Collaborative Program to Evaluate Real World Data for Use in Clinical Studies and Regulatory Decision Making.

The 21st Century Cures Act allows the US Food and Drug Administration to consider real world data (RWD) for new indications or post approval study requirements. However, there is limited guidance as to the relative quality of different RWD types. The ACE-RWD program will compare the quality of EHR clinical data, EHR billing data, and linked healthcare claims data to traditional clinical trial data collection methods. ACE-RWD is being conducted alongside 5-10 ancillary studies, with five sponsors, across multiple therapeutic areas. Each ancillary study will be conducted after or in parallel with its parent clinical study at a minimum of two clinical sites. Although not required, it is anticipated that EHR clinical and EHR billing data will be obtained via EHR-to-eCRF mechanisms that are based on the Health Level Seven (HL7) Fast Healthcare Interoperability Resources (FHIR®) standard.

Endoscopic retrograde cholangiopancreatography in the comorbid elderly: a retrospective comparative study in New Zealand.

AIM: To ascertain if endoscopic retrograde cholangiopancreatography (ERCP) in the elderly is associated with an increased risk of complications. METHODS: Retrospective study of 509 consecutive ERCPs on 338 patients in one year (2019-2020). Patients were categorised as >75 years old (elderly test group) or ≤75 (controls). The primary outcome was ERCP complications. Secondary outcomes were the length of hospital stay after complications, intensive care admissions, and all-cause mortality at 30 and 90 days. RESULTS: Forty-four complications occurred in a group of 42 (8%) patients; 11 (2%) were severe, including four deaths. The most common complication was pancreatitis n=33 (6%). There was no difference in complication rates between the elderly and younger controls. Length of stay after complications was similar (median five versus four days; p=0.354). All-cause mortality was higher in the elderly at 30-days (8.5% versus 2%; p=0.002) and 90-days (19.7% versus 6.9%; p=0.001), mostly attributed to malignancy. Logistic analysis showed that neither age >75 years nor Charlson Comorbidity Index (CCI) ≥5 was associated with post-ERCP pancreatitis, but a CCI≥5 strongly increased the odds of death at 90-days (AOR=74.44; 95% confidence interval (CI): 9.78- 566.38, p<0.001). CONCLUSION: ERCP is relatively safe in elderly patients, but comorbidities should be considered to avoid subjecting vulnerable individuals with a short life expectancy to unnecessary procedures.

Bleeding risk of oral anticoagulants in liver cirrhosis.

AIM: The safety of dabigatran is poorly studied in patients with liver cirrhosis and has rarely been compared to warfarin in terms of bleeding risks. METHOD: We undertook a retrospective cohort study across three tertiary centres in Auckland, New Zealand, between 2008 to 2020. Adults 18 years and over and those with a clinically confirmed diagnosis of cirrhosis were included. Data collected included demographic data and clinical characteristics, baseline medication and comorbidities. The primary outcome measure was the incidence of any bleeding event that resulted in hospital admission. RESULTS: Overall, 100 patients were included in this study. A total of 52 patients took warfarin, and 48 took dabigatran. Baseline characteristics for both groups were generally similar. The incidence rate of bleeds for patients taking warfarin was 14.4 per 100 person-years (95% CI, 8.8-23.5) compared to 9.1 per 100 person-years (95% CI, 4.5-18.1) for patients taking dabigatran. The incidence rate ratio comparing dabigatran to warfarin was 0.63 (95% CI, 0.23-1.60), p=0.25. CONCLUSION: Our study found that patients on dabigatran may have a lower bleeding risk than patients taking warfarin, but this was not statistically significant.

Finding the facts in an infodemic: framing effective COVID-19 messages to connect people to authoritative content.

The public's need for timely and trusted COVID-19 information remains high. Governments and global health agencies such as the WHO have sought to disseminate accurate and timely information to counteract misinformation and disinformation that has arisen as part of an 'infodemic'-the overabundance of information on COVID-19-some accurate and some not. In early 2020, WHO began a collaboration with Google to run online public service announcements on COVID-19, in the form of search ads displayed above results of Google Search queries. Web-based text ads can drive online searchers of COVID-19 information to authoritative COVID-19 content but determining what message is most effective is a challenge. WHO wanted to understand which message framing, that is, the way in which ad information is worded for the public, leads searchers to click through to WHO content. WHO tested 71 text ads in English across four COVID-19 topics using a mix of message frames: descriptive, collective, gain, loss, appeals to values and emphasising reasons. Between 11 September 2020 and 23 November 2020, there were 13 million views of the experimental WHO text ads leading to 1.4 million click-throughs to the WHO website. Within the set of 71 ads, there was a large spread between the most effective and least effective messages; for messages on COVID-19, the best performing framings were more than twice as effective as the worst performing framings (18.7% vs 8.5% engagement rate). Health practitioners can apply the messaging tactics WHO found to be successful to rapidly optimise messages for their own public health campaigns and better reach the public with authoritative information. Similar collaboration between big technology companies and governments and global health agencies has the potential to advance public health.

Quality of life after oesophageal stenting in patients with palliative oesophageal cancer.

AIM: Patients with incurable oesophageal cancer have poor outcomes, with disabling symptoms and a poor quality of life (QOL), which may be improved by oesophageal stenting. We aimed to measure change in symptoms related specifically to oesophageal cancer and overall QOL before and 30 days after stent insertion, to measure adverse effects and to define any patient factors that may be significant in predicting patients who may benefit most. METHODS: We prospectively enrolled patients in an observational study at Middlemore Hospital, New Zealand, and administered validated QOL- and symptomatology-based questionnaires before and 30 days after stent insertion. Additional patient-related demographics, procedural characteristics, adverse events and outcomes were collected. RESULTS: Between 31 March 2014 and 3 July 2020, 57 patients were initially recruited. Four patients withdrew from the study, and 13 patients died before 30 days. Forty patients (29 males; mean±SD age, 72±12 years) completed the study. A significant improvement was noted at one-month post stent insertion in the overall global QOL score (mean 35 to 46, p=0.01). The most significant score improvements were seen in dysphagia, trouble eating, trouble swallowing saliva and dry mouth (p<0.001). Physical, emotional, cognitive and social functioning did not change. Post-procedural adverse events occurred in 17 patients (43%). A poorer initial level of functioning was associated with reduced improvement in global QOL (p≤0.04). Patients followed-up died a mean of 2.8 months after insertion. CONCLUSION: In patients surviving longer than 30 days, there is significant improvement of overall QOL and dysphagia one-month post oesophageal stent insertion for malignant, palliative dysphagia. Multiple psychosocial facets were unchanged with this intervention. Stent-related adverse events were common.

Hypertension, renin-angiotensin-aldosterone-system-blocking agents, and COVID-19.

BACKGROUND: There have been concerns regarding the safety of renin-angiotensin-aldosterone-system (RAAS)-blocking agents including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) during the coronavirus disease 2019 (COVID-19) pandemic. This study sought to evaluate the impact of hypertension and the use of ACEI/ARB on clinical severity in patients with COVID-19. METHODS: A total of 3,788 patients aged 30 years or older who were confirmed with COVID-19 with real time reverse transcription polymerase chain reaction were identified from a claims-based cohort in Korea. The primary study outcome was severe clinical events, a composite of intensive care unit admission, need for ventilator care, and death. RESULTS: Patients with hypertension (n = 1,190, 31.4 %) were older and had higher prevalence of comorbidities than those without hypertension. The risk of the primary study outcome was significantly higher in the hypertension group, even after multivariable adjustment (adjusted odds ratio [aOR], 1.67; 95 % confidence interval [CI], 1.04 to 2.69). Among 1,044 patients with hypertensive medical treatment, 782 (74.9 %) were on ACEI or ARB. The ACEI/ARB subgroup had a lower risk of severe clinical outcomes compared to the no ACEI/ARB group, but this did not remain significant after multivariable adjustment (aOR, 0.68; 95 % CI, 0.41 to 1.15). CONCLUSIONS: Patients with hypertension had worse COVID-19 outcomes than those without hypertension, while the use of RAAS-blocking agents was not associated with increased risk of any adverse study outcomes. The use of ACE inhibitors or ARBs did not increase the risk of adverse COVID-19 outcomes, supporting current guidance to continue these medications when indicated.

Clinical utility of viscoelastic testing in chronic liver disease: A systematic review.

BACKGROUND: Conventional coagulation tests are widely used in chronic liver disease to assess haemostasis and to guide blood product transfusion. This is despite the fact that conventional tests do not reliably separate those with a clinically significant coagulopathy from those who do not. Viscoelastic testing such as thromboelastography (TEG) correlate with bleeding risk and are more accurate in identifying those who will benefit from blood product transfusion. Despite this, viscoelastic tests have not been widely used in patients with chronic liver disease outside the transplant setting. AIM: To assess the utility of Viscoelastic Testing guided transfusion in chronic liver disease patients presenting with bleeding or who require an invasive procedure. METHODS: PubMed and Google Scholar searches were performed using the key words "thromboelastography", "TEG" or "viscoelastic" and "liver transplantation", "cirrhosis" or "liver disease" and "transfusion", "haemostasis", "blood management" or "haemorrhage". A full text review was undertaken and data was extracted from randomised control trials that evaluated the outcomes of viscoelastic test guided transfusion in those with liver disease. The study subjects, inclusion and exclusion criteria, methods, outcomes and length of follow up were examined. Data was extracted by two independent individuals using a standardized collection form. The risk of bias was assessed in the included studies. RESULTS: A total of five randomised control trials included in the analysis examined the use of TEG guided blood product transfusion in cirrhosis prior to invasive procedures (n = 118), non-variceal haemorrhage (n = 96), variceal haemorrhage (n = 60) and liver transplantation (n = 28). TEG guided transfusion was effective in all five studies with a statistically significant reduction in overall blood product transfusion compared to standard of care. Four of the five studies reported a significant reduction in transfusion of fresh frozen plasma and platelets. Two studies showed a significant reduction in cryoprecipitate transfusion. No increased risk of bleeding was reported in the three trials where TEG was used perioperatively or prior to an invasive procedure. Two trials in the setting of cirrhotic variceal and non-variceal bleeding showed no difference in control of initial bleeding. In those with variceal bleeding, there was a statistically significant reduction in rate of re-bleeding at 42 d in the TEG arm 10% (vs 26.7% in the standard of care arm P = 0.012). Mortality data reported at various time points for all five trials from 6 wk up to 3 years was not statistically different between each arm. One trial in the setting of non-variceal bleeding demonstrated a significant reduction in adverse transfusion events in the TEG arm 30.6% (vs 74.5% in the control arm P < 0.01). In this study there was no significant difference in total hospital stay although length of stay in intensive care unit was reduced by an average of 2 d in the TEG arm (P = 0.012). CONCLUSION: Viscoelastic testing has been shown to reduce blood product usage in chronic liver disease without compromising safety and may enable guidelines to be developed to ensure patients with liver disease are optimally managed.

Novel single-domain antibodies against the EGFR domain III epitope exhibit the anti-tumor effect.

BACKGROUND: Monoclonal antibodies (mAbs) have been used for cancer therapy. They are large and have some disadvantages limiting their use. Smaller antibody fragments are needed as their alternatives. A fully human single-domain antibody (sdAb) has a small size of only 15 kDa and consists of only the variable domain of the human antibody heavy chain (VH). It has no immunogenicity. It can easily penetrate into tumor tissues, target an epitope inaccessible to mAb and be manufactured in bacteria for a low cost. Epidermal growth factor receptor (EGFR) is over-expressed in many cancer cells and is a good target for cancer therapy. METHODS: The EGFR protein fragment located on the EGFR extracellular domain III was chosen to screen a human sdAb library. Five human anti-EGFR sdAbs were identified. Their specific binding to EGFR was confirmed by ELISA, Western blotting and flow cytometry. Their anti-tumor effects were tested. RESULTS: Five novel fully human anti-EGFR sdAbs were isolated. They specifically bound to EGFR, not to the seven unrelated proteins as negative controls. They also bound to the three different human cancer cell lines, but not to the two cell lines as negative controls. They inhibited cell proliferation, migration and invasion and increased apoptosis of these three cancer cell lines. Two of them were tested for their anti-tumor effect in vivo and showed the anti-tumor activity in a mouse xenograft model for human lung cancer. Immunohistochemical staining of xenograft tumors also showed that their anti-tumor effects were associated with the inhibition of cancer cell proliferation and the promotion of cancer cell apoptosis. CONCLUSIONS: This study clearly demonstrated that the anti-EGFR sdAbs could inhibit cancer cell growth in vitro and tumor growth in vivo. They could be potential therapeutics for the treatment of different human cancers.

Electroretinographic Abnormalities and Sex Differences Detected with Mesopic Adaptation in a Mouse Model of Schizophrenia: A and B Wave Analysis.

Purpose: Mesopic flash electroretinography (fERG) as a tool to identify N-methyl-d-aspartate receptor (NMDAR) hypofunction in subjects with schizophrenia shows great potential. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from gene silencing of serine racemase (SR) expression (SR-/-), an established risk gene for schizophrenia. We analyzed fERG parameters under various background light adaptations to determine the most significant variables to allow for early identification of people at risk for schizophrenia, prior to onset of psychosis. SR is a risk gene for schizophrenia, and negative and cognitive symptoms antedate the onset of psychosis that is required for diagnosis. Methods: The scotopic, photopic, and mesopic fERGs were analyzed in male and female mice in both SR-/- and wild-type (WT) mice and also analyzed for sex differences. Amplitude and implicit time of the a- and b-wave components, b-/a-wave ratio, and Fourier transform analysis were analyzed. Results: Mesopic a- and b-wave implicit times were significantly delayed, and b-wave amplitudes, b/a ratios, and Fourier transform were significantly decreased in the male SR-/- mice compared to WT, but not in female SR-/- mice. No significant differences were observed in photopic or scotopic fERGs between genotype. Conclusions: The fERG prognostic capability may be improved by examination of background light adaptation, a larger array of light intensities, considering sex as a variable, and performing Fourier transform analyses of all waveforms. This should improve the ability to differentiate between controls and subjects with schizophrenia characterized by NMDAR hypofunction.

Anti-CXCR4 Single-Chain Variable Fragment Antibodies Have Anti-Tumor Activity.

Monoclonal antibodies (mAbs) are large and have limitations as cancer therapeutics. Human single-chain variable fragment (scFv) is a small antibody as a good alternative. It can easily enter cancer tissues, has no immunogenicity and can be produced in bacteria to decrease the cost. The chemokine receptor CXCR4 is overexpressed in different cancer cells. It plays an important role in tumor growth and metastasis. Its overexpression is associated with poor prognosis in cancer patients and is regarded as an attractive target for cancer treatment. In this study, a peptide on the CXCR4 extracellular loop 2 (ECL2) was used as an antigen for screening a human scFv antibody library by yeast two-hybrid method. Three anti-CXCR4 scFv antibodies were isolated. They could bind to CXCR4 protein and three cancer cell lines (DU145, PC3, and MDA-MB-231) and not to 293T and 3T3 cells as negative controls. These three scFvs could decrease the proliferation, migration, and invasion of these cancer cells and promote their apoptosis. The two scFvs were further examined in a mouse xenograft model, and they inhibited the tumor growth. Tumor immunohistochemistry also demonstrated that the two scFvs decreased cancer cell proliferation and tumor angiogenesis and increased their apoptosis. These results show that these anti-CXCR4 scFvs can decrease cancer cell proliferation and inhibit tumor growth in mice, and may provide therapy for various cancers.

The Significance of Equivocal Exercise Treadmill ECG for Intermediate Risk Chest Pain Assessment - Insight From Coronary CT Angiography Data.

BACKGROUND: Exercise treadmill test (ETT) is commonly the first-line investigation in troponin-negative chest pain patients. Inconclusive results are common and often lead to repeated functional testings. Coronary computed tomographic angiography (CCTA) has excellent negative predictive value for coronary artery disease detection and may play an important role in their diagnostic workup. We aim to analyse ETT and CCTA findings to understand their modern roles in intermediate risk chest pain population with inconclusive ETT. METHODS: Patients who underwent both ETT and CCTA at our institution between August 2011 and February 2013 were retrospectively investigated. The ETTs were blindly reviewed, with equivocal ETTs defined as any indeterminate results not strictly adhering to ACC/AHA guidelines for positive ETT. Baseline demographics, clinical characteristics and investigation results were collated. Follow-up outcome data for subsequent investigations, representations, major cardiac adverse events (MACE) and unexpected revascularisations were also analysed. RESULTS: 346 consecutive patients were identified (age 57±10years, 53% females, body mass index (BMI) 28±4, Dukes Clinical Score 48±30%, mean follow-up 2.1±0.4years). The ETT was positive in 31%, equivocal in 54% and negative in 15%. Obstructive coronary artery disease (CAD) prevalence was 25% (29% males, 13% females). Those with negative ETTs had obstructive CAD in 8%, with no adverse outcomes during follow-up. Obstructive CAD was seen in 20% with "equivocal" ETTs and 29% with "positive" ETTs. In females, obstructive CAD prevalence was low, and similar in those with equivocal or positive ETT (16% and 11% respectively). In males, obstructive CAD was almost 50% in those with positive ETT (p=0.005). CONCLUSIONS: Obstructive CAD was found in one in five "equivocal" ETTs, hence, not all should be considered negative. Obstructive CAD was only found in one in three "positive" ETTs, hence not all should proceed to invasive angiography. CCTA may be an important gatekeeper test in those with low-intermediate pre-test probability of obstructive CAD.

Impact of Direct to Consumer Store-and-Forward Teledermatology on Access to Care, Satisfaction, Utilization, and Costs in a Commercial Health Plan Population.

PURPOSE: Store-and-forward teledermatology can improve access to dermatology by enabling asynchronous consults. This study assesses it on access, satisfaction, utilization, and costs in a commercial health plan setting. METHODOLOGY: In this prospective observational study with matched control, 47,411 individuals were provided access to teledermatology services staffed by board-certified, licensed dermatologists for 6 months. Two hundred forty-three individuals used the service. One hundred fifty-two participants successfully matched to similar users of in-person services for comparison. Average number of dermatology-related visits and dermatology-related costs in 30, 60, and 90 days postvisit, most frequent diagnoses, time to consult, patient satisfaction, and number of procedures were measured. RESULTS: Average time to consult for the teledermatology group was 16.31 h. Patient satisfaction was 4.38/5. Total dermatology utilization in the postvisit period for the teledermatology and the control groups respectively was 9 and 21 visits at 30 days (p = 0.074), 15 and 46 visits at 60 days (p = 0.005), and 26 and 74 at 90 days (p = 0.001). The dermatology-related spend for the teledermatology and control groups, respectively, was $59 and $113 on the day of the initial consult (p < 0.01), $70 and $202 for 30 days (p = 0.03), $78 and $ 221 for 60 days (p = 0.02), and $86 and $307 for 90 days (p = 0.08) following initial visit. Total number of procedures conducted in the control group at the index visit was 26. In the postvisit period, the total number of procedures in the study and control groups, respectively, were 5 and 15 at 30 days (p = 0.053), 10 and 26 at 60 days (p = 0.088), and 14 and 32 at 90 days (p = 0.082). CONCLUSIONS: Teledermatology services are accessible within hours and associated with high patient satisfaction. There is no evident increased utilization or costs postvisit.

Assessing the Impact of Medication Adherence on Long-Term Cardiovascular Outcomes.

BACKGROUND: Although guideline-recommended therapies reduce major adverse cardiovascular events (MACE) in patients after myocardial infarction (MI) or those with atherosclerotic disease (ATH), adherence is poor. OBJECTIVES: The goal of this study was to determine the association between medication adherence levels and long-term MACE in these patients. METHODS: We queried the claims database of a large health insurer for patients hospitalized for MI or with ATH. The primary outcome measure was a composite of all-cause death, MI, stroke, or coronary revascularization. Using proportion of days covered for statins and angiotensin-converting enzyme inhibitors, patients were stratified as fully adherent (≥80%), partially adherent (≥40% to ≤79%), or nonadherent (<40%). Per-patient annual direct medical (ADM) costs were estimated by using unit costs from 2 national files. RESULTS: Data were analyzed for 4,015 post-MI patients and 12,976 patients with ATH. In the post-MI cohort, the fully adherent group had a significantly lower rate of MACE than the nonadherent (18.9% vs. 26.3%; hazard ratio [HR]: 0.73; p = 0.0004) and partially adherent (18.9% vs. 24.7%; HR: 0.81; p = 0.02) groups at 2 years. The fully adherent group had reduced per-patient ADM costs for MI hospitalizations of $369 and $440 compared with the partially adherent and nonadherent groups, respectively. In the ATH cohort, the fully adherent group had a significantly lower rate of MACE than the nonadherent (8.42% vs. 17.17%; HR: 0.56; p < 0.0001) and the partially adherent (8.42% vs. 12.18%; HR: 0.76; p < 0.0001) groups at 2 years. The fully adherent group had reduced per-patient ADM costs for MI hospitalizations of $371 and $907 compared with the partially adherent and nonadherent groups. CONCLUSIONS: Full adherence to guideline-recommended therapies was associated with a lower rate of MACE and cost savings, with a threshold effect at >80% adherence in the post-MI population; at least a 40% level of long-term adherence needs to be maintained to continue to accrue benefit. Novel approaches to improve adherence may significantly reduce cardiovascular events.

Semantic interoperability of Health Risk Assessments.

The health insurance and benefits industry has administered Health Risk Assessments (HRAs) at an increasing rate. These are used to collect data on modifiable health risk factors for wellness and disease management programs. However, there is significant variability in the semantics of these assessments, making it difficult to compare data sets from the output of 2 different HRAs. There is also an increasing need to exchange this data with Health Information Exchanges and Electronic Medical Records. To standardize the data and concepts from these tools, we outline a process to determine presence of certain common elements of modifiable health risk extracted from these surveys. This information is coded using concept identifiers, which allows cross-survey comparison and analysis. We propose that using LOINC codes or other universal coding schema may allow semantic interoperability of a variety of HRA tools across the industry, research, and clinical settings.

Clinical validity of alerts generated by the CareEngine Claims-Driven Decision Support Engine.

Clinical decision support based on administrative data is an important "real-world" challenge. At an academic medical center, we reviewed medical charts to assess the accuracy of 182 clinical alerts generated from administrative claims, pharmacy data, and lab results by a computerized clinical decision support (CDS) system. Overall accuracy was 82%. The primary factor affecting alert accuracy was availability of complete data. Claims-driven CDS may be sufficiently accurate to be a valuable adjunct to quality improvement.

Brief report: Multiprogram evaluation of reading habits of primary care internal medicine residents on ambulatory rotations.

OBJECTIVE: To assess the reading habits and educational resources of primary care internal medicine residents for their ambulatory medicine education. DESIGN: Cross-sectional, multiprogram survey of primary care internal medicine residents. PARTICIPANTS/SETTING: Second- and third-year residents on ambulatory care rotations at 9 primary care medicine programs (124 eligible residents; 71% response rate). MEASUREMENTS AND MAIN RESULTS: Participants were asked open-ended and 5-point Likert-scaled questions about reading habits: time spent reading, preferred resources, and motivating and inhibiting factors. Participants reported reading medical topics for a mean of 4.3+/-3.0 SD hours weekly. Online-only sources were the most frequently utilized medical resource (mean Likert response 4.16+/-0.87). Respondents most commonly cited specific patients' cases (4.38+/-0.65) and preparation for talks (4.08+/-0.89) as motivating factors, and family responsibilities (3.99+/-0.65) and lack of motivation (3.93+/-0.81) as inhibiting factors. CONCLUSIONS: To stimulate residents' reading, residency programs should encourage patient- and case-based learning; require teaching assignments; and provide easy access to online curricula.

Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.

Human embryonic stem (hES) cells hold promise for generating an unlimited supply of cells for replacement therapies. To characterize hES cells at the molecular level, we obtained 148,453 expressed sequence tags (ESTs) from undifferentiated hES cells and three differentiated derivative subpopulations. Over 32,000 different transcripts expressed in hES cells were identified, of which more than 16,000 do not match closely any gene in the UniGene public database. Queries to this EST database revealed 532 significantly upregulated and 140 significantly downregulated genes in undifferentiated hES cells. These data highlight changes in the transcriptional network that occur when hES cells differentiate. Among the differentially regulated genes are several components of signaling pathways and transcriptional regulators that likely play key roles in hES cell growth and differentiation. The genomic data presented here may facilitate the derivation of clinically useful cell types from hES cells.