001417 - KL2TR001419 - UL1TR001881NIH National Center for Advancing Translational Sciences (NCATS) - U01HL089897 - U01HL089856 - R01HL124233 - R01HL089856 - R01HL08989

Does early enteral calories in ARDS improve outcome? A retrospective evaluation of the EDEN trial

Summary: Objective: To determine if calories delivered within the first 6-days of mechanical ventilation for ARDS improved 60-day mortality in patients with ARDS. Design and Setting: Retrospective evaluation of randomized open label, multicenter trial; NIH ARDS Net. Patients: ARDS patients who had received mechanical ventilation for 3000 kcal group (21.5% ± 4.5 vs 5.8 ± 2.4%, P 100, Bilirubin, Phosphorus, bacteremia and ventilatory fee days appeared to be significant co-factors with a HR of 2.36 (CI: 1.45–3.85, P = 0.005) for the observed increased mortality rate seen in the low-calorie group. Conclusion: Receiving > 3000 kcal within the first 6-days of mechanical ventilation for ARDS was associated with a lower mortality. Six additional factors appear to influence higher mortality observed in the low-calorie group. Strategies to identify factors that explain this observed increased mortality and ways to reduce this risk in prospective randomized clinical trials are needed. Clinical Trials Identifier: NCT00609180 and NCT00883948

Dynamic left ventricular outflow tract obstruction : clinical and echocardiographic risk factor association in critically ill patients

Journal Article published 6 Aug 2016 in Research in Cardiovascular Medicine, volume Inpress, issue Inpress..Originally published: Mittal, M. K., Pak, Y., Dellsperger, K. C., & Chockalingam, A. (2016). Dynamic Left Ventricular Outflow Tract Obstruction: Clinical and Echocardiographic Risk Factor Association in Critically Ill Patients. Research in Cardiovascular Medicine, Inpress(Inpress). doi:10.5812/cardiovascmed.35012Background: Dynamic left ventricular outflow tract obstruction (LVOTO) is increasingly recognized in critically ill patients and is a cause of significant morbidity and mortality. OBJECTIVES: To identify clinical risk predictors that may identify patient at high-risk of developing LVOTO based on their echocardiographic features. METHODS: Clinical and demographic data of all patients diagnosed with acute LVOTO were matched with a randomly derived control group to develop a clinical scoring model (development cohort). Subsequently, a cross sectional study was conducted to validate the scoring model using 143 consecutive patients admitted to intensive care units who underwent echocardiography (validation cohort). A blinded observer classified all patients as either high or low echocardiographic risk for developing LVOTO. Results: The retrospective cross sectional study (of validation cohort) could not validate the clinical score (developed from the development cohort) because it did not differentiate between different LVOTO risk groups (P = 0.54). Univariate analysis suggested female gender (high vs low risk, 64% vs 32%; P = 0.009), age > 60 years (74.8 14.1 vs 57.8 18.4; P = 0.0004) and lack of inotrope use (35% vs 61%; P = 0.03) to be significantly associated with high-risk LVOTO group. All other variables were statistically non-significant. Based on the multiple logistic regression analysis, age > 60 (P = 0.003) was found to be the only independent predictor of high risk for developing LVOTO, with the estimated area under the ROC curve being 0.81. CONCLUSIONS: Elderly patients are at high risk of developing dynamic LVOTO. Other clinical and demographic parameters did not reliably predict risk in our study. Further studies are warranted to improve risk prediction and identification of this, rare but potentially life threatening, cardiac condition before its clinical manifestation.Mayank K Mittal (1), Youngju Pak (2), Kevin C Dellsperger (3) and Anand Chockalingam (1). -- 1) Division of Cardiovascular Medicine, Department of Medicine, University of Missouri--Columbia, Missouri, United States ; 2) Department of Biostatistics, UCLA Clinical and Translational Science Institute, Torrance, CA, United States ; 3) Georgia Regents Health System, Augusta, GA, United States ; Corresponding author: Anand Chockalingam, Associate Professor of Clinical Medicine, Division of Cardiology, University of Missouri--Columbia

Use of Dipstick Assay and Rapid PCR-DNA Analysis of Nasal Secretions for Diagnosis of Bacterial Sinusitis in Children With Chronic Cough

Background Chronic cough in children is a diagnostic challenge. Objective To discover the utility of nasal dipsticks and polymerase chain reaction (PCR)-DNA analysis in differentiating bacterial sinusitis from other causes of chronic cough and identifying pathogens from the nasal cavity. Method We recruited 22 patients under 15 years of age with cough lasting longer than 4 weeks (group 1), 7 controls with allergic rhinitis (group 2), and 10 controls without respiratory symptoms (group 3). Based on symptoms, the results of nasal secretion assays, and nasal endoscopy, a diagnosis of clinical bacterial sinusitis was made. We identified potential pathogens by quantitative PCR of nasal secretions. Results Group 1A (cough with clinical bacterial sinusitis n = 10): Eight (80%) patients had bacterial sinusitis associated with dominant potential pathogenic bacteria (PPB): Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis . Group 1B (cough without clinical bacterial sinusitis n = 12): None had dominant PPB. Group 2 (allergic rhinitis n = 7): None had dominant PPB. Group 3 (asymptomatic n = 10): None had dominant PPB. Twenty to 57% of all groups were colonized with Staphylococcus aureus . Fifty to 70% were colonized with Staphylococcus epidermidis , Corynebacterium pseudodiphtheriticum , and Dolosigranulum pigrum . Conclusion In children with chronic cough, clinicians can utilize a simple and inexpensive nasal secretion dipstick assay for rapid diagnosis of sinusitis and identify PPB by DNA-PCR test for specific antibiotic treatment

The Effect of Testosterone Replacement Therapy on Nonalcoholic Fatty Liver Disease in Older Hypogonadal Men.

ContextMale hypogonadism is associated with visceral obesity and the metabolic syndrome: factors important for the development of nonalcoholic fatty liver disease (NAFLD). The Testosterone Trials (The T Trials) showed testosterone (T) treatment compared to placebo in older hypogonadal men was associated with decreases in cholesterol and insulin levels suggesting that T treatment may improve NAFLD.ObjectiveCompare effects of T versus placebo treatment on NAFLD scores and liver scans in elderly hypogonadal men.MethodsSecondary data analyses from 479 older hypogonadal men with total T &lt;275 ng/dL from The T Trials were performed. Three clinical liver fat scores: lipid accumulation product (LAP) index, hepatic steatosis index (his), nonalcoholic fatty liver disease-metabolic syndrome (NAFLD-MS) score, and liver computed tomography (CT) Hounsfield unit (HU) and liver to spleen ratio (LSR) were evaluated at baseline and 12 months after treatment.ResultsThere were no statistically significant differences of change in LAP index (p=0.98), HSI (p=0.67), and NAFLD-MS (p=0.52) in 246 men treated with T compared to 233 treated with placebo for 12 months. Liver CT showed no statistically significant difference of change in HU (p=0.24; n=71 for T, n=69 for placebo) and LSR (p=0.74; n=55 for T, n=62 for placebo) between the two groups.ConclusionsOur study did not show improvement of NAFLD in older hypogonadal men after 12 months of T versus placebo treatment, as assessed by three clinical scores and liver CT for hepatic steatosis. Future studies with longer treatment duration and additional NAFLD diagnostic modalities as primary outcome are warranted