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BACKGROUND Hospital-acquired pneumonia (HAP) and the need for positive-pressure ventilation (PPV) are significant postoperative pulmonary complications (PPCs) that increase patients' lengths of stay, mortality, and costs. Current tools used to predict PPCs use nonmodifiable preoperative factors; thus, they cannot assess provided respiratory therapy effectiveness. The Respiratory Assessment and Allocation of Therapy (RAAT) tool was created to identify HAP and the need for PPV and assist in assigning respiratory therapies. This study aimed to assess the RAAT tool's reliability and validity and determine if allocated respiratory procedures based on scores prevented HAP and the need for PPV. METHODS Electronic medical record data for nonintubated surgical ICU subjects scored with the RAAT tool were pulled from July 1, 2015-January 31, 2016, using a consecutive sampling technique. Sensitivity, specificity, and jackknife analysis were generated based on total RAAT scores. A unit-weighted analysis and mean differences of consecutive RAAT scores were analyzed with RAAT total scores ≥ 10 and the need for PPV. RESULTS The first or second RAAT score of ≤ 5 (unlikely to receive PPV) and ≥ 10 (likely to receive PPV) provided a sensitivity of 0.833 and 0.783 and specificity of 0.761 and 0.804, respectively. Jackknifed sensitivity and specificity for identified cutoffs above were 0.800-0.917 and 0.775-0.739 for the first RAAT score and 0.667-0.889 and 0.815-0.79 for the second RAAT score. The initial RAAT scores of ≥ 10 predicted the need for PPV (P < .001) and was associated with higher in-hospital mortality (P < .001). Mean differences between consecutive RAAT scores revealed decreasing scores did not need PPV. CONCLUSIONS The RAAT scoring tool demonstrated an association with the need for PPV using modifiable factors and appears to provide a quantitative method of determining if allocated respiratory therapy is effective.

Background: SeptiCyte RAPID is a molecular test for distinguishing sepsis from non-infectious systemic inflammation. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospective (banked) and prospectively collected patient samples. Methods: The cartridge-based SeptiCyte RAPID assay accepts a PAXgene blood RNA sample and provides sample-to-answer processing in about 1 hour. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (banked) and prospective samples from adult patients in ICU either having systemic inflammatory response syndrome (SIRS), or suspected of sepsis under either the Sepsis-2 or Sepsis-3 definition were tested, and results were compared to a gold standard of clinical evaluation by a blinded, three-physician external panel. A multivariable analysis was performed, in which SeptiScore was combined with other clinical variables. Results: With adjudication under the Sepsis-2 definition, SeptiCyte RAPID performance for the complete cohort (356 retrospective + 63 prospective patients) had Area Under the ROC Curve (AUC) ranging from 0.82-0.85, negative predictive value 0.91 (sensitivity 0.94) for SeptiScores between 0.1 and 5.0 (Band 1, lowest risk of sepsis), and positive predictive value 0.81 (specificity 0.90) for SeptiScores between 7.4 and 15 (Band 4, highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. Comparable results were obtained when the data were reanalyzed under the Sepsis-3 definition. Conclusions: This study validates SeptiCyte RAPID for differentiating patients with sepsis vs. SIRS, on the first day of ICU admission. Trial Registration:NCT01905033(MARS),NCT02127502(VENUS),NCT05469048(NEPTUNE, retrospectively registered) at clinicaltrials.gov. Keywords: sepsis, diagnosis, host response, SIRS, sepsis scoring systems

Rationale & Objective Clinical practice guidelines recommend delivering a continuous renal replacement therapy (CRRT) dose of 20 to 25 mL/kg/h. However, practice patterns nationwide are highly variable; this inconsistent prescribing may lead to errors in medication dosing and increase rates of electrolyte and acid-base abnormalities. We describe an initiative to standardize CRRT practice patterns and reduce dosing variability. Study Design Quality improvement study. Setting & Participants Adult patients treated with CRRT at the University of Colorado Hospital between January 2016 and October 2017. Quality Improvement Activities An assessment of the magnitude of the variability in CRRT dosing and the following specific interventions were implemented during the course of 1 year: (1) modification of the electronic medical record (EMR) to include calculated average 24-hour dose in real time, (2) modification of the CRRT procedure note to include comments on dosing, (3) modification of the CRRT order set to display calculations, and (4) yearly educational sessions for renal fellows outlining CRRT-specific dosing targets. Outcomes The primary outcome was weekly percentage of CRRT treatments with an average delivered daily dose of 20 to 25 mL/kg/h. Process and balancing outcomes included CRRT flowsheet accuracy, documentation of rates of delivered dose, and nursing satisfaction. Analytical Approach Rates of weekly CRRT dosing in compliance with national guidelines were determined and used to create run charts showing compliance rates before and after the quality improvement interventions. Results Among 837 treatments before the intervention, 279 (33%) daily CRRT sessions achieved an average dose of 20 to 25 mL/kg/h. Following implementation of interventions, 631 of 952 (66%) treatments achieved this goal. Week-to-week variation in dosing was significantly reduced. Limitations A single-center study generating data that may not be generalizable to institutions with different CRRT nursing models or different EMR systems. Conclusions Changes to the EMR and documentation templates and education of CRRT providers about dosing were associated with doubling of the rate of appropriate CRRT dosing and reduction in dosing variability.

The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia.Preoperative and postoperative computed tomography imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non-small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site.New hiatal hernias were seen in 9.6% of patients after lung resection (5.6% after wedge or segmentectomy and 12.4% after lobectomy;Both open and minimally invasive lung resection for clinical early-stage lung cancer are associated with new or enlarging postoperative hiatal hernia, especially after resections involving the left lower lobe.

Purpose Chronic Obstructive Pulmonary Disease (COPD) includes chronic bronchitis, small airways disease, and emphysema. Diagnosis of COPD requires spirometric evidence and may be normal even when small airways disease or emphysema is present. Emphysema increases the risk of exacerbations, and is associated with all-cause mortality and increased risk of lung cancer. We evaluated the prevalence of emphysema in participants with and without a prior history of COPD. Methods We reviewed a prospective cohort of 52,726 subjects who underwent baseline low dose CT screening for lung cancer from 2003 to 2016 in the International Early Lung Cancer Action Program. Results Of 52,726 participants, 23.8%(12,542) had CT evidence of emphysema. Of these 12,542 participants with emphysema, 76.5%(9595/12,542) had no prior COPD diagnosis even though 23.6% (2258/9595) had moderate or severe emphysema. Among 12,542 participants, significant predictors of no prior COPD diagnosis were: male (OR = 1.47, p Conclusion Emphysema was identified in 23.8% participants undergoing LDCT and was unsuspected in 76.5%. LDCT provides an opportunity to identify emphysema, and recommend smoking cessation.

Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.

Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.

Background Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting. Methods We conducted a post hoc analysis of previously collected data from a prospective, observational trial (N = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa (κfree) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups. Results Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator (κfree 0.68), (2) the consensus discharge diagnosis of the site investigators (κfree 0.62), and (3) the consensus diagnosis of the external expert panel (κfree 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel (κfree 0.79). When stratified by infection site, κfree for agreement between initial and later diagnoses had a mean value + 0.24 (range − 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics. Conclusions Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis. Electronic supplementary material The online version of this article (10.1186/s40560-019-0368-2) contains supplementary material, which is available to authorized users.

To determine long-term survival of visceral pleural invasion (VPI) and parenchymal invasion (PAI) (angiolymphatic and/or vascular) on survival of NSCLCs less than 30 mm in maximum diameter.Kaplan-Meier survivals for NSCLCs, with and without VPI and/or PAI, were determined for a prospective cohort of screening participants stratified by pathologic tumor size (≤10 mm, 11-20 mm, and 21-30 mm) and nodule consistency. Log-rank test statistics were calculated.The frequency of PAI versus VPI was significantly lower in patients with subsolid nodules than in those with solid nodules (4.9% versus 27.7% [p0.0001]), and correspondingly, Kaplan-Meier lung cancer survival was significantly higher among patients with subsolid nodules (99.1% versus 91.3% [p = 0.0009]). Multivariable Cox regression found that only tumor diameter (adjusted hazard ratio [HR] =1.07, 95% confidence interval [CI]: 1.01-1.14, p = 0.02) and PAI (adjusted HR = 3.15, 95% CI: 1.25-7.90, p = 0.01) remained significant, whereas VPI was not significant (p = 0.15). When clinical and computed tomography findings were included with the pathologic findings, Cox regression showed that the risk of dying of lung cancer increased 10-fold (HR = 10.06, 95% CI: 1.35-75.30) for NSCLCs in patients with solid nodules and more than twofold (by a factor of 2.27) in patients with moderate to severe emphysema (HR = 2.27, 95% CI: 1.01-5.11), as well as with increasing tumor diameter (HR = 1.06, 95% CI: 1.01-1.13), whereas PAI was no longer significant (p = 0.19).Nodule consistency on computed tomography was a more significant prognostic indicator than either PAI or VPI. We propose that patients with NSCLC with VPI and a maximum tumor diameter of 30 mm or less not be upstaged to T2 without further large, multicenter studies of NSCLCs, stratified by the new T status and that classification be considered separately for patients with subsolid or solid nodules.

A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility.This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults.The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts.In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity.SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).

OBJECTIVE. Appropriate radiologic interpretation of screening CT can minimize unnecessary workup and intervention. This is particularly challenging in the baseline round. We report on the quality assurance process we developed for the International Early Lung Cancer Action Program. MATERIALS AND METHODS. After initial training at the coordinating center, radiologists at 10 participating institutions and at the center independently interpreted the first 100 baseline screenings. The radiologist at the institutions had access to the center interpretations before issuing the final reports. After the first 100 screenings, the interpretations were jointly discussed. This report summarizes the results of the initial 100 dual interpretations at the 10 institutions. RESULTS. The final institution interpretations agreed with the center in 895 of the 1000 interpretations. Compared with the center, the frequency of positive results was higher at eight of the 10 institutions. The most frequent reason of discrepant interpretations was not following the protocol (n = 55) and the least frequent was not identifying a nodule (n = 3). CONCLUSION. The quality assurance process helped focus educational programs and provided an excellent vehicle for review of the protocol with participating physicians. It also suggests that the rate of positive results can be reduced by such measures.

We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.

Tuberculosis continues to be a global threat. Efforts to eradicate this disease are hampered by the long course and potential toxicity of currently available treatment regimens, the increasing prevalence of tuberculosis-HIV coinfection, the evolution of drug resistant organisms, and the lack of a highly effective vaccine. Recent studies have suggested methods to improve the cost effectiveness of existing treatment strategies. Decreasing the relapse rate among high-risk individuals by extending therapy can be balanced by the cost savings of self-administered therapy for low-risk individuals. For the first time in over 30 years, new medications are flowing through the drug discovery pipeline. New agents with activity against slowly dividing bacilli have the potential to shorten the duration of therapy. Many have a more favorable side-effect profile than currently available medications. And even extensively drug-resistant organisms will be susceptible to these secret weapons. The fully sequenced genome of Mycobacterium tuberculosis has been exploited to develop safer and more effective candidate vaccines. Highly immunogenic mycobacterial fragments, revved-up versions of the existing vaccine, and toned-down versions of M. tuberculosis are all in various phases of clinical testing. This expanded arsenal has the potential to deliver a fatal blow to one of humanity's greatest enemies.

The present study reports on a 72-year-old female initially treated as a presumed chronic obstructive pulmonary disease (COPD) exacerbation, but she was ultimately discovered to have Aspergillus tracheobronchitis. Bronchoscopic findings were characteristic, revealing diffuse plaque-like inflammatory lesions extending from midtrachea into the mainstem bronchi. Evidence suggests that the rise in cases is attributable to the growing number of individuals who are immunocompromised secondary to underlying disease, combined with the expanding number of patients receiving glucocorticoids and immunomodulating medications to treat chronic, nonmalignant disorders. The present observations emphasize the importance of including Aspergillus tracheobronchitis in the differential diagnosis for patients receiving medications with immunosuppressive potential that present with dyspnea, cough, or fever and who fail to improve with empiric antimicrobial therapy.

Background: Palliative radiation therapy (RT) is an established tool in the management of symptoms caused by malignancies. RT is effective at palliating both locally advanced and metastatic cancer, including related symptoms of pain, bleeding, or obstruction. Most data on palliative RT is in regard to its use in the treatment of painful bone metastases. There are also data that support RT palliation for locally advanced or recurrent rectal, prostate, and gynecological cancers. With regard to bladder cancer there is some evidence of the benefit of palliative RT for the control of urinary symptoms and hematuria; however, there is little evidence for the use of palliative RT for pain associated with locally recurrent bladder cancer. We report a case of locally advanced recurrent bladder cancer which was refractory to medical pain management, and was found to be highly responsive to palliative RT. Case Report: An 80-year-old woman with recurrent bladder cancer and intractable pelvic pain refractory to oral and transdermal pain medications, received palliative pelvic RT to a dose of 50 Gy (5000 cGy) in 25 fractions with complete resolution of pain. The patient was originally found to have dysuria, frequency, and hematuria, secondary to an invasive high grade transitional cell carcinoma of the bladder with an adenocarcinoma component, AJCC pT2b N1 M0 Stage IV, for which she underwent a radical cystectomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, partial vaginectomy, and ileal conduit reconstruction. After undergoing 4 cycles of adjuvant chemotherapy, the patient did well for 5 months with no evidence of symptomatic, clinical, or radiographic recurrence of disease. Repeat staging CT of the abdomen and pelvis confirmed tumor recurrence in the left pelvis. The patient was treated with another course of chemotherapy and pain was managed with relatively low doses of opioid medication (25mcg transdermal fentanyl patch, and oxycodone 5mg bid). However at the fourth month, there was rapid escalation of severe pain with the patient becoming bed bound due to pain with an associated decrease in ambulation and anorexia. Ultimately a pain medication regimen of 200mcg transdermal fentanyl patch q2 days, oxycontin 20mg bid, oxycodone 5 – 10mg q 4 hours, ibuprofen 400mg q 8 hours, and gabapentin 600mg TID was not effective in controlling pain. The patient was then referred to Radiation Oncology 6 months after the pain initially began for evaluation. She received a total of 5000cGy over 25 fractions to a small pelvis field over 5 weeks and reported complete pain resolution. She was able to decrease pain medications, increase overall activity, and gain significant improvement in sleep quality and appetite even early on in the course of her radiation therapy. Conclusions: Palliative radiation therapy has been well studied in the setting of bone metastases and treatment of hematuria for locally advanced bladder cancer. There is little data that we are aware of on the use of RT for pain control with patients that have recurrent, locally advanced bladder cancer. We have presented a case in which an excellent outcome in pain control was seen for a patient with medically unmanageable pain. RT is an excellent option for pain management in recurrent bladder cancer and should be offered to patients whose pain is not otherwise optimally controlled. Palliative RT is an important component in the multimodality approach to cancer pain management and optimization of quality of life. Key words: palliation, bladder cancer, radiation therapy

The genome of Mycobacterium leprae, the etiologic agent of leprosy, has been sequenced and annotated revealing a genome in apparent disarray and in stark contrast to the genome of the related human pathogen, M. tuberculosis. With less than 50% coding capacity of a 3.3-Mb genome and 1,116 pseudogenes, the remaining genes help define the minimal gene set necessary for in vivo survival of this mycobacterial pathogen as well as genes potentially required for infection and pathogenesis seen in leprosy. To identify genes transcribed during infection, we surveyed gene transcripts from M. leprae growing in athymic nude mice using reverse transcriptase-polymerase chain reaction (RT-PCR) and cross-species DNA microarray technologies. Transcripts were detected for 221 open reading frames, which included genes involved in DNA replication, cell division, SecA-dependent protein secretion, energy production, intermediary metabolism, iron transport and storage and genes associated with virulence. These results suggest that M. leprae actively catabolizes fatty acids for energy, produces a large number of secretory proteins, utilizes the full array of sigma factors available, produces several proteins involved in iron transport, storage and regulation in the absence of recognizable genes encoding iron scavengers and transcribes several genes associated with virulence in M. tuberculosis. When transcript levels of 9 of these genes were compared from M. leprae derived from lesions of multibacillary leprosy patients and infected nude mouse foot pad tissue using quantitative real-time RT-PCR, gene transcript levels were comparable for all but one of these genes, supporting the continued use of the foot pad infection model for M. leprae gene expression profiling. Identifying genes associated with growth and survival during infection should lead to a more comprehensive understanding of the ability of M. leprae to cause disease.

Objective Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies. Methods Patients (n = 224 stage I non–small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81). Results Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher ( P = .001, P P = .002, and P = .011, respectively) than those with non–small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + β), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance—achieving a (validated) negative predictive value of 100%. Conclusions Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.

Inflammation may play an important role in the pathophysiology of sickle cell disease (SCD), and recent studies have identified the 70-kDa heat shock protein (Hsp70) as an important mediator of inflammatory responses. Here we demonstrate a significant increase in circulating serum Hsp70 level in SCD during vaso-occlusive crisis (VOC) as compared with baseline steady-state levels (P < 0.05) and a significant increase in Hsp70 levels in SCD at baseline compared with normal controls (P < 0.05). Taken together, these results indicate that circulating serum Hsp70 might be a marker for VOC in SCD.

Purpose: In human subjects and animal models with acute and chronic lung injury, the bioactive lysophosphatidylcholine (LPC) is elevated in lung lining fluids. The increased LPC can promote an inflammatory microenvironment resulting in lung injury. Furthermore, pathological lung conditions are associated with upregulated phospholipase A2 (PLA2), the predominant enzyme producing LPC in tissues by hydrolysis of phosphatidylcholine. However, the lung cell populations responsible for increases of LPC have yet to be systematically characterized. The goal was to investigate the LPC generation by bronchial epithelial cells in response to pathological mediators and determine the major LPC species produced. Methods: Primary human bronchial epithelial cells (NHBE) were challenged by vascular endothelial growth factor (VEGF) for 1 or 6 hours, and condition medium and cells collected for quantification of predominant LPC species by high performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The cells were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for PLA2. The direct effects of LPC in inducing inflammatory activities on NHBE were assessed by transepithelial resistance as well as expression of interleukin-8 (IL-8) and matrix metalloprotein ase-1 (MMP-1). Results: VEGF stimulation of NHBE for 1 or 6 hours, significantly increased concentrations of LPC16:0, LPC18:0, and LPC18:1 in condition medium compared to control. The sPLA2-selective inhibitor (oleyloxyethyl phosphorylcholine) inhibited the VEGF-induced release of LPC16:0 and LPC18:1 and PLA2 activity. In contrast, NHBE stimulated with TNF did not induce LPC release. VEGF did not increase mRNA of PLA2 subtypes sPLA2-X, sPLA2-XIIa, cPLA2-IVa, and iPLA2-VI. Exogenous LPC treatment increased expression of IL-8 and MMP-1, and reduced the transepithelial resistance in NHBE. Conclusions: Our findings indicate that VEGF-stimulated bronchial epithelial cells are a key source of extracellular LPCs, which can function as an autocrine mediator with potential to induce airway epithelial inflammatory injury.

Palliative radiation therapy (RT) is an established tool in the management of symptoms caused by malignancies. RT is effective at palliating both locally advanced and metastatic cancer, including related symptoms of pain, bleeding, or obstruction. Most data on palliative RT is in regard to its use in the treatment of painful bone metastases. There are also data that support RT palliation for locally advanced or recurrent rectal, prostate, and gynecological cancers. With regard to bladder cancer there is some evidence of the benefit of palliative RT for the control of urinary symptoms and hematuria; however, there is little evidence for the use of palliative RT for pain associated with locally recurrent bladder cancer. We report a case of locally advanced recurrent bladder cancer which was refractory to medical pain management, and was found to be highly responsive to palliative RT.An 80-year-old woman with recurrent bladder cancer and intractable pelvic pain refractory to oral and transdermal pain medications, received palliative pelvic RT to a dose of 50 Gy (5000 cGy) in 25 fractions with complete resolution of pain. The patient was originally found to have dysuria, frequency, and hematuria, secondary to an invasive high grade transitional cell carcinoma of the bladder with an adenocarcinoma component, AJCC pT2b N1 M0 Stage IV, for which she underwent a radical cystectomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, partial vaginectomy, and ileal conduit reconstruction. After undergoing 4 cycles of adjuvant chemotherapy, the patient did well for 5 months with no evidence of symptomatic, clinical, or radiographic recurrence of disease. Repeat staging CT of the abdomen and pelvis confirmed tumor recurrence in the left pelvis. The patient was treated with another course of chemotherapy and pain was managed with relatively low doses of opioid medication (25mcg transdermal fentanyl patch, and oxycodone 5mg bid). However at the fourth month, there was rapid escalation of severe pain with the patient becoming bed bound due to pain with an associated decrease in ambulation and anorexia. Ultimately a pain medication regimen of 200mcg transdermal fentanyl patch q2 days, oxycontin 20mg bid, oxycodone 5 - 10mg q 4 hours, ibuprofen 400mg q 8 hours, and gabapentin 600mg TID was not effective in controlling pain. The patient was then referred to Radiation Oncology 6 months after the pain initially began for evaluation. She received a total of 5000cGy over 25 fractions to a small pelvis field over 5 weeks and reported complete pain resolution. She was able to decrease pain medications, increase overall activity, and gain significant improvement in sleep quality and appetite even early on in the course of her radiation therapy.Palliative radiation therapy has been well studied in the setting of bone metastases and treatment of hematuria for locally advanced bladder cancer. There is little data that we are aware of on the use of RT for pain control with patients that have recurrent, locally advanced bladder cancer. We have presented a case in which an excellent outcome in pain control was seen for a patient with medically unmanageable pain. RT is an excellent option for pain management in recurrent bladder cancer and should be offered to patients whose pain is not otherwise optimally controlled. Palliative RT is an important component in the multimodality approach to cancer pain management and optimization of quality of life.

The genome of Mycobacterium leprae, the etiologic agent of leprosy, has been sequenced and annotated revealing a genome in apparent disarray and in stark contrast to the genome of the related human pathogen, M. tuberculosis. With less than 50% coding capacity of a 3.3-Mb genome and 1,116 pseudogenes, the remaining genes help define the minimal gene set necessary for in vivo survival of this mycobacterial pathogen as well as genes potentially required for infection and pathogenesis seen in leprosy. To identify genes transcribed during infection, we surveyed gene transcripts from M. leprae growing in athymic nude mice using reverse transcriptase-polymerase chain reaction (RT-PCR) and cross-species DNA microarray technologies. Transcripts were detected for 221 open reading frames, which included genes involved in DNA replication, cell division, SecA-dependent protein secretion, energy production, intermediary metabolism, iron transport and storage and genes associated with virulence. These results suggest that M. leprae actively catabolizes fatty acids for energy, produces a large number of secretory proteins, utilizes the full array of sigma factors available, produces several proteins involved in iron transport, storage and regulation in the absence of recognizable genes encoding iron scavengers and transcribes several genes associated with virulence in M. tuberculosis. When transcript levels of 9 of these genes were compared from M. leprae derived from lesions of multibacillary leprosy patients and infected nude mouse foot pad tissue using quantitative real-time RT-PCR, gene transcript levels were comparable for all but one of these genes, supporting the continued use of the foot pad infection model for M. leprae gene expression profiling. Identifying genes associated with growth and survival during infection should lead to a more comprehensive understanding of the ability of M. leprae to cause disease.

The rabbit model of tuberculosis has been used historically to differentiate betweenMycobacterium tuberculosisandMycobacterium bovisbased on their relative virulence in this animal host.M. tuberculosisinfection in market rabbits is cleared over time, whereas infection withM. bovisresults in chronic, progressive, cavitary disease leading to death. Because of the innate resistance of commercial rabbits toM. tuberculosis, 320 to 1,890 log-phase, actively growing inhaled bacilli were required to form one grossly visible pulmonary tubercle at 5 weeks. The range of inhaled doses required to make one tubercle allows us to determine the relative pathogenicities of different strains. Fewer inhaled organisms of theM. tuberculosisErdman strain were required than ofM. tuberculosisH37Rv to produce a visible lesion at 5 weeks. Furthermore, with the Erdman strain, only 7 of 15 rabbits had healed lesions at 16 to 18 weeks; among the other animals, two had chronic, progressive cavitary disease, a phenotype usually seen only withM. bovisinfection. Genotypic investigation of the Erdman strain with an H37Rv-based microarray identified gene differences in the RD6 region. Southern blot and PCR structural genetic analysis showed significant differences betweenM. tuberculosisstrains in this region. Correlation of the relative pathogenicity, including disease severity, in the rabbit model with the strain genotype may help identify stage-specificM. tuberculosisgenes important in human disease.

Purpose: Asthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A 2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro-atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids. Methods: Eight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry. Results: LPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asth ma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X). Conclusions: The increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma.

Introduction: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography–based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography–based screening and promote its rapid implementation. Methods: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign ( n = 67) cases and lung cancer ( n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign ( n = 61) or malignant ( n = 20) indeterminate lung nodules. Results: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2Rα, stromal cell-derived factor-1α+β, tumor necrosis factor α, and macrophage inflammatory protein 1 α. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. Conclusion: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.