Understanding the Technical Implementation of a Clinical Decision Support SmartApp: A Qualitative Analysis.

CONCERN is a SmartApp that identifies patients at risk for deterioration. This study aimed to understand the technical components and processes that should be included in our Implementation Toolkit. In focus groups with technical experts five themes emerged: 1) implementation challenges, 2) implementation facilitators, 3) project management, 4) stakeholder engagement, and 5) security assessments. Our results may aid other teams in implementing healthcare SmartApps.

Identifying Barriers to The Implementation of Communicating Narrative Concerns Entered by Registered Nurses, An Early Warning System SmartApp.

BACKGROUND: Nurses are at the frontline of detecting patient deterioration. We developed Communicating Narrative Concerns Entered by Registered Nurses (CONCERN), an early warning system for clinical deterioration that generates a risk prediction score utilizing nursing data. CONCERN was implemented as a randomized clinical trial at two health systems in the Northeastern United States. Following the implementation of CONCERN, our team sought to develop the CONCERN Implementation Toolkit to enable other hospital systems to adopt CONCERN. OBJECTIVE: The aim of this study was to identify the optimal resources needed to implement CONCERN and package these resources into the CONCERN Implementation Toolkit to enable the spread of CONCERN to other hospital sites. METHODS: To accomplish this aim, we conducted qualitative interviews with nurses, prescribing providers, and information technology experts in two health systems. We recruited participants from July 2022 to January 2023. We conducted thematic analysis guided by the Donabedian model. Based on the results of the thematic analysis, we updated the α version of the CONCERN Implementation Toolkit. RESULTS: There was a total of 32 participants included in our study. In total, 12 themes were identified, with four themes mapping to each domain in Donabedian's model (i.e., structure, process, and outcome). Eight new resources were added to the CONCERN Implementation Toolkit. CONCLUSIONS: This study validated the α version of the CONCERN Implementation Toolkit. Future studies will focus on returning the results of the Toolkit to the hospital sites to validate the ß version of the CONCERN Implementation Toolkit. As the development of early warning systems continues to increase and clinician workflows evolve, the results of this study will provide considerations for research teams interested in implementing early warning systems in the acute care setting.

Multisite Pragmatic Cluster-Randomized Controlled Trial of the CONCERN Early Warning System.

Importance: Late predictions of hospitalized patient deterioration, resulting from early warning systems (EWS) with limited data sources and/or a care team's lack of shared situational awareness, contribute to delays in clinical interventions. The COmmunicating Narrative Concerns Entered by RNs (CONCERN) Early Warning System (EWS) uses real-time nursing surveillance documentation patterns in its machine learning algorithm to identify patients' deterioration risk up to 42 hours earlier than other EWSs. Objective: To test our a priori hypothesis that patients with care teams informed by the CONCERN EWS intervention have a lower mortality rate and shorter length of stay (LOS) than the patients with teams not informed by CONCERN EWS. Design: One-year multisite, pragmatic controlled clinical trial with cluster-randomization of acute and intensive care units to intervention or usual-care groups. Setting: Two large U.S. health systems. Participants: Adult patients admitted to acute and intensive care units, excluding those on hospice/palliative/comfort care, or with Do Not Resuscitate/Do Not Intubate orders. Intervention: The CONCERN EWS intervention calculates patient deterioration risk based on nurses' concern levels measured by surveillance documentation patterns, and it displays the categorical risk score (low, increased, high) in the electronic health record (EHR) for care team members. Main Outcomes and Measures: Primary outcomes: in-hospital mortality, LOS; survival analysis was used. Secondary outcomes: cardiopulmonary arrest, sepsis, unanticipated ICU transfers, 30-day hospital readmission. Results: A total of 60 893 hospital encounters (33 024 intervention and 27 869 usual-care) were included. Both groups had similar patient age, race, ethnicity, and illness severity distributions. Patients in the intervention group had a 35.6% decreased risk of death (adjusted hazard ratio [HR], 0.644; 95% confidence interval [CI], 0.532-0.778; P<.0001), 11.2% decreased LOS (adjusted incidence rate ratio, 0.914; 95% CI, 0.902-0.926; P<.0001), 7.5% decreased risk of sepsis (adjusted HR, 0.925; 95% CI, 0.861-0.993; P=.0317), and 24.9% increased risk of unanticipated ICU transfer (adjusted HR, 1.249; 95% CI, 1.093-1.426; P=.0011) compared with patients in the usual-care group. Conclusions and Relevance: A hospital-wide EWS based on nursing surveillance patterns decreased in-hospital mortality, sepsis, and LOS when integrated into the care team's EHR workflow. Trial Registration: ClinicalTrials.gov Identifier: NCT03911687.

Tweak induces mammary epithelial branching morphogenesis.

Members of the tumor necrosis factor (TNF) superfamily regulate cell survival and proliferation and have been implicated in cancer. Tweak (TNF-related weak inducer of apoptosis) has pleiotropic biological functions including proapoptotic, proangiogenic and proinflammatory activities. We explored a role for Tweak in mammary gland transformation using a three-dimensional model culture system. Tweak stimulates a branching morphogenic phenotype, similar to that induced by pro-oncogenic factors, in Eph4 mammary epithelial cells cultured in matrigel. Increased proliferation and invasiveness are observed, with a concomitant inhibition of functional differentiation. Levels of matrix metalloproteinase-9 (MMP-9) are significantly increased following Tweak treatment. Notably, MMP inhibitors are sufficient to block the branching phenotype induced by Tweak. The capacity to promote proliferation, inhibit differentiation and induce invasion suggests a role for Tweak in mammary gland tumorigenesis. Consistent with this, we have observed elevated protein levels of the Tweak receptor, Fn14, in human breast tumor cell lines and xenograft models as well as in primary human breast tumors. Together, our results suggest that the Tweak/Fn14 pathway may be protumorigenic in human breast cancer.

Rapid aptasensor capable of simply diagnosing prostate cancer.

Using guanine (G)-rich DNA aptamer-conjugated 6-carboxyfluorescein (6-FAM) capable of rapidly capturing prostate specific antigen (PSA) in human serum, cost-effective and simple biosensor with guanine chemiluminescence detection was developed for early diagnosis of prostate cancer. Free G-rich DNA aptamer-conjugated 6-FAM emits bright light in guanine chemiluminescence reaction based on the principle of chemiluminescent resonance energy transfer (CRET). However, G-rich DNA aptamer-conjugated 6-FAM bound with PSA cannot emit light because PSA acts as a strong interference in CRET between 6-FAM and high-energy intermediate formed from the reaction of 3,4,5-trimethoxylphenylglyoxal (TMPG) and guanine of G-rich DNA aptamer. A chemiluminescent biosensor, developed using the different properties of G-rich DNA aptamer-conjugated 6-FAM in the absence and presence of PSA in guanine chemiluminescence reaction, was able to quantify trace levels of PSA in human serum within 30 min without time-consuming and complicated procedures (e.g., multiple incubation and washings) required for conventional immunoassays operated with expensive and intractable antibodies. The limit of detection of chemiluminescent biosensor having a wide linear dynamic range (1.9-125 ng/ml) was 1.0 ng/ml. The excellent correlation (R=0.985) between chemiluminescent biosensor and conventional enzyme immunoassay indicates that the accurate, precise, and rapid chemiluminescent biosensor can be applied as a new method for early diagnosis of prostate cancer.

Rapid and simple G-quadruplex DNA aptasensor with guanine chemiluminescence detection.

Cost-effective and sensitive aptasensor with guanine chemiluminescence detection capable of simply quantifying thrombin in human serum was developed using thrombin aptamer (TBA), one of the G-quadruplex DNA aptamers, without expensive nanoparticles and complicated procedures. Guanines of G-quadruplex TBA-conjugated carboxyfluorescein (6-FAM) bound with thrombin do not react with 3,4,5-trimethoxylphenylglyoxal (TMPG) in the presence of tetra-n-propylammonium hydroxide (TPA), whereas guanines of free TBA- and TBA-conjugated 6-FAM immobilized on the surface of graphene oxide rapidly react with TMPG to emit light. Thus, guanine chemiluminescence in 5% human serum with thrombin was lower than that without thrombin when TBA-conjugated 6-FAM was added in two samples and incubated for 20 min. In other words, the brightness of guanine chemiluminescence was quenched due to the formation of G-quadruplex TBA-conjugated 6-FAM bound with thrombin in a sample. High-energy intermediate, capable of emitting dim light by itself, formed from the reaction between guanines of TBA and TMPG in the presence of TPA, transfers energy to 6-FAM to emit bright light based on the principle of chemiluminescence energy transfer (CRET). G-quadruplex TBA aptasensor devised using the rapid interaction between TBA-conjugated 6-FAM and thrombin quantified trace levels of thrombin without complicated procedures. The limit of detection (LOD = background + 3 × standard deviation) of G-quadruplex TBA aptasensor with good linear calibration curve, accuracy, precision, and recovery was as low as 12.3 nM in 5% human serum. Using the technology reported in this research, we expect that various types of G-quadruplex DNA aptasensors capable of specifically sensing a target molecule such as ATP, HIV, ochratoxin, potassium ions, and thrombin can be developed.

Prevalence of clinical and subclinical thyroid disease in a peritoneal dialysis population.

AIMS: We investigated dialysis duration, dose of erythropoietin (EPO), and clinical manifestations in peritoneal dialysis (PD) patients with subclinical hypothyroidism. METHODS: This cross-sectional study, performed in 3 centers, assessed 122 adult patients on PD for more than 6 months with regard to demographic data, dialysis duration, thyroid function, biochemical data, EPO dose, and clinical manifestations. Thyroid dysfunction was determined by serum thyroid-stimulating hormone, free thyroxine, total thyroxine, total triiodothyronine, antithyroid peroxidase antibodies, and auto-antibodies against thyroglobulin. RESULTS: Of the 122 study patients, 98 (80.3%) were assessed as having euthyroidism; 19 (15.6%), subclinical hypothyroidism; and 5 (4.1%), subclinical hyperthyroidism. The proportion of women (74.2% vs. 57.1%, p = 0.038), the mean duration of PD (58.1 months vs. 37.9 months, p = 0.032), and the weighted mean monthly EPO dose (1.22 µg/kg vs. 1.64 µg/kg, p = 0.009) were significantly higher in the subclinical hypothyroidism group than in the euthyroidism group, but the prevalences of coronary artery disease and cerebrovascular disease were not. From the multivariate model, PD duration was more significant than sex as a risk factor for subclinical hypothyroidism (p = 0.0132). CONCLUSIONS: Subclinical hypothyroidism is frequent in PD patients, especially female patients and patients with a longer PD duration. Compared with euthyroid patients, patients with subclinical hyperthyroidism need a higher dose of EPO to maintain a stable hemoglobin level.

Agreement between long-term neonatal background classification by conventional and amplitude-integrated EEG.

Conventional EEG (CEEG) in neonates is considered the gold standard for evaluating EEG background and detecting electrographic seizures. However, CEEG is expensive and cumbersome for long-term monitoring. A simplified method, amplitude-integrated EEG (AEEG) has been rapidly adopted to accomplish the same goals. The purpose of this study was to measure the agreement between the methods of classification in long-term EEG background assessments by CEEG and AEEG. Infants underwent CEEG monitoring after cardiac surgery and the background during four 12-hour epochs classified as "normal" or "mildly," "moderately," or "markedly" abnormal. CEEGs were converted to a single-channel AEEG and independently interpreted as "normal," "moderately abnormal," or "markedly abnormal" by standard amplitude criteria. The distributions of CEEG and AEEG interpretations were statistically compared, and the associations between CEEG and AEEG interpretations were measured. Generalized estimating equations were used to measure the effects of seizures and patient age on the agreement between AEEG and CEEG scores. Paired CEEGs and AEEGs were available for 637 epochs recorded from 179 infants. The distribution of CEEG backgrounds included 60% normal, 22% mildly abnormal, 13% moderately abnormal, and 5% markedly abnormal. The distribution of AEEG backgrounds was significantly different from CEEG and included 22% normal, 73% moderately abnormal, and 5% markedly abnormal. Nevertheless, the two techniques exhibited a significant, moderate positive association. Generalized estimating equations focusing on those with moderately abnormal AEEGs showed that younger patients with seizures were significantly more likely to have moderately or markedly abnormal CEEGs than older patients without seizures. Although there was overall significant moderate agreement between the two techniques, the distribution of backgrounds assigned by AEEG was significantly different from CEEG. Most moderately abnormal AEEGs were associated with normal or mildly abnormal CEEGs. However, the ability of moderately abnormal AEEGs to correctly predict moderately or markedly abnormal CEEG was significantly associated with the knowledge of the patient's age and the presence of seizures on CEEG.

Development of an Fn14 agonistic antibody as an anti-tumor agent.

TWEAK, a TNF family ligand with pleiotropic cellular functions, was originally described as capable of inducing tumor cell death in vitro. TWEAK functions by binding its receptor, Fn14, which is up-regulated on many human solid tumors. Herein, we show that intratumoral administration of TWEAK, delivered either by an adenoviral vector or in an immunoglobulin Fc-fusion form, results in significant inhibition of tumor growth in a breast xenograft model. To exploit the TWEAK-Fn14 pathway as a therapeutic target in oncology, we developed an anti-Fn14 agonistic antibody, BIIB036. Studies described herein show that BIIB036 binds specifically to Fn14 but not other members of the TNF receptor family, induces Fn14 signaling, and promotes tumor cell apoptosis in vitro. In vivo, BIIB036 effectively inhibits growth of tumors in multiple xenograft models, including colon (WiDr), breast (MDA-MB-231), and gastric (NCI-N87) tumors, regardless of tumor cell growth inhibition response observed to BIIB036 in vitro. The anti-tumor activity in these cell lines is not TNF-dependent. Increasing the antigen-binding valency of BIB036 significantly enhances its anti-tumor effect, suggesting the contribution of higher order cross-linking of the Fn14 receptor. Full Fc effector function is required for maximal activity of BIIB036 in vivo, likely due to the cross-linking effect and/or ADCC mediated tumor killing activity. Taken together, the anti-tumor properties of BIIB036 validate Fn14 as a promising target in oncology and demonstrate its potential therapeutic utility in multiple solid tumor indications.

Benefit of fluoroscopically guided intraarticular, long-acting corticosteroid injection for subtalar arthritis in juvenile idiopathic arthritis.

BACKGROUND: Children with arthritis may endure a lifetime of disfigurement, dysfunction, and pain if acute inflammation progresses to chronic changes in the joint cartilage and underlying bone. Intraarticular steroids have become an integral component of treatment, but at times are difficult to deliver to joints, such as the subtalar joint, that have complex anatomies. OBJECTIVE: We describe our technique and outcomes using fluoroscopically guided intraarticular subtalar steroid injection in patients with active symptoms of juvenile idiopathic arthritis (JIA). MATERIALS AND METHODS: Fluoroscopically guided subtalar joint injections were performed in 38 children (mean age 6.7 years). Medical records were reviewed retrospectively and improvement was evaluated clinically by the degree of foot movement in eversion and inversion. RESULTS: Subtalar joint injection was technically successful in 100% of the JIA patients with improvement in physical symptoms in 34/38 (89%). Of the 38 children, 32 were followed up within 13 weeks of the initial injection and, therefore, satisfied the eligibility criteria for resolution of arthritis. Of these 32 children, 14 showed clinical resolution (44%). The mean duration of improvement was 1.2 +/- 0.9 years. Children with a longer interval (>1 year) from diagnosis to treatment had significantly less resolution (P = 0.04). Local subcutaneous atrophy or hypopigmentation were observed in 53% of the children after steroid injection (20/38). These minor complications were associated with a greater volume of steroid injected into the site per child (P = 0.02). CONCLUSION: Fluoroscopically guided subtalar joint injection is an effective treatment for subtalar arthropathy. Prompt referral for intraarticular steroid treatment in the acute phase improves response. Skin changes often occur at the injection site, and specific precautions should be employed to reduce this risk. Prospective study is indicated to determine the most effective treatment strategy to prevent long-term pain and disability.