An Electronic Health Record–Compatible Model to Predict Personalized Treatment Effects From the Diabetes Prevention Program: A Cross-Evidence Synthesis Approach Using Clinical Trial and Real-World Data

ObjectiveTo develop an electronic health record (EHR)-based risk tool that provides point-of-care estimates of diabetes risk to support targeting interventions to patients most likely to benefit.Patients and MethodsA risk prediction model was developed and validated in a large observational database of patients with an index visit date between January 1, 2012, and December 31, 2016, with treatment effect estimates from risk-based reanalysis of clinical trial data. The risk model development cohort included 1.1 million patients with prediabetes from the OptumLabs Data Warehouse (OLDW); the validation cohort included a distinct sample of 1.1 million patients in OLDW. The randomly assigned clinical trial cohort included 3081 people from the Diabetes Prevention Program (DPP) study.ResultsEleven variables reliably obtainable from the EHR were used to predict diabetes risk. This model validated well in the OLDW (C statistic = 0.76; observed 3-year diabetes rate was 1.8% (95% confidence interval [CI], 1.7 to 1.9) in the lowest-risk quarter and 19.6% (19.4 to 19.8) in the highest-risk quarter). In the DPP, the hazard ratio (HR) for lifestyle modification was constant across all levels of risk (HR, 0.43; 95% CI, 0.35 to 0.53), whereas the HR for metformin was highly risk dependent (HR, 1.1; 95% CI, 0.61 to 2.0 in the lowest-risk quarter vs HR, 0.45; 95% CI, 0.35 to 0.59 in the highest-risk quarter). Fifty-three percent of the benefits of population-wide dissemination of the DPP lifestyle modification and 73% of the benefits of population-wide metformin therapy can be obtained by targeting the highest-risk quarter of patients.ConclusionThe Tufts–Predictive Analytics and Comparative Effectiveness DPP Risk model is an EHR-compatible tool that might support targeted diabetes prevention to more efficiently realize the benefits of the DPP interventions.     

The Role of Biological Effective Dose in Predicting Obliteration After Stereotactic Radiosurgery of Cerebral Arteriovenous Malformations

ObjectiveTo determine whether biological effective dose (BED) was predictive of obliteration after stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVMs).Patients and MethodsWe studied patients undergoing single-session AVM SRS between January 1, 1990, and December 31, 2014, with at least 2 years of imaging follow-up. Excluded were patients with syndromic AVM, previous SRS or embolization, and patients treated with volume-staged SRS. Biological effective dose was calculated using a mono-exponential model described by Jones and Hopewell. The primary outcome was likelihood of total obliteration defined by digital subtraction angiography or magnetic resonance imaging (MRI). Variables were analyzed as continuous and dichotomous variables based on the maximum value of (sensitivity–[1–specificity]).ResultsThis study included 352 patients (360 AVM, median follow-up, 5.9 years). The median margin dose prescribed was 18.75 Gy (interquartile range [IQR]: 18 to 20 Gy). Two hundred fifty-nine patients (71.9%) had obliteration shown by angiography (n=176) or MRI (n=83) at a median of 36 months after SRS (IQR: 26 to 44 months). Higher BED was associated with increased likelihood of obliteration in univariate Cox regression analyses, when treated as either a dichotomous (≥133 Gy; hazard ratio [HR],1.52; 95% confidence interval [CI], 1.19 to 1.95; P<.001) or continuous variable (HR, 1.00, 95% CI, 1.0002 to 1.005; P=.04). In multivariable analyses including dichotomized BED and location, BED remained associated with obliteration (P=.001).ConclusionBiological effective dose ≥133 Gy was predictive of AVM obliteration after single-session SRS within the prescribed margin dose range 15 to 25 Gy. Further study is warranted to determine whether BED optimization should be considered as well as treatment dose for AVM SRS planning.     

Early Detection of Pancreatic Cancer in Patients With Chronic Liver Disease Under Hepatocellular Carcinoma Surveillance

ObjectiveTo evaluate whether patients with hepatitis B virus (HBV)– and hepatitis C virus (HCV)–related chronic liver disease were diagnosed as having pancreatic cancer (PC) at an early stage during abdominal imaging surveillance for hepatocellular carcinoma (HCC).Patients and MethodsWe retrospectively examined 447 patients with PC diagnosed at Ehime University Hospital and affiliated centers (2011-2013). Data were collected regarding HBV and HCV status, likelihood of PC diagnosis, and Union for International Cancer Control (UICC) stage. Intergroup comparisons were performed using the χ² test.ResultsThe UICC stage distribution in the HCC surveillance group (n=16) was stage 0 (n=2, 12.5%), stage IA (n=3, 18.8%), stage IB (n=2, 12.5%), stage IIA (n=2, 12.5%), stage IIB (n=2, 12.5%), stage III (n=1, 6.3%), and stage IV (n=4, 25%). The UICC stage distribution in the nonsurveillance group (n=431) was stage 0 (n=4, 0.9%), stage IA (n=28, 6.5%), stage IB (n=27, 6.3%), stage IIA (n=86, 20.0%), stage IIB (n=48, 11.1%), stage III (n=56, 13.0%), and stage IV (n=182, 42.2%). The HCC surveillance group had significantly more patients with stage 0 disease than with stages IA through IV (P=.02). Similar results were observed when including stages IA (P=.007) and IB (P=.004) as early stages but not stage IIA (P=.10). A dilated pancreatic duct led to a PC diagnosis in all 6 patients with stage 0 disease.ConclusionPatients with HBV- and HCV-related chronic liver disease had an early PC diagnosis during HCC surveillance. Careful evaluation of the pancreas is warranted during HCC surveillance.     

Characteristics,Treatment Patterns,and Clinical Outcomes After Heart Failure Hospitalizations During the COVID-19 Pandemic,March to October 2020

ObjectiveTo compare clinical characteristics, treatment patterns, and 30-day all-cause readmission and mortality between patients hospitalized for heart failure (HF) before and during the coronavirus disease 2019 (COVID-19) pandemic.Patients and MethodsThe study was conducted at 16 hospitals across 3 geographically dispersed US states. The study included 6769 adults (mean age, 74 years; 56% [5033 of 8989] men) with cumulative 8989 HF hospitalizations: 2341 hospitalizations during the COVID-19 pandemic (March 1 through October 30, 2020) and 6648 in the pre–COVID-19 (October 1, 2018, through February 28, 2020) comparator group. We used Poisson regression, Kaplan-Meier estimates, multivariable logistic, and Cox regression analysis to determine whether prespecified study outcomes varied by time frames.ResultsThe adjusted 30-day readmission rate decreased from 13.1% (872 of 6648) in the pre–COVID-19 period to 10.0% (234 of 2341) in the COVID-19 pandemic period (relative risk reduction, 23%; hazard ratio, 0.77; 95% CI, 0.66 to 0.89). Conversely, all-cause mortality increased from 9.7% (645 of 6648) in the pre–COVID-19 period to 11.3% (264 of 2341) in the COVID-19 pandemic period (relative risk increase, 16%; number of admissions needed for one additional death, 62.5; hazard ratio, 1.19; 95% CI, 1.02 to 1.39). Despite significant differences in rates of index hospitalization, readmission, and mortality across the study time frames, the disease severity, HF subtypes, and treatment patterns remained unchanged (P>0.05).ConclusionThe findings of this large tristate multicenter cohort study of HF hospitalizations suggest lower rates of index hospitalizations and 30-day readmissions but higher incidence of 30-day mortality with broadly similar use of HF medication, surgical interventions, and devices during the COVID-19 pandemic compared with the pre–COVID-19 time frame.     

Prevalence and Risk Factors for Inappropriate Continuation of Proton Pump Inhibitors After Discharge From the Intensive Care Unit

ObjectiveTo determine the prevalence and risk factors for inappropriate discharge on proton pump inhibitor (PPI) therapy started in the intensive care unit (ICU) for stress ulcer prophylaxis.Patients and MethodsThis was a retrospective cohort study of adults initiated on treatment with a PPI in any of 9 affiliated ICUs from January 1, 2014, to December 31, 2018. Patients were excluded if they had an appropriate long-term PPI indication. Logistic regression modeling was used to identify characteristics associated with discharge on treatment with an inappropriate PPI.ResultsOf 24,751 patients admitted to an ICU, 4127 were initiated on treatment with a new PPI, with 2467 (60%) lacking a long-term PPI indication. Of these 2467, a total of 1122 (45%) were continued on PPI therapy after transfer to the floor and 668 (27%) were discharged on PPI therapy. On multivariable analysis, risk factors for inappropriate discharge on PPI therapy included having an upper endoscopy (adjusted odds ratio [aOR], 1.70; 95% CI, 1.08-2.66), admission to the surgical compared with medical ICU (aOR, 2.03; 95% CI, 1.32-3.10), and discharge to a nursing home or rehabilitation facility (aOR, 1.43; 95% CI, 1.04-1.96; and aOR, 2.29; 95% CI, 1.62-3.24, respectively).ConclusionAmong patients started on treatment with a PPI in the ICU without an indication for outpatient PPI use, 27% (668 of 2467) were nonetheless discharged on PPI therapy. Medically complex and surgical ICU patients are at increased risk for receiving PPIs without appropriate documented indications, and careful review of medication lists at discharge should occur in these high-risk groups.     

Determinants of Discharge Disposition From Acute Care for Survivors of Hypoxic-Ischemic Brain Injury: Results From a Large Population-Based Cohort Data Set

ObjectiveTo identify determinants of discharge disposition from acute care among survivors of hypoxic-ischemic brain injury (HIBI), stratified by sex.DesignPopulation-based retrospective cohort study using provincial data in Ontario, Canada. The determinants were grouped into predisposing, need, and enabling factors using the Anderson Behavioral Model.SettingAcute care.ParticipantsSurvivors of HIBI aged ≥20 years at the time of hospitalization and discharged alive from acute care between April 1, 2002, and March 31, 2017. There were 7492 patients with HIBI, of whom 28% (N=2077) survived their acute care episode.InterventionsNot applicable.Main Outcome MeasuresDischarge disposition from acute care, categorized as complex continuing care (CCC), long-term care (LTC), inpatient rehabilitation (IR), home with support, home without support, and transferred to another acute care.ResultsThe discharge dispositions for the 2077 survivors were IR 23.4% (n=487), CCC 19.5% (n=404), LTC 6.2% (n=128), home without support 31.2% (n=647), home with support 15.1% (n=314), and other 4.6%. Multinomial multivariable logistic regression analysis using home without support as the reference category revealed that female patients were significantly more likely than male patients to be discharged to LTC/CCC. Those who were older, were frail, and had longer stay in acute care or special care unit (SCU) were more likely to be discharged to LTC/CCC. The only significant determinant for IR was longer stay in acute care. Survivors with cardiac-related injury were less likely to be discharged to LTC/CCC. Income was a significant factor for male patients but not for female patients in the sex-stratified analysis. The following variables were investigated but were not significant determinants in this study: need factors (comorbidity score, prior psychiatric disorders, health care utilization) and enabling factors (income quintile, rural area of residence).ConclusionsPredisposing (age, sex) and need factors (frailty, acute care days, SCU days, type of injury) were significant determinants of discharge disposition from acute care after HIBI. In spite of a system with universal coverage, sex differences were found, with more female patients being discharged to CCC/LTC rather than IR, controlling for age and other confounders. These findings should be considered in appropriate discharge planning from acute care for survivors of HIBI.     

Contextualized Treatment in Traumatic Brain Injury Inpatient Rehabilitation: Effects on Outcomes During the First Year After Discharge

ObjectiveTo evaluate the effect of providing a greater percentage of therapy as contextualized treatment on acute traumatic brain injury (TBI) rehabilitation outcomes.DesignPropensity score methods are applied to the TBI Practice-Based Evidence (TBI-PBE) database, a database consisting of multi-site, prospective, longitudinal observational data.SettingAcute inpatient rehabilitation.ParticipantsPatients enrolled in the TBI-PBE study (N=1843), aged 14 years or older, who sustained a severe, moderate, or complicated mild TBI, received their first inpatient rehabilitation facility admission in the US, and consented to follow-up 3 and 9 months post discharge from inpatient rehabilitation.InterventionsNot applicable.Main Outcome MeasuresParticipation Assessment with Recombined Tools-Objective (PART-O)-17, FIM Motor and Cognitive scores, Satisfaction with Life Scale, and Patient Health Questionnaire-9.ResultsIncreasing the percentage of contextualized treatment during inpatient TBI rehabilitation leads to better outcomes, specifically in regard to community participation.ConclusionsIncreasing the proportion of treatment provided in the context of real-life activities appears to have a beneficial effect on outcome. Although the effect sizes are small, the results are consistent with other studies supporting functional-based interventions effecting better outcomes. Furthermore, any positive findings, regardless of size or strength, are endorsed as important by consumers (survivors of TBI). While the findings do not imply that decontextualized treatment should not be used, when the therapy goal can be addressed with either approach, the findings suggest that better outcomes may result if the contextualized approach is used.     

Recurrence of Functional Versus Organic Mitral Regurgitation After Transcatheter Mitral Valve Repair: Implications from Three-Dimensional Echocardiographic Analysis of Mitral Valve Geometry and Left Ventricular Dilation for a Point of No Return

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Curbing the Delta Surge: Clinical Outcomes After Treatment With Bamlanivimab-Etesevimab,Casirivimab-Imdevimab,or Sotrovimab for Mild to Moderate Coronavirus Disease 2019

ObjectiveTo describe and compare the clinical outcomes of bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab treatment of mild to moderate coronavirus disease 2019 (COVID-19) during the severe acute respiratory coronavirus 2 (SARS-CoV-2) B.1.617.2 Delta surge.MethodsThis is a retrospective study of high-risk patients who received bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab for mild to moderate COVID-19 between August 1, 2021, and December 1, 2021. Rates of severe disease, hospitalization, intensive care unit admission, and death were assessed.ResultsAmong 10,775 high-risk patients who received bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab for mild to moderate COVID-19 during the Delta surge, 287 patients (2.7%) developed severe disease that led to hospitalization, oxygen supplementation, or death within 30 days after treatment. The rates of severe disease were low among patients treated with bamlanivimab-etesevimab (1.2%), casirivimab-imdevimab (2.9%), and sotrovimab (1.6%; P<.01). The higher rate of severe outcomes among patients treated with casirivimab-imdevimab may be related to a significantly lower COVID-19 vaccination rate in that cohort. Intensive care unit admission was comparable among patients treated bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab (1.0%, 1.0%, and 0.4%, respectively).ConclusionThis real-world study of a large cohort of high-risk patients shows low rates of severe disease, hospitalization, intensive care unit admission, and mortality after treatment with bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab for mild to moderate COVID-19 during the SARS-CoV-2 Delta surge.     

Clinical Characteristics,Treatment, and Outcomes of Critically Ill Patients With COVID-19: A Scoping Review

A growing number of studies on coronavirus disease 2019 (COVID-19) are becoming available, but a synthesis of available data focusing on the critically ill population has not been conducted. We performed a scoping review to synthesize clinical characteristics, treatment, and clinical outcomes among critically ill patients with COVID-19. Between January 1, 2020, and May 15, 2020, we identified high-quality clinical studies describing critically ill patients with a sample size of greater than 20 patients by performing daily searches of the World Health Organization and LitCovid databases on COVID-19. Two reviewers independently reviewed all abstracts (2785 unique articles), full text (218 articles), and abstracted data (92 studies). The 92 studies included 61 from Asia, 16 from Europe, 10 from North and South America, and 5 multinational studies. Notable similarities among critically ill populations across all regions included a higher proportion of older males infected and with severe illness, high frequency of comorbidities (hypertension, diabetes, and cardiovascular disease), abnormal chest imaging findings, and death secondary to respiratory failure. Differences in regions included newly identified complications (eg, pulmonary embolism) and epidemiological risk factors (eg, obesity), less chest computed tomography performed, and increased use of invasive mechanical ventilation (70% to 100% vs 15% to 47% of intensive care unit patients) in Europe and the United States compared with Asia. Future research directions should include proof-of-mechanism studies to better understand organ injuries and large-scale collaborative clinical studies to evaluate the efficacy and safety of antivirals, antibiotics, interleukin 6 receptor blockers, and interferon. The current established predictive models require further verification in other regions outside China.     

Microvascular Disease and Risk of Cardiovascular Events and Death From Intensive Treatment in Type 2 Diabetes: The ACCORDION Study

ObjectiveTo assess whether the presence of microvascular complications modifies the effect of intensive glucose reduction on long-term outcomes in patients with type 2 diabetes.Patients and MethodsUsing ACCORD and ACCORDION study data, we investigated the risk of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) or death in relation to the prerandomization type and extent of microvascular complications. Interaction terms were fitted in survival models to estimate the risk of both outcomes across levels of an overall microvascular disease score (range 0 to 100) and its individual components: diabetic nephropathy, retinopathy, and neuropathy.ResultsDuring a mean follow-up of 7.7 years, 1685 primary outcomes and 1806 deaths occurred in 9405 participants. The outcome-specific microvascular score was ≤30 in 97.9% of subjects for the primary outcome and in 98.5% for death. For participants with scores of 0 and 30, respectively, the 10-year absolute risk difference between intensive glucose control and standard treatment ranged from ?0.8% (95% CI, ?2.6, 1.1) to ?3.0% ?7.1, 1.1) for the primary outcome and from ?0.5% (?2.1, 1.1) to 0.7% (?4.2, 5.6) for mortality. Retinopathy was associated with the largest effects, with a 10-year absolute risk difference of ?6.5% (?11.1 to ?2.0) for the primary outcome and ?3.9% (?7.8 to 0.1) for mortality.ConclusionThis hypothesis-generating study identifies diabetic retinopathy as predictor of the beneficial effect of intensive glucose control on the risk of cardiovascular disease and possibly death. Further long-term studies are required to confirm these findings.     

Readability of Participant Informed Consent Forms and Informational Documents: From Phase 3 COVID-19 Vaccine Clinical Trials in the United States

ObjectiveTo assess the readability of the informed consent forms from the phase 3 COVID-19 vaccine trials conducted in the United States.Patients and MethodsEnglish consent forms were used for patients in phase 3 COVID-19 vaccine clinical trials. Consent forms were obtained in October 2020. Using Microsoft Word tools, we analyzed the readability (ie, the ease of reading) of written consent forms and informational documents from phase 3 COVID-19 vaccine clinical trials in the United States from the following manufacturers: AstraZeneca, Moderna, Pfizer, Johnson & Johnson, and Novavax.ResultsOwing to low readability and several format factors, this study determined that none of the consent forms or informational documents from the recent phase 3 COVID-19 vaccine clinical trials conducted in the United States met readability standards at the recommended 7th grade readability level for the average vaccine research volunteer in any readability category. The average English-speaking vaccine trial volunteer would have great difficulty comprehending the information provided in the consent forms and informational documents. To ensure that study subjects receive and fully comprehend information regarding a clinical study and can provide reliable consent, greater attention should be given to the development and use of simplified consent forms, multimedia formatting, personal discussion, and comprehension assessments.