Real-World Use of AKI Biomarkers: A Quality Improvement Project Using Urinary Tissue Inhibitor Metalloprotease-2 and Insulin-Like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7]).

INTRODUCTION: Novel urinary biomarkers, including tissue inhibitor metalloprotease-2 and insulin-like growth factor binding protein 7 ([TIMP-2]*[IGFBP7]), have been developed to identify patients at risk for acute kidney injury (AKI). We investigated the "real-world" clinical utility of [TIMP-2]*[IGFBP7] in preventing AKI. METHODS: We performed a before and after single-center quality improvement study of intensive care unit (ICU) patients at risk for severe (KDIGO stage 2 or 3) AKI. In the prospective cohort, ICU providers were allowed to order [TIMP-2]*[IGFBP7] for patients at their discretion, then offered AKI practice recommendations based on the results. Outcomes were compared to a historical cohort in which biomarker values were not reported to clinical teams. RESULTS: There was no difference in 7-day progression to severe AKI between the prospective (n = 116) and historical cohorts (n = 63) when [TIMP-2]*[IGFBP7] ≥0.3 (24 [28%] versus 8 [21%], p = 0.38) despite more stage 1 AKI at time of biomarker measurement in the prospective cohort (58 [67%] versus 9 [23%], p < 0.001). In the prospective cohort, patients with higher [TIMP-2]*[IGFBP7] values were more likely to receive a nephrology consult. Early consultation (within 24 h of biomarker measurement, n = 20) had a nonsignificant trend toward net negative volume balance (-1,787 mL [6,716 mL] versus + 4,974 mL [15,540 mL]) and more diuretic use (19 [95%] versus 8 [80%]) and was associated with less severe AKI (9 [45%] versus 10 [100%], p = 0.004) and inpatient dialysis (2 [10%] versus 7 [70%], p = 0.002) compared to delayed consultation (n = 10). CONCLUSIONS: Despite the prospective cohort having more preexisting stage 1 AKI, there were equal rates of progression to severe AKI in the prospective and historical cohorts. In the setting of [TIMP-2]*[IGFBP7] reporting, there were more nephrology consults in response to elevated biomarker levels. Early nephrology consultation resulted in improved volume balance and favorable outcomes compared to delayed consultation.

MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages.

Cancers evade immune surveillance, which can be reversed through immune-checkpoint therapy in a small subset of cases. Here, we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune-checkpoint expression, predicted nonresponsiveness to immune-checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI-mediated antigen presentation, which in turn impeded T-cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to the recruitment of proinflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune-checkpoint responsiveness and a key driver of immune evasion through the suppression of proinflammatory macrophages. The immune evasion induced by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade. SIGNIFICANCE: Macrophage-mediated immune evasion is a therapeutic vulnerability of MYC-driven cancers, which has implications for prioritizing MYC-driven hepatocellular carcinoma for combination immunotherapy.

Promoting cultural competency and osteopathic medicine awareness among premedical students through a summer premedical rural enrichment program.

CONTEXT: Premedical preparatory programs at osteopathic medical schools that recruit students from medically underserved areas (MUAs) may promote interest in practicing osteopathic medicine in underserved or rural areas. In these programs, emphasis on cultural competency may increase diversity among medical school applicants and decrease healthcare disparities in the future. OBJECTIVES: The goal of this study is to determine whether a summer premedical rural enrichment program (PREP) held at an osteopathic medical school located in a MUA will foster greater prioritization of cultural competency in medicine, enhance interest in practicing in rural or underserved areas, and increase familiarity with osteopathic medicine. METHODS: An eight-week summer PREP was hosted at the California Health Sciences University College of Osteopathic Medicine (CHSU-COM) in Clovis, California. Seventy-eight diverse participants were recruited from the Central Valley, an underserved region of California. Attendees were required to finish the formal application process and were recommended to have completed medical school prerequisite courses. The curriculum included Medical College Admission Test (MCAT) preparation through team-based learning sessions, introduction to the osteopathic medical school curriculum, osteopathic philosophy, and osteopathic manipulative medicine, as well as integrated anatomy and physiology sessions, medical school application workshops, mock interviews, simulation workshops, and sociology and cultural competency sessions. Data were collected via a voluntary and anonymous survey administered before and after the program with questions about familiarity with osteopathy, interest in practicing in underserved areas, medical school preparedness, and a post-course survey about cultural competency. The surveys had students rate statements on a Likert scale. RESULTS: Seventy-four of the 78 premedical students (95%) completed the pre-and postsurvey. There was a significant increase in agreement to statements evaluating medical school preparedness, osteopathic familiarity, and desire to practice medicine locally in the postprogram survey, compared to the preprogram survey. In the cultural competency postsurvey, 75.0% of the responses to questions that evaluated the positive effect of the course were "Agree" or "Strongly Agree." Of the reported postcourse outcomes, the average MCAT score was 504 ± 6.2 (38 students reported, 50.7%). Of the 27 participants who reported matriculation, 16 (59.2%) were admitted to osteopathic medical schools, 9 (33.3%) to allopathic medical schools, and 2 to other health programs. CONCLUSIONS: After completing the PREP program, premedical participants reported that they have better understanding of cultural competency and improvement in preparation for medical school, including familiarity with osteopathic medicine, and interest in serving MUAs. These findings indicate that similar programs may have a positive impact on MUAs. These programs may help create diverse and culturally competent osteopathic physicians.

A-lines and B-lines in patients with acute heart failure.

AIMS: Lung ultrasound (LUS) relies on detecting artefacts, including A-lines and B-lines, when assessing dyspnoeic patients. A-lines are horizontal artefacts and characterize normal lung, whereas multiple vertical B-lines are associated with increased lung density. We sought to assess the prevalence of A-lines and B-lines in patients with acute heart failure (AHF) and examine their clinical correlates and their relationship with outcomes. METHODS AND RESULTS: In a prospective cohort study of adults with AHF, eight-zone LUS and echocardiography were performed early during the hospitalization and pre-discharge at an imaging depth of 18 cm. A- and B-lines were analysed separately off-line, blinded to clinical and outcome data. Of 164 patients [median age 71 years, 61% men, mean ejection fraction (EF) 40%], the sum of A-lines at baseline ranged from 0 to 19 and B-line number from 0 to 36. One hundred and fifty-six patients (95%) had co-existing A-lines and B-lines at baseline. Lower body mass index and lower chest wall thickness were associated with a higher number of A-lines (P trend < 0.001 for both). In contrast to B-lines, there was no significant change in the number of A-lines from baseline to discharge (median 6 vs. 5, P = 0.80). While B-lines were associated with 90-day HF readmission or death, A-lines were not [HR 1.67, 95% confidence interval (CI) 1.11-2.51 vs. HR 0.97, 95% CI 0.65-1.43]. CONCLUSIONS: A-lines and B-lines on LUS co-exist in the vast majority of hospitalized patients with AHF. In contrast to B-lines, A-lines were not associated with adverse outcomes.

Quantification of pleural effusions on thoracic ultrasound in acute heart failure.

BACKGROUND: Although pleural effusions are common among patients with acute heart failure, the relevance of pleural effusion size assessed on thoracic ultrasound has not been investigated systematically. METHODS: In this prospective observational study, we included patients hospitalised for acute heart failure and performed a thoracic ultrasound early after admission (thoracic ultrasound 1) and at discharge (thoracic ultrasound 2) independently of routine clinical management. A semiquantitative score was applied offline blinded to clinical findings to categorise and monitor pleural effusion size. RESULTS: Among 188 patients (median age 72 years, 62% men, 78% white, median left ventricular ejection fraction 38%), pleural effusions on thoracic ultrasound 1 were present in 66% of patients and decreased in size during the hospitalisation in 75% based on the pleural effusion score (P<0.0001). Higher values of the pleural effusion score were associated with higher pleural effusion volumes on computed tomography (P<0.001), higher NT-pro brain natriuretic peptide values (P=0.001) and a greater number of B-lines on lung ultrasound (P=0.004). Nevertheless, 47% of patients were discharged with persistent pleural effusions, 19% with large effusions. However, higher values of the pleural effusion score on thoracic ultrasound 2 did not identify patients at increased risk of 90-day heart failure rehospitalisations or death (adjusted hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.92-1.19; P=0.46) whereas seven or more B-lines on lung ultrasound at discharge were independently associated with adverse events (adjusted HR 2.43, 95% CI 1.11-5.37; P=0.027). CONCLUSION: Among patients with acute heart failure, pleural effusions are associated with other clinical, imaging and laboratory markers of congestion and improve with heart failure therapy. The prognostic relevance of persistent pleural effusions at discharge should be investigated in larger studies.

Body mass index and B-lines on lung ultrasonography in chronic and acute heart failure.

AIMS: Increased body mass index (BMI) is common in heart failure (HF) patients and is associated with lower levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). We evaluated the influence of BMI on lung ultrasonography (LUS) findings indicative of pulmonary congestion (i.e. B-lines) in patients with chronic and acute HF (AHF). METHODS AND RESULTS: We analysed ambulatory chronic HF (n = 118) and hospitalized AHF (n = 177) patients (mean age 70 years, 64% men, mean BMI 29 kg/m2 , mean ejection fraction 42%) undergoing echocardiography and LUS in eight chest zones. B-lines and chest wall thickness (skin to pleura) on ultrasound were quantified offline and blinded to clinical findings. NT-proBNP was available in AHF patients (n = 167). In chronic HF, B-line number decreased by 18% per 5 unit increase in BMI [95% confidence interval (CI) -35% to +5%, P = 0.11]. In AHF, the number of B-lines decreased by 12% per 5 unit increase in BMI (95% CI -19% to -5%, P = 0.001), whereas NT-proBNP concentration decreased by 28% per 5 unit increase in BMI (95% CI -40% to -16%, P < 0.001). For AHF, B-line number declined to a lesser degree than NT-proBNP concentration with increasing BMI (P = 0.020), and >6 B-lines were observed in half of AHF patients with severe obesity. There was an inverse relationship between B-line number and chest wall thickness, and this association varied by chest region. CONCLUSIONS: Despite an inverse relationship between B-lines and BMI, B-lines declined to a lesser degree than NT-proBNP with increasing BMI. These data suggest that LUS may be useful in patients with HF despite obesity.

Ability of non-physicians to perform and interpret lung ultrasound: A systematic review.

BACKGROUND: Lung ultrasound is a useful tool in the assessment of pulmonary congestion in heart failure that is typically performed and interpreted by physicians at the point-of-care. AIMS: To investigate the ability of nurses, students, and paramedics to accurately identify B-lines and pleural effusions for the detection of pulmonary congestion in heart failure and to examine the training necessary. METHODS AND RESULTS: We conducted a systematic review and searched online databases for studies that investigated the ability of nurses, students, and paramedics to perform lung ultrasound and detect B-lines and pleural effusions. Of 979 studies identified, 14 met our inclusion criteria: five in nurses, eight in students, and one in paramedics. After 0-12 h of didactic training and 58-62 practice lung ultrasound examinations, nurses were able to identify B-lines and pleural effusions with a sensitivity of 79-98% and a specificity of 70-99%. In image adequacy studies, medical students with 2-9 h of training were able to acquire adequate images for B-lines and pleural effusions in 50-100%. Only one eligible study investigated paramedic-performed lung ultrasound which did not support the ability of paramedics to adequately acquire and interpret lung ultrasound images after 2 h of training. CONCLUSIONS: Our findings suggest that nurses and students can accurately acquire and interpret lung ultrasound images after a brief training period in a majority of cases. The examination of heart failure patients with lung ultrasound by non-clinicians appears feasible and warrants further investigation.

Lung Ultrasound in Acute Heart Failure: Prevalence of Pulmonary Congestion and Short- and Long-Term Outcomes.

OBJECTIVES: This study sought to assess the prevalence, changes in, and prognostic importance of B-lines, a pulmonary congestion measure by using a simplified lung ultrasonography (LUS) method in acute heart failure (AHF). BACKGROUND: Pulmonary congestion is an important finding in AHF, but conventional methods for its detection are insensitive. METHODS: In a 2-site, prospective, observational study, 4-zone LUS was performed early during hospitalization for AHF (LUS1) and at discharge (LUS2). B-lines were quantified off-line, blinded to clinical findings and outcomes, by a core laboratory. RESULTS: Among 349 patients (median, 75 years of age; 59% men; mean ejection fraction 39%), the sum of B-lines in 4 zones ranged from 0 to 18 (LUS1). The risk of an adverse in-hospital event increased with rising number of B-lines on LUS1: the odds ratio for each B-line tertile was 1.82 (95% confidence interval [CI]: 1.14 to 2.88; p = 0.011). B-line count decreased from a median of 6 (LUS1) to 4 (LUS2; p < 0.001) over 6 days (median). In 132 patients with LUS2 images, the risk of HF hospitalization or all-cause death was greater in patients with a higher number of B-lines at discharge. This relationship was stronger closer to discharge: unadjusted hazard ratio (HR) at 60 days was 3.30 (95% CI: 1.52 to 7.17; p = 0.002); 2.94 at 90 days (95% CI: 1.46 to 5.93; p = 0.003); and 2.01 at 180 days (95% CI: 1.11 to 3.64; p = 0.021). The association between number of B-lines and short- and long-term outcomes persisted after adjusting for important clinical variables, including N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Pulmonary congestion using a simplified 4-zone LUS method was common in patients with AHF and improved with therapy. A higher number of B-lines at baseline and discharge identified patients at increased risk for adverse events.

Interpretation of biological experiments changes with evolution of the Gene Ontology and its annotations.

Gene Ontology (GO) enrichment analysis is ubiquitously used for interpreting high throughput molecular data and generating hypotheses about underlying biological phenomena of experiments. However, the two building blocks of this analysis - the ontology and the annotations - evolve rapidly. We used gene signatures derived from 104 disease analyses to systematically evaluate how enrichment analysis results were affected by evolution of the GO over a decade. We found low consistency between enrichment analyses results obtained with early and more recent GO versions. Furthermore, there continues to be a strong annotation bias in the GO annotations where 58% of the annotations are for 16% of the human genes. Our analysis suggests that GO evolution may have affected the interpretation and possibly reproducibility of experiments over time. Hence, researchers must exercise caution when interpreting GO enrichment analyses and should reexamine previous analyses with the most recent GO version.