UCLA Health

Jew B., Alvarez M., Rahmani E., Miao Z., Ko A., Garske K.M., Sul J.H., Pietiläinen K.H., Pajukanta P., Halperin E.

We present Bisque, a tool for estimating cell type proportions in bulk expression. Bisque implements a regression-based approach that utilizes single-cell RNA-seq (scRNA-seq) or single-nucleus RNA-seq (snRNA-seq) data to generate a reference expression profile and learn gene-specific bulk expression transformations to robustly decompose RNA-seq data. These transformations significantly improve decomposition performance compared to existing methods when there is significant technical variation in the generation of the reference profile and observed bulk expression. Importantly, compared to existing methods, our approach is extremely efficient, making it suitable for the analysis of large genomic datasets that are becoming ubiquitous. When applied to subcutaneous adipose and dorsolateral prefrontal cortex expression datasets with both bulk RNA-seq and snRNA-seq data, Bisque replicates previously reported associations between cell type proportions and measured phenotypes across abundant and rare cell types. We further propose an additional mode of operation that merely requires a set of known marker genes. Traditional methods for determining cell type composition lack scalability, while single-cell technologies remain costly and noisy compared to bulk RNA-seq. Here, the authors present a highly efficient tool to measure cellular heterogeneity in bulk expression through robust integration of single-cell information.

Dai H., Saccardo S., Han M.A., Roh L., Raja N., Vangala S., Modi H., Pandya S., Sloyan M., Croymans D.M.

Enhancing vaccine uptake is a critical public health challenge1. Overcoming vaccine hesitancy2,3 and failure to follow through on vaccination intentions3 requires effective communication strategies3,4. Here we present two sequential randomized controlled trials to test the effect of behavioural interventions on the uptake of COVID-19 vaccines. We designed text-based reminders that make vaccination salient and easy, and delivered them to participants drawn from a healthcare system one day (first randomized controlled trial) (n = 93,354 participants; clinicaltrials number NCT04800965) and eight days (second randomized controlled trial) (n = 67,092 individuals; clinicaltrials number NCT04801524) after they received a notification of vaccine eligibility. The first reminder boosted appointment and vaccination rates within the healthcare system by 6.07 (84%) and 3.57 (26%) percentage points, respectively; the second reminder increased those outcomes by 1.65 and 1.06 percentage points, respectively. The first reminder had a greater effect when it was designed to make participants feel ownership of the vaccine dose. However, we found no evidence that combining the first reminder with a video-based information intervention designed to address vaccine hesitancy heightened its effect. We performed online studies (n = 3,181 participants) to examine vaccination intentions, which revealed patterns that diverged from those of the first randomized controlled trial; this underscores the importance of pilot-testing interventions in the field. Our findings inform the design of behavioural nudges for promoting health decisions5, and highlight the value of making vaccination easy and inducing feelings of ownership over vaccines. Two randomized controlled trials demonstrate the ability of text-based behavioural ‘nudges’ to improve the uptake of COVID-19 vaccines, especially when designed to make participants feel ownership over their vaccine dose.

Chawla S., Blay J., Rutkowski P., Le Cesne A., Reichardt P., Gelderblom H., Grimer R.J., Choy E., Skubitz K., Seeger L., Schuetze S.M., Henshaw R., Dai T., Jandial D., Palmerini E.

Giant-cell tumour of bone (GCTB) is a rare, locally aggressive osteoclastogenic stromal tumour of the bone. This phase 2 study aimed to assess the safety and activity of denosumab in patients with surgically salvageable or unsalvageable GCTB.In this multicentre, open-label, phase 2 study done at 30 sites in 12 countries we enrolled adults and skeletally mature adolescents (aged ≥12 years) weighing at least 45 kg with histologically confirmed and radiographically measurable GCTB, Karnofsky performance status 50% or higher (Eastern Cooperative Oncology Group status 0, 1, or 2), and measurable active disease within 1 year of study enrolment. Patients had surgically unsalvageable GCTB (cohort 1), had surgically salvageable GCTB with planned surgery expected to result in severe morbidity (cohort 2), or were enrolled from a previous study of denosumab for GCTB (cohort 3). Patients received 120 mg subcutaneous denosumab once every 4 weeks during the treatment phase, with loading doses (120 mg subcutaneously) administered on study days 8 and 15 to patients in cohorts 1 and 2 (patients in cohort 3 did not receive loading doses). The primary endpoint was safety in terms of the type, frequency, and severity of adverse events; secondary endpoints included time to disease progression from cohort 1 and the proportion of patients without surgery at month 6 for cohort 2. The safety analysis set included all enrolled patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, number NCT00680992, and has been completed.Between Sept 9, 2008, and Feb 25, 2016, 532 patients were enrolled: 267 in cohort 1, 253 in cohort 2, and 12 in cohort 3. At data cutoff on Feb 24, 2017, median follow-up was 58·1 months (IQR 34·0-74·4) in the overall patient population, and 65·8 months (40·9-82·4) in cohort 1, 53·4 months (28·2-64·1) in cohort 2, and 76·4 months (61·2-76·5) in cohort 3. During the treatment phase, the most common grade 3 or worse adverse events were hypophosphataemia (24 [5%] of 526 patients), osteonecrosis of the jaw (17 [3%], pain in extremity (12 [2%]), and anaemia (11 [2%]). Serious adverse events were reported in 138 (26%) of 526 patients; the most common were osteonecrosis of the jaw (17 [3%]), anaemia (6 [1%]), bone giant cell tumour (6 [1%]), and back pain (5 [1%]). 28 (5%) patients had positively adjudicated osteonecrosis of the jaw, four (1%) had atypical femur fracture, and four (1%) had hypercalcaemia occurring 30 days after denosumab discontinuation. There were four cases (1%) of sarcomatous transformation, consistent with historical data. Ten (2%) treatment-emergent deaths occurred (two of which were considered treatment-related; bone sarcoma in cohort 2 and sarcoma in cohort 1). Median time to progression or recurrence for patients in cohort 1 during the first treatment phase was not reached (28 [11%] of 262 patients had progression or recurrence). 227 (92%; 95% CI 87-95) of 248 patients who received at least one dose of denosumab in cohort 2 had no surgery in the first 6 months of the study.The types and frequencies of adverse events were consistent with the known safety profile of denosumab, which showed long-term disease control for patients with GCTB with unresectable and resectable tumours. Our results suggest that the overall risk to benefit ratio for denosumab treatment in patients with GCTB remains favourable.Amgen.

Murphy C.N., Fowler R., Balada-Llasat J.M., Carroll A., Stone H., Akerele O., Buchan B., Windham S., Hopp A., Ronen S., Relich R.F., Buckner R., Warren D.A., Humphries R., Campeau S., et. al.

The ability to provide timely identification of the causative agents of lower respiratory tract infections can promote better patient outcomes and support antimicrobial stewardship efforts. Current diagnostic testing options include culture, molecular testing, and antigen detection. These methods may require collection of various specimens, involve extensive sample treatment, and can suffer from low sensitivity and long turnaround times. This study assessed the performance of the BioFire FilmArray Pneumonia Panel (PN panel) and Pneumonia Plus Panel (PNplus panel), an FDA-cleared sample-to-answer assay that enables the detection of viruses, atypical bacteria, bacteria, and antimicrobial resistance marker genes from lower respiratory tract specimens (sputum and bronchoalveolar lavage [BAL] fluid).

Shah M.A., Kennedy E.B., Alarcon-Rozas A.E., Alcindor T., Bartley A.N., Malowany A.B., Bhadkamkar N.A., Deighton D.C., Janjigian Y., Karippot A., Khan U., King D.A., Klute K., Lacy J., Lee J.J., et. al.

PURPOSE To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS For human epidermal growth factor receptor 2 (HER2)–negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Day L.W., Muthusamy V.R., Collins J., Kushnir V.M., Sawhney M.S., Thosani N.C., Wani S.

Gastrointestinal (GI) endoscopy is highly effective for the prevention, diagnosis, and treatment of many digestive diseases.1 Endoscopes used in endoscopy are complex, diverse, and essential devices that require meticulous cleaning and reprocessing in strict accordance with manufacturer guidelines before being reused on patients. Multiple risks are associated with endoscopic procedures; one such risk includes patients developing an exogenous infection (ie, pathogen introduced through a contaminated device).

Kamdar N.V., Huverserian A., Jalilian L., Thi W., Duval V., Beck L., Brooker L., Grogan T., Lin A., Cannesson M.

With health care practice consolidation, the increasing geographic scope of health care systems, and the advancement of mobile telecommunications, there is increasing interest in telemedicine-based health care consultations. Anesthesiology has had experience with telemedicine consultation for preoperative evaluation since 2004, but the majority of studies have been conducted in rural settings. There is a paucity of literature of use in metropolitan areas. In this article, we describe the implementation of a telemedicine-based anesthesia preoperative evaluation and report the program's patient satisfaction, clinical case cancellation rate outcomes, and cost savings in a large metropolitan area (Los Angeles, CA).This is a descriptive study of a telemedicine-based preoperative anesthesia evaluation process in an academic medical center within a large metropolitan area. In a 2-year period, we evaluated 419 patients scheduled for surgery by telemedicine and 1785 patients who were evaluated in-person.Day-of-surgery case cancellations were 2.95% and 3.23% in the telemedicine and the in-person cohort, respectively. Telemedicine patients avoided a median round trip driving distance of 63 miles (Q1 24; Q3 119) and a median time saved of 137 (Q1 95; Q3 195) and 130 (Q1 91; Q3 237) minutes during morning and afternoon traffic conditions, respectively. Patients experienced time-based savings, particularly from traveling across a metropolitan area, which amounted to $67 of direct and opportunity cost savings. From patient satisfaction surveys, 98% (129 patients out of 131 completed surveys) of patients who were consulted via telemedicine were satisfied with their experience.This study demonstrates the implementation of a telemedicine-based preoperative anesthesia evaluation from an academic medical center in a metropolitan area with high patient satisfaction, cost savings, and without increase in day-of-procedure case cancellations.

Toh H., Mori S., Izawa Y., Fujita H., Miwa K., Suzuki M., Takahashi Y., Toba T., Watanabe Y., Kono A.K., Tretter J.T., Hirata K.

Abstract Aims Mitral annular disjunction is fibrous separation between the attachment of the posterior mitral leaflet and the basal left ventricular myocardium initially described in dissected hearts. Currently, it is commonly evaluated by echocardiography, and potential relationships with mitral valve prolapse and ventricular arrhythmia have been suggested. However, controversy remains as its prevalence and extent have not been fully elucidated in normal living subjects. Methods and results Systolic datasets of cardiac computed tomography obtained from 98 patients (mean age, 69.1 ± 12.6 years; 81% men) with structurally normal hearts were assessed retrospectively. Circumferential extent of both mitral leaflets and disjunction was determined by rotating orthogonal multiplanar reconstruction images around the central axis of the mitral valvar orifice. Distribution angle within the circumference of the mitral valvar attachment and maximal height of disjunction were quantified. In total, 96.0% of patients demonstrated disjunction. Average distribution angles of the anterior and posterior mitral leaflets were 91.3 ± 9.4° and 269.8 ± 9.7°, respectively. Average distribution angle of the disjunction was 105.1 ± 49.2°, corresponding to 39.0 ± 18.2% of the entire posterior mitral valvar attachment. Median value of the maximal height of disjunction was 3.0 (1.5–7.0) mm. Distribution prevalence map of the disjunction revealed characteristic double peaks, with frequent sites of the disjunction located at the anterior to antero-lateral and inferior to infero-septal regions. Conclusion Mitral annular disjunction is a rather common finding in the normal adult heart with bimodal distribution predominantly observed involving the P1 and P3 scallops of the posterior mitral leaflet.

Nielsen J.C., Lin Y., de Oliveira Figueiredo M.J., Sepehri Shamloo A., Alfie A., Boveda S., Dagres N., Di Toro D., Eckhardt L.L., Ellenbogen K., Hardy C., Ikeda T., Jaswal A., Kaufman E., Krahn A., et. al.

Alvarez M., Rahmani E., Jew B., Garske K.M., Miao Z., Benhammou J.N., Ye C.J., Pisegna J.R., Pietiläinen K.H., Halperin E., Pajukanta P.

Single-nucleus RNA sequencing (snRNA-seq) measures gene expression in individual nuclei instead of cells, allowing for unbiased cell type characterization in solid tissues. We observe that snRNA-seq is commonly subject to contamination by high amounts of ambient RNA, which can lead to biased downstream analyses, such as identification of spurious cell types if overlooked. We present a novel approach to quantify contamination and filter droplets in snRNA-seq experiments, called Debris Identification using Expectation Maximization (DIEM). Our likelihood-based approach models the gene expression distribution of debris and cell types, which are estimated using EM. We evaluated DIEM using three snRNA-seq data sets: (1) human differentiating preadipocytes in vitro, (2) fresh mouse brain tissue, and (3) human frozen adipose tissue (AT) from six individuals. All three data sets showed evidence of extranuclear RNA contamination, and we observed that existing methods fail to account for contaminated droplets and led to spurious cell types. When compared to filtering using these state of the art methods, DIEM better removed droplets containing high levels of extranuclear RNA and led to higher quality clusters. Although DIEM was designed for snRNA-seq, our clustering strategy also successfully filtered single-cell RNA-seq data. To conclude, our novel method DIEM removes debris-contaminated droplets from single-cell-based data fast and effectively, leading to cleaner downstream analysis. Our code is freely available for use at https://github.com/marcalva/diem.