Decreasing Misdiagnoses of Urinary Tract Infections in a Pediatric Emergency Department.

BACKGROUND AND OBJECTIVES: Urinary tract infection (UTI) is a common diagnosis in the emergency department (ED), often resulting in empirical antibiotic treatment before culture results. Diagnosis of a UTI, particularly in children, can be challenging and misdiagnosis is common. The aim of this initiative was to decrease the misdiagnosis of uncomplicated pediatric UTIs by 50% while improving antimicrobial stewardship in the ED over 4 years. METHODS: By using the Model for Improvement, 3 interventions were developed: (1) an electronic UTI diagnostic algorithm, (2) a callback system, and (3) a standardized discharge antibiotic prescription. Outcome measures included the percentage of patients with UTI misdiagnosis (prescribed antibiotics, but urine culture results negative) and antibiotic days saved. As a balancing measure, positive urine culture results without a UTI diagnosis were reviewed for ED return visits or hospitalization. Statistical process control and run charts were used for analysis. RESULTS: From 2017 to 2021, the mean UTI misdiagnosis decreased from 54.6% to 26.4%. The adherence to the standardized antibiotic duration improved from 45.1% to 84.6%. With the callback system, 2128 antibiotic days were saved with a median of 89% of patients with negative culture results contacted to discontinue antibiotics. Of 186 patients with positive urine culture results with an unremarkable urinalysis, 14 returned to the ED, and 2 were hospitalized for multiresistant organism UTI treatment. CONCLUSIONS: A UTI diagnostic algorithm coupled with a callback system safely reduced UTI misdiagnoses and antibiotic usage. Embedding these interventions electronically as a decision support tool, targeted audit and feedback, reminders, and education all supported long-term sustainability.

Absence of evidence for Palaeoproterozoic eclogite-facies metamorphism in East Antarctica: no record of subduction orogenesis during Nuna development.

The cratonic elements of proto-Australia, East Antarctica, and Laurentia constitute the nucleus of the Palaeo-Mesoproterozoic supercontinent Nuna, with the eastern margin of the Mawson Continent (South Australia and East Antarctica) positioned adjacent to the western margin of Laurentia. Such reconstructions of Nuna fundamentally rely on palaeomagnetic and geological evidence. In the geological record, eclogite-facies rocks are irrefutable indicators of subduction and collisional orogenesis, yet occurrences of eclogites in the ancient Earth (> 1.5 Ga) are rare. Models for Palaeoproterozoic amalgamation between Australia, East Antarctica, and Laurentia are based in part on an interpretation that eclogite-facies metamorphism and, therefore, collisional orogenesis, occurred in the Nimrod Complex of the central Transantarctic Mountains at c. 1.7 Ga. However, new zircon petrochronological data from relict eclogite preserved in the Nimrod Complex indicate that high-pressure metamorphism did not occur in the Palaeoproterozoic, but instead occurred during early Palaeozoic Ross orogenesis along the active convergent margin of East Gondwana. Relict c. 1.7 Ga zircons from the eclogites have trace-element characteristics reflecting the original igneous precursor, thereby casting doubt on evidence for a Palaeoproterozoic convergent plate boundary along the current eastern margin of the Mawson Continent. Therefore, rather than a Palaeoproterozoic (c. 1.7 Ga) history involving subduction-related continental collision, a pattern of crustal shortening, magmatism, and high thermal gradient metamorphism connected cratons in Australia, East Antarctica, and western Laurentia at that time, leading eventually to amalgamation of Nuna at c. 1.6 Ga.

Impact of Nivolumab versus Docetaxel on Health-Related Quality of Life and Symptoms in Patients with Advanced Squamous Non-Small Cell Lung Cancer: Results from the CheckMate 017 Study.

INTRODUCTION: In the phase III CheckMate 017 study, nivolumab prolonged overall survival versus docetaxel in previously treated patients with advanced squamous NSCLC. Study objectives included health-related quality of life (HRQoL) and symptom assessments. METHODS: Patients serially completed the Lung Cancer Symptom Scale (LCSS) and European Quality of Life Five Dimensions (EQ-5D) questionnaires. The LCSS average symptom burden index (ASBI) (mean score for six lung cancer-specific symptoms; range 0-100), LCSS three-item global index, EQ-5D utility index, and EQ-5D visual analog scale scores were analyzed. The proportion of patients exhibiting clinically meaningful improvement (a ≥10-point decrease) in ASBI scores by week 12 was a secondary end point. Mixed-effect model repeated measures analysis of HRQoL changes from baseline and analyses of time to HRQoL deterioration were conducted. RESULTS: Baseline mean plus or minus SD LCSS ASBI scores were similar in the nivolumab (29.6 ± 16.4) and docetaxel (29.6 ± 14.7) groups. By week 12, the proportions of patients (95% confidence interval) with clinically meaningful improvement in ASBI scores were 20.0% (13.6-27.7) with nivolumab and 21.9% (15.3-29.8) with docetaxel. At weeks 16 to 54, significant improvements in ASBI scores from baseline were seen with nivolumab; clinically meaningful improvements were observed at weeks 42 to 84. No significant changes in ASBI scores from baseline were observed with docetaxel; at week 36, a clinically meaningful deterioration was seen. Improvements in HRQoL with nivolumab versus with docetaxel were supported by other measures, and time to first HRQoL deterioration was longer. CONCLUSION: Nivolumab alleviates symptom burden and improves health status versus docetaxel as second-line squamous NSCLC treatment.

Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial.

BACKGROUND: Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). METHODS: CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. FINDINGS: Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. INTERPRETATION: In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. FUNDING: Bristol-Myers Squibb.

FGFR1 amplification in squamous cell carcinoma of the lung.

INTRODUCTION: Amplification of fibroblast growth factor receptor 1 (FGFR1) has been reported in squamous cell lung carcinoma and may be a molecular target for therapy. Little is known, however, about the clinical and demographic correlates of FGFR1 amplification. METHODS: The study is an Institutional Review Board approved retrospective analysis of 226 patients with squamous cell lung cancer seen at the Massachusetts General Hospital from 2005 to 2011. Clinical and demographic characteristics of all patients were obtained, as well as treatment details including surgery, radiation, and chemotherapy, and overall survival. fluorescence in situ hybridization was performed for FGFR1 on formalin-fixed paraffin-embedded tumor tissue. Clinical genotyping results were also reviewed where available. RESULTS: Thirty-seven of 226 patients (16%) with squamous cell lung cancer were found positive for amplification using a definition of amplification of a gene to copy number control ratio of 2.2 or higher. FGFR1 amplification status was not associated with age, sex, stage, histologic subtype within squamous cell, smoking history, or pack-years of smoking. We found no significant difference in overall survival by FGFR1 amplification status as a whole; in the advanced stage subset, our findings are inconclusive because of the small sample size. CONCLUSION: FGFR1 amplification was found in 16% of a clinical cohort of squamous cell lung cancer patients. The lack of any specific clinicodemographic features that correlates with FGFR1 amplification suggests that all squamous cell patients should be tested for this genomic change.