Extended-age Out-of-sample Validation of Risk Stratification Index 3.0 Models Using Commercial All-payer Claims.

BACKGROUND: The authors previously reported a broad suite of individualized Risk Stratification Index 3.0 (Health Data Analytics Institute, Inc., USA) models for various meaningful outcomes in patients admitted to a hospital for medical or surgical reasons. The models used International Classification of Diseases, Tenth Revision, trajectories and were restricted to information available at hospital admission, including coding history in the previous year. The models were developed and validated in Medicare patients, mostly age 65 yr or older. The authors sought to determine how well their models predict utilization outcomes and adverse events in younger and healthier populations. METHODS: The authors' analysis was based on All Payer Claims for surgical and medical hospital admissions from Utah and Oregon. Endpoints included unplanned hospital admissions, in-hospital mortality, acute kidney injury, sepsis, pneumonia, respiratory failure, and a composite of major cardiac complications. They prospectively applied previously developed Risk Stratification Index 3.0 models to the younger and healthier 2017 Utah and Oregon state populations and compared the results to their previous out-of-sample Medicare validation analysis. RESULTS: In the Utah dataset, there were 55,109 All Payer Claims admissions across 40,710 patients. In the Oregon dataset, there were 21,213 admissions from 16,951 patients. Model performance on the two state datasets was similar or better than in Medicare patients, with an average area under the curve of 0.83 (0.71 to 0.91). Model calibration was reasonable with an R2 of 0.93 (0.84 to 0.97) for Utah and 0.85 (0.71 to 0.91) for Oregon. The mean sensitivity for the highest 5% risk population was 28% (17 to 44) for Utah and 37% (20 to 56) for Oregon. CONCLUSIONS: Predictive analytical modeling based on administrative claims history provides individualized risk profiles at hospital admission that may help guide patient management. Similar predictive performance in Medicare and in younger and healthier populations indicates that Risk Stratification Index 3.0 models are valid across a broad range of adult hospital admissions.

Risk Stratification Index 3.0, a Broad Set of Models for Predicting Adverse Events during and after Hospital Admission.

BACKGROUND: Risk stratification helps guide appropriate clinical care. Our goal was to develop and validate a broad suite of predictive tools based on International Classification of Diseases, Tenth Revision, diagnostic and procedural codes for predicting adverse events and care utilization outcomes for hospitalized patients. METHODS: Endpoints included unplanned hospital admissions, discharge status, excess length of stay, in-hospital and 90-day mortality, acute kidney injury, sepsis, pneumonia, respiratory failure, and a composite of major cardiac complications. Patient demographic and coding history in the year before admission provided features used to predict utilization and adverse events through 90 days after admission. Models were trained and refined on 2017 to 2018 Medicare admissions data using an 80 to 20 learn to test split sample. Models were then prospectively tested on 2019 out-of-sample Medicare admissions. Predictions based on logistic regression were compared with those from five commonly used machine learning methods using a limited dataset. RESULTS: The 2017 to 2018 development set included 9,085,968 patients who had 18,899,224 inpatient admissions, and there were 5,336,265 patients who had 9,205,835 inpatient admissions in the 2019 validation dataset. Model performance on the validation set had an average area under the curve of 0.76 (range, 0.70 to 0.82). Model calibration was strong with an average R 2 for the 99% of patients at lowest risk of 1.00. Excess length of stay had a root-mean-square error of 0.19 and R 2 of 0.99. The mean sensitivity for the highest 5% risk population was 19.2% (range, 11.6 to 30.1); for positive predictive value, it was 37.2% (14.6 to 87.7); and for lift (enrichment ratio), it was 3.8 (2.3 to 6.1). Predictive accuracies from regression and machine learning techniques were generally similar. CONCLUSIONS: Predictive analytical modeling based on administrative claims history can provide individualized risk profiles at hospital admission that may help guide patient management. Similar results from six different modeling approaches suggest that we have identified both the value and ceiling for predictive information derived from medical claims history.

Covid-19 and excess mortality in medicare beneficiaries.

We estimated excess mortality in Medicare recipients in the United States with probable and confirmed Covid-19 infections in the general community and amongst residents of long-term care (LTC) facilities. We considered 28,389,098 Medicare and dual-eligible recipients from one year before February 29, 2020 through September 30, 2020, with mortality followed through November 30th, 2020. Probable and confirmed Covid-19 diagnoses, presumably mostly symptomatic, were determined from ICD-10 codes. We developed a Risk Stratification Index (RSI) mortality model which was applied prospectively to establish baseline mortality risk. Excess deaths attributable to Covid-19 were estimated by comparing actual-to-expected deaths based on historical (2017-2019) comparisons and in closely matched concurrent (2020) cohorts with and without Covid-19. Overall, 677,100 (2.4%) beneficiaries had confirmed Covid-19 and 2,917,604 (10.3%) had probable Covid-19. A total of 472,329 confirmed cases were community living and 204,771 were in LTC. Mortality following a probable or confirmed diagnosis in the community increased from an expected incidence of about 4.0% to actual incidence of 7.5%. In long-term care facilities, the corresponding increase was from 20.3% to 24.6%. The absolute increase was therefore similar at 3-4% in the community and in LTC residents. The percentage increase was far greater in the community (89.5%) than among patients in chronic care facilities (21.1%) who had higher baseline risk of mortality. The LTC population without probable or confirmed Covid-19 diagnoses experienced 38,932 excess deaths (34.8%) compared to historical estimates. Limitations in access to Covid-19 testing and disease under-reporting in LTC patients probably were important factors, although social isolation and disruption in usual care presumably also contributed. Remarkably, there were 31,360 (5.4%) fewer deaths than expected in community dwellers without probable or confirmed Covid-19 diagnoses. Disruptions to the healthcare system and avoided medical care were thus apparently offset by other factors, representing overall benefit. The Covid-19 pandemic had marked effects on mortality, but the effects were highly context-dependent.

Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction.

We have determined the solution structure of the complex between an arginine-glycine-rich RGG peptide from the human fragile X mental retardation protein (FMRP) and an in vitro-selected guanine-rich (G-rich) sc1 RNA. The bound RNA forms a newly discovered G-quadruplex separated from the flanking duplex stem by a mixed junctional tetrad. The RGG peptide is positioned along the major groove of the RNA duplex, with the G-quadruplex forcing a sharp turn of R(10)GGGGR(15) at the duplex-quadruplex junction. Arg10 and Arg15 form cross-strand specificity-determining intermolecular hydrogen bonds with the major-groove edges of guanines of adjacent Watson-Crick G•C pairs. Filter-binding assays on RNA and peptide mutations identify and validate contributions of peptide-RNA intermolecular contacts and shape complementarity to molecular recognition. These findings on FMRP RGG domain recognition by a combination of G-quadruplex and surrounding RNA sequences have implications for the recognition of other genomic G-rich RNAs.

Detection of esophageal varices using CT and MRI.

BACKGROUND AND AIMS: The development of esophageal varices in cirrhotic patients carries a significant risk of hemorrhage and associated morbidity/mortality. Universal endoscopic screening, however, is invasive and expensive. Conversely, cirrhotic patients often have imaging findings which suggest portal hypertension. The aim of this study was to evaluate the ability of CT and/or MRI to detect esophageal varices compared to EGD. METHODS: Medical records from 2000 to 2007 were retrospectively reviewed. CT and/or MRI images were included if performed within 90 days of EGD. Two blinded, experienced radiologists were asked to review images for the presence of esophageal varices, as well as other findings associated with portal hypertension. Sensitivity, specificity, PPV and NPV were calculated using EGD findings as the gold standard. RESULTS: A total of 195 patients and 142 patients met criteria for CT and MRI, respectively. The sensitivity of CT to detect EGD varices was 58-89%, but increased to 65-100% when specifically looking at large endoscopic varices. Overall specificity was 68-82%, but increased to 97-100% when applying ≥4 mm varices criteria. CT was superior to MRI in the detection of endoscopic varices; the addition of other portal hypertension stigmata did not improve results. CONCLUSIONS: The exclusion of large endoscopic varices by CT, using standardized criteria, may obviate the need or frequency of EGD screening in select patient populations. Alternatively, CT findings highly suggestive of esophageal varices in cirrhotic patients may warrant further investigation and/or treatment. Further studies are needed to validate these findings.

Retreatment of patients nonresponsive to pegylated interferon and ribavirin with daily high-dose consensus interferon.

Background. Current treatment of chronic hepatitis C with pegylated interferon and ribavirin has the ability to eliminate viral infection in about half of the patients treated. Therapeutic options, for those with remaining chronic hepatitis, will remain limited until novel antivirals become available in the future. Consensus interferon is currently available and has demonstrated clinical efficacy with superior invitro antiviral activity, but the maximum tolerated dose is not defined. Methods. We assessed the efficacy of daily high-dose (24 ug) consensus interferon with weight-based (1000-1200 mg daily) ribavirin in HCV genotype 1-infected non-responder patients. Results. Six adverse events were documented in five patients, and the trial was terminated with no subject achieving viral clearance. Conclusions. The occurrence of serious adverse events effectively defined the upper limit of acceptable dose, while also revealing that this dose did not offer enhanced sustained viral clearance.

Hepatic lipogranulomas in patients with chronic liver disease: association with hepatitis C and fatty liver disease.

AIM: To study the significance and clinical implication of hepatic lipogranuloma in chronic liver diseases, including fatty liver disease and hepatitis C. METHODS: A total of 376 sequential, archival liver biopsy specimens were reviewed. Lipogranuloma, steatosis and steato-fibrosis were evaluated with combined hematoxylin and eosin and Masson's trichrome staining. RESULTS: Fifty-eight (15.4%) patients had lipogranuloma, including 46 patients with hepatitis C, 14 patients with fatty liver disease, and 5 patients with other diseases. Hepatic lipogranuloma was more frequently seen in patients with hepatitis C (21%) and fatty liver disease (18%), and its incidence was significantly higher than that in control group (P < 0.0002 and P < 0.007, respectively). In addition, 39 out of the 58 patients with lipogranuloma were associated with steatosis and/or steato-fibrosis. Of the 18 lipogranuloma patients with clinical information available for review, 15 (83%) had risk factors associated with fatty liver disease, such as alcohol use, obesity, hyperlipidemia, and diabetes mellitus. Although the incidence of these risk factors was greater in patients with lipogranuloma than in control group (60%), it did not reach statistical significance. CONCLUSION: Hepatic lipogranuloma is not limited to mineral oil use and commonly associated with hepatic steatosis, hepatitis C and fatty liver disease. With additional histological features of steato-fibrosis, lipogranuloma can also be used as a marker of prior hepatic steatosis.

Trends in the indication and method of liver biopsy for hepatitis B and C.

BACKGROUND AND AIMS: Liver biopsy plays a crucial role in assessing inflammation and fibrosis in chronic hepatitis. The aim of this study was to compare the indications and methods for performing a liver biopsy over a 15-year period when there were evolving strategies and increasing therapeutic options for the treatment for chronic hepatitis B (HBV) and C (HCV). METHODS: We reviewed all percutaneous liver biopsies performed at our center from 1992 to 2007 using a pathology database. Variables collected included indication for biopsy, use of real-time ultrasound (US) guidance, and complications associated with the biopsy. RESULTS: A total of 3,572 total liver biopsies were performed between 1992 and 2007 with a gradual increase in annual liver biopsies from 1992 to 2001. After a peak in 2003, there was a gradual decline in liver biopsies performed. The number of liver biopsies done for HCV peaked in 2003, followed by an annual decrease until 2006, while the number of annual biopsies done for HBV increased during the same period. In addition, the proportion of liver biopsies performed with real-time US-guidance increased steadily since 1997. CONCLUSIONS: Changes in liver biopsy trends at our center may be related to several factors, including the evolving treatment strategies for HCV and HBV. Percutaneous liver biopsies were increasingly performed using real-time US-guidance over the past decade, a change that may reflect practice patterns around the country.

Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment.

The low-density lipoprotein receptor (LDLR) has been proposed as a candidate receptor for the hepatitis C virus (HCV). Competitive inhibition of HCV binding to the LDLR by low-density lipoprotein (LDL) has been shown in vitro. If similar inhibition occurs in vivo, an elevated serum concentration of beta-lipoproteins may reduce the efficiency of infecting hepatocytes with HCV by competitively inhibiting HCV viral receptor binding. We investigated the role of baseline lipid values in influencing the outcome of HCV treatment. We conducted a retrospective chart review of patients treated with an interferon-based regimen at our liver and gastroenterology clinics between 1998 and 2004. Of 99 patients enrolled in the study, 49 (49.5%) had HCV genotype 1 (LDL 100.2 +/- 30.2 mg/dL [mean +/- SD]), and 50 patients (50.5%) had genotype 2 or 3 (LDL 110.1 +/- 40 mg/dL) infection. Early viral response (EVR), end-of-treatment response (ETR), and sustained viral response (SVR) were documented in 99, 88, and 77 patients, respectively. LDL and cholesterol levels prior to treatment were found to be higher in patients with positive EVR, ETR, and SVR. This difference remained significant independent of age. Multivariate analysis controlling for genotype and age showed that the higher the cholesterol and LDL levels prior to treatment, the greater the odds of responding to treatment. In conclusion, having higher serum LDL and cholesterol levels before treatment may be significant prognostic indicators for treatment outcome of those with chronic hepatitis C infection, particularly in genotypes 1 and 2.

Interferon-alpha-2b and ribavirin for retreatment of chronic hepatitis C.

BACKGROUND/AIMS: Subjects with chronic hepatitis C who fail treatment with interferon-alpha are generally divided into two groups: "relapsers" who normalized serum aminotransferase activity and have undetectable viral RNA during treatment and "non-responders" who do not achieve these results. The aim of this study was to examine retreatment of such subjects. METHODOLOGY: We studied 117 subjects with chronic hepatitis C who failed treatment with interferon-alpha, 87 of whom were "non-responders" and 30 "relapsers." Retreatment was with either interferon-alpha-2b plus ribavirin for 48 weeks or with interferon-alpha-2b plus placebo for 24 weeks followed by 24 weeks of combined therapy. RESULTS: Sustained response rates, defined as undetectable viral RNA in serum 6 months after retreatment, were 53% in "relapsers" and 10% in "non-responders" (P < 0.005). There was no significant difference if ribavirin was given for 24 or 48 weeks. In "non-responders" infected with genotypes other than type 1, 42% achieved a sustained response compared to 5% infected with genotype 1 (P = 0.027; odds ratio 7.09). CONCLUSIONS: Treatment with interferon-alpha-2b plus ribavirin is effective in approximately 50% of "relapsers" and "non-responders" infected with non-type 1 genotypes of hepatitis C virus. This therapy is only marginally effective in "non-responders" infected with genotype 1a or 1b.