Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.

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.

AARC Clinical Practice Guidelines: Artificial Airway Suctioning.

Artificial airway suctioning is a key component of airway management and a core skill for clinicians charged with assuring airway patency. Suctioning of the artificial airway is a common procedure performed worldwide on a daily basis. As such, it is imperative that clinicians are familiar with the most-effective and efficient methods to perform the procedure. We conducted a systematic review to assist in the development of evidence-based recommendations that pertain to the care of patients with artificial airways. From our systematic review, we developed guidelines and recommendations that addressed questions related to the indications, complications, timing, duration, and methods of artificial airway suctioning. By using a modified version of the RAND/UCLA Appropriateness Method, the following recommendations for suctioning were developed for neonatal, pediatric, and adult patients with an artificial airway: (1) breath sounds, visual secretions in the artificial airway, and a sawtooth pattern on the ventilator waveform are indicators for suctioning pediatric and adult patients, and an acute increase in airway resistance may be an indicator for suctioning in neonates; (2) as-needed only, rather than scheduled, suctioning is sufficient for neonatal and pediatric patients; (3) both closed and open suction systems may be used to safely and effectively remove secretions from the artificial airway of adult patients; (4) preoxygenation should be performed before suctioning in pediatric and adult patients; (5) the use of normal saline solution should generally be avoided during suctioning; (6) during open suctioning, sterile technique should be used; (7) suction catheters should occlude < 70% of the endotracheal tube lumen in neonates and < 50% in pediatric and adult patients, and suction pressure should be kept below -120 mm Hg in neonatal and pediatric patients and -200 mm Hg in adult patients; (8) suction should be applied for a maximum of 15 s per suctioning procedure; (9) deep suctioning should only be used when shallow suctioning is ineffective; (10) routine bronchoscopy for secretion removal is not recommended; and (11) devices used to clear endotracheal tubes may be used when airway resistance is increased due to secretion accumulation.

A Scoring Tool That Identifies the Need for Positive-Pressure Ventilation and Determines the Effectiveness of Allocated Respiratory Therapy.

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.

New weapons in the war on tuberculosis.

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.

Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.

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 < .001, 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 + ß), 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.

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

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+ß, 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.