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Human genomic sequencing has potential diagnostic, prognostic, and therapeutic value across a wide breadth of clinical disciplines. One barrier to widespread adoption is the paucity of evidence for improved outcomes in patients who do not already have an indication for more focused testing. In this Series paper, we review clinical outcome studies in genomic medicine and discuss the important features and key challenges to building evidence for next generation sequencing in the context of routine patient care.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Background - Streptococcus pneumoniae is considered the leading bacterial cause of pneumonia in adults. Yet, it was not commonly detected by traditional culture-based and conventional urinary testing in a recent multicenter etiology study of adults hospitalized with community-acquired pneumonia (CAP). We used novel serotype-specific urinary antigen detection (SSUAD) assays to determine whether pneumococcal cases were missed by traditional testing.
Methods - We studied adult patients hospitalized with CAP at 5 hospitals in Chicago and Nashville (2010-2012) and enrolled in the Etiology of Pneumonia in the Community (EPIC) study. Traditional diagnostic testing included blood and sputum cultures and conventional urine antigen detection (ie, BinaxNOW). We applied SSUAD assays that target serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) to stored residual urine specimens.
Results - Among 1736 patients with SSUAD and ≥1 traditional pneumococcal test performed, we identified 169 (9.7%) cases of pneumococcal CAP. Traditional tests identified 93 (5.4%) and SSUAD identified 76 (4.4%) additional cases. Among 14 PCV13-serotype cases identified by culture, SSUAD correctly identified the same serotype in all of them. Cases identified by SSUAD vs traditional tests were similar in most demographic and clinical characteristics, although disease severity and procalcitonin concentration were highest among those with positive blood cultures. The proportion of pneumonia cases caused by serotypes exclusively covered by PCV13 was not significantly different between the first and second July-June study periods (6.4% vs 4.0%).
Conclusions - Although restricted to the detection of only 13 serotypes, SSUAD testing substantially increased the detection of pneumococcal pneumonia among adults hospitalized with CAP.
PURPOSE - Meckel diverticula containing gastric heterotopia predispose to local hyperacidity, mucosal ulceration, and gastrointestinal bleeding in children. Eradication of acid-producing oxyntic cells is performed by either of two surgical methods: segmental enterectomy including the diverticulum or diverticulectomy only.
METHODS - Retrospective review of all children having surgical resection of a Meckel diverticulum at a tertiary-referral children's hospital from 2002 to 2016 was performed. Demographic data, surgical method, pathological specimens, and outcomes were evaluated.
RESULTS - 102 children underwent surgical resection of a Meckel diverticulum during the study period. 27 (26.5%) children presented with bleeding, of which 16 (59%) had diverticulectomy only, and 11 (41%) had segmental ileal resection. All Meckel diverticula in children presenting with bleeding contained gastric heterotopia, and resection margins were free of gastric mucosa. Histologically, 19 specimens showed microscopic features of ulceration, on average 2.95mm (SD 4.49) from the nearest gastric mucosa (range: 0-16mm). Mean length of hospitalization after ileal resection was 4.0days (SD 1.2) compared to 1.6days (SD 0.9) for diverticulectomy only (p<0.001), with no re-bleeding occurrences.
CONCLUSION - In the operative management of children having a bleeding Meckel diverticulum, diverticulectomy-only completely eradicates gastric heterotopia without increased risk of continued bleeding or complications and significantly shortens hospitalization.
LEVEL OF EVIDENCE - Treatment Study: Level III.
Copyright © 2017 Elsevier Inc. All rights reserved.
BACKGROUND - Rural/urban variations in admissions for heart failure may be influenced by severity at hospital presentation and local practice patterns. Laboratory data reflect clinical severity and guide hospital admission decisions and treatment for heart failure, a costly chronic illness and a leading cause of hospitalization among the elderly. Our main objective was to examine the role of laboratory test results in measuring disease severity at the time of admission for inpatients who reside in rural and urban areas.
METHODS - We retrospectively analyzed discharge data on 13,998 hospital discharges for heart failure from three states, Hawai'i, Minnesota, and Virginia. Hospital discharge records from 2008 to 2012 were derived from the State Inpatient Databases of the Healthcare Cost and Utilization Project, and were merged with results of laboratory tests performed on the admission day or up to two days before admission. Regression models evaluated the relationship between clinical severity at admission and patient urban/rural residence. Models were estimated with and without use of laboratory data.
RESULTS - Patients residing in rural areas were more likely to have missing laboratory data on admission and less likely to have abnormal or severely abnormal tests. Rural patients were also less likely to be admitted with high levels of severity as measured by the All Patient Refined Diagnosis Related Groups (APR-DRG) severity subclass, derivable from discharge data. Adding laboratory data to discharge data improved model fit. Also, in models without laboratory data, the association between urban compared to rural residence and APR-DRG severity subclass was significant for major and extreme levels of severity (OR 1.22, 95% CI 1.03-1.43 and 1.55, 95% CI 1.26-1.92, respectively). After adding laboratory data, this association became non-significant for major severity and was attenuated for extreme severity (OR 1.12, 95% CI 0.94-1.32 and 1.43, 95% CI 1.15-1.78, respectively).
CONCLUSION - Heart failure patients from rural areas are hospitalized at lower severity levels than their urban counterparts. Laboratory test data provide insight on clinical severity and practice patterns beyond what is available in administrative discharge data.
BACKGROUND - National guidelines for the management of community-acquired pneumonia (CAP) in children were published in 2011. These guidelines discourage most diagnostic testing for outpatients, as well as repeat testing for hospitalized patients who are improving. We sought to evaluate the temporal trends in diagnostic testing associated with guideline implementation among children with CAP.
METHODS - Children 1 to 18 years old who were discharged with pneumonia after emergency department (ED) evaluation or hospitalization from January 1, 2008 to June 30, 2014 at any of 32 children's hospitals participating in the Pediatric Health Information System were included. We excluded children with complex chronic conditions and those requiring intensive care or who underwent early pleural drainage. We compared use of diagnostic testing (blood culture, complete blood count [CBC], C-reactive protein [CRP], and chest radiography [CXR]) before and after release of the guidelines, and assessed for temporal trends using interrupted time series analysis. We also calculated the cost impact of these changes on diagnostic utilization and evaluated the variability of the guideline's impact across hospitals.
RESULTS - Overall, 220,539 patients were included; 53% were male and the median age was 4 years (interquartile range, 2-7). For patients discharged from the ED with CAP, diagnostic utilization rates for blood culture, CBC, CRP, and CXR were higher after guideline publication compared with expected utilization rates without guidelines. In contrast, initial testing and repeat testing among patients hospitalized with CAP was lower after guideline publication. There were modest reductions in estimated costs associated with these changes. However, wide variability was observed in the impact of the guidelines across hospitals.
CONCLUSIONS - Publication of national pneumonia guidelines in 2011 was associated with modest changes in diagnostic testing for children with CAP. However, the changes varied across hospitals, and the financial impact was modest. Local implementation efforts are warranted to ensure widespread guideline adherence. Journal of Hospital Medicine 2016;11:317-323. © 2016 Society of Hospital Medicine.
© 2015 Society of Hospital Medicine.
BACKGROUND - Ventilator-associated pneumonia (VAP) remains a common complication in critically ill surgical patients, and its diagnosis remains problematic. Exhaled breath contains aerosolized droplets that reflect the lung microbiota. We hypothesized that exhaled breath condensate fluid (EBCF) in hygroscopic condenser humidifier/heat and moisture exchanger (HCH/HME) filters would contain bacterial DNA that qualitatively and quantitatively correlate with pathogens isolated from quantitative BAL samples obtained for clinical suspicion of pneumonia.
METHODS - Forty-eight adult patients who were mechanically ventilated and undergoing quantitative BAL (n = 51) for suspected pneumonia in the surgical ICU were enrolled. Per protocol, patients fulfilling VAP clinical criteria undergo quantitative BAL bacterial culture. Immediately prior to BAL, time-matched HCH/HME filters were collected for study of EBCF by real-time polymerase chain reaction. Additionally, convenience samples of serially collected filters in patients with BAL-diagnosed VAP were analyzed.
RESULTS - Forty-nine of 51 time-matched EBCF/BAL fluid samples were fully concordant (concordance > 95% by κ statistic) relative to identified pathogens and strongly correlated with clinical cultures. Regression analysis of quantitative bacterial DNA in paired samples revealed a statistically significant positive correlation (r = 0.85). In a convenience sample, qualitative and quantitative polymerase chain reaction analysis of serial HCH/HME samples for bacterial DNA demonstrated an increase in load that preceded the suspicion of pneumonia.
CONCLUSIONS - Bacterial DNA within EBCF demonstrates a high correlation with BAL fluid and clinical cultures. Bacterial DNA within EBCF increases prior to the suspicion of pneumonia. Further study of this novel approach may allow development of a noninvasive tool for the early diagnosis of VAP.
The prognosis of patients diagnosed with pancreatic adenocarcinoma remains dismal. Of the 15-20 % of patients who are candidates for potentially curative resection, 66-92 % will develop recurrent disease. Although guidelines for surveillance in the postoperative setting exist, they are not evidence based, and there is wide variability of strategies utilized. Current surveillance guidelines as suggested by the National Comprehensive Cancer Network (NCCN) include routine history and physical, measurement of serum cancer-associated antigen 19-9 (CA19-9) levels, and computed tomographic imaging at 3- to 6-month intervals for the first 2 years, and annually thereafter. However, the lack of prospective clinical data examining the efficacy of different surveillance strategies has led to a variability of the intensity of follow-up and a lack of consensus on its necessity and efficacy. Recent therapeutic advances may have the potential to significantly alter survival after recurrence, but a careful consideration of current surveillance strategies should be undertaken to optimize existing approaches in the face of high recurrence and low survival rates.
BACKGROUND - We have previously demonstrated that elevated serum estradiol (E(2)) at intensive care unit (ICU) admission is associated with death in the critically ill, regardless of sex. However, little is known about how changes in initial E(2) during the course of care might signal increasing patient acuity or risk of death. We hypothesized that changes from baseline serum E(2) during the course of critical illness are more strongly associated with mortality than a single E(2) level at admission.
STUDY DESIGN - A prospective cohort of 1,408 critically ill or injured nonpregnant adult patients requiring ICU care for ≥48 hours with admission and subsequent E(2) levels was studied. Demographics, illness severity, and E(2) levels were examined, and the probability of mortality was modeled with multivariate logistic regression. Changes in E(2) were examined by both analysis of variance and logistic regression.
RESULTS - Overall mortality was 14.1% [95% confidence interval (CI) 12.3% to 16%]. Both admission and subsequent E(2) levels were independently associated with mortality [admission E(2) odds ratio 1.1 (CI 1.0 to 1.2); repeat estradiol odds ratio 1.3 (CI 1.2 to1.4)], with subsequent values being stronger. Changes in E(2) were independently associated with mortality [odds ratio 1.1 (CI 1.0 to 1.16)] and improved regression model performance. The regression model produced an area under the receiver operating characteristic curve of 0.80 (CI 0.77 to 0.83).
CONCLUSIONS - Although high admission levels of E(2) are associated with mortality, changes from baseline E(2) in critically ill or injured adults are independently associated with mortality. Future studies of E(2) dynamics may yield new indicators of patient acuity and illuminate underlying mechanisms for targeted therapy.
Copyright © 2011 American College of Surgeons. Published by Elsevier Inc. All rights reserved.