Decoding disease: Scott Patterson's perspectives on the power of biomarkers in drug development.

Scott Patterson (Gilead Sciences Inc., CA, USA) speaks to Ashling Cannon, Journal Development Editor at BioTechniques, about his career. Patterson is a biochemist and proteomics and biomarker/translational expert with over 30 years of industry experience following 13 years in an academic setting. Patterson earned his BSc and PhD in Physiology and Pharmacology from the University of Queensland (Australia) while working full time in the Department of Physiology and Pharmacology, rising to a Senior Research Officer. Throughout his career, Patterson has been actively involved in advancing technologies, how they can be applied to address biological questions and the interplay of bioinformatics and large datasets leveraging biomarkers and diagnostics. He has held pivotal roles at renowned institutions and companies such as Cold Spring Harbor Laboratory (NY, USA), Amgen, Inc. (CA, USA), Celera Genomics Group (MD, USA) and Gilead Sciences, Inc. Notably, he served as a Staff Investigator at Cold Spring Harbor Laboratory and was honored with the Long Island Biological Association New Investigator award in addition to being the 2002 Barnett Lecturer at Northeastern University (MA, USA). In early 2015 Patterson joined Gilead Sciences, Inc., bringing his extensive expertise to lead biomarker discovery and development as well as in vitro diagnostics initiatives across all therapeutic domains.

RNA-seq RNAaccess identified as the preferred method for gene expression analysis of low quality FFPE samples.

Clinical tumor tissues that are preserved as formalin-fixed paraffin-embedded (FFPE) samples result in extensive cross-linking, fragmentation, and chemical modification of RNA, posing significant challenges for RNA-seq-based gene expression profiling. This study sought to define an optimal RNA-seq protocol for FFPE samples. We employed a common RNA extraction method and then compared RNA-seq library preparation protocols including RNAaccess, RiboZero and PolyA in terms of sequencing quality and concordance of gene expression using FFPE and case-matched fresh-frozen (FF) triple-negative breast cancer (TNBC) tissues. We found that RNAaccess, a method based on exome capture, produced the most concordant results. Applying RNAaccess to FFPE gastric cancer tissues, we established a minimum RNA DV200 requirement of 10% and a RNA input amount of 10ng that generated highly reproducible gene expression data. Lastly, we demonstrated that RNAaccess and NanoString platforms produced highly concordant expression profiles from FFPE samples for shared genes; however, RNA-seq may be preferred for clinical biomarker discovery work because of the broader coverage of the transcriptome. Taken together, these results support the selection of RNA-seq RNAaccess method for gene expression profiling of FFPE samples. The minimum requirements for RNA quality and input established here may allow for inclusion of clinical FFPE samples of sub-optimal quality in gene expression analyses and ultimately increasing the statistical power of such analyses.

Findings from a Peer-Facilitated, Social Isolation Intervention in the Veterans Health Administration Healthcare System: A Mixed-Methods, Pilot Feasibility Study.

BACKGROUND: Social isolation is a global public health threat. Veterans are particularly at risk for social isolation due to high rates of comorbid physical and mental health problems. Yet, effective interventions are limited. OBJECTIVES: Our primary objective was to assess the feasibility and acceptability of CONNECTED, a novel, transdiagnostic intervention to reduce social isolation that includes individual and group components and is delivered by peers via telehealth. Secondary objectives were to identify appropriate outcome measures and explore preliminary intervention effects. METHODS: This was a two-phase study. In Phase 1, to evaluate study feasibility, we surveyed 200 veterans to assess prevalence of social isolation and their interest in social connectedness interventions. In Phase 2, we employed a mixed-methods, pre-post study design in which we piloted CONNECTED with 19 veterans through 2 successive cohorts to further assess feasibility, to evaluate acceptability, and to explore preliminary effectiveness. Quantitative analyses involved descriptive and bivariate analyses as well as multivariate modeling. Qualitative interviews were analyzed using thematic analysis. RESULTS: For Phase 1, 39% of veterans surveyed were socially isolated. Participants who were ≤ 55 years old, caregivers, and those who experienced unmet social needs were more likely to report social isolation. Over 61% expressed interest in VA programs to reduce social isolation. For Phase 2, the pilot intervention, recruitment rate was 88% and the enrollment rate was 86%. Retention rates for the two cohorts were 80% and 50%, respectively, and satisfaction rates among intervention completers were 100%. Results also showed statistically significant improvements in social isolation (+ 5.91, SD = 4.99; p = .0028), social support (+ 0.74, SD = 1.09; p = .03), anxiety (-3.92, SD = 3.73; p = .003), and depression (-3.83, SD = 3.13; p = .001). Results for the other measures were not statistically significant. CONCLUSION: CONNECTED is a feasible and acceptable intervention and is likely to be an effective tool to intervene on social isolation among veterans.

Care Retention Among Veterans with Serious Mental Illness who were once lost-to-Veterans Health Administration care.

OBJECTIVE: To evaluate care retention among Veterans with serious mental illness (SMI) who were lost to Veterans Health Administration (VHA) care for at least one year and subsequently returned to VHA care via the SMI Re-Engagement program, an outreach program for Veterans with SMI who are lost-to-care. METHODS: For the 410 Veterans with SMI who returned to care via SMI Re-Engagement between April 4th, 2016 and January 31, 2018, we assessed VHA in-person and telehealth utilization (overall, primary care, mental health care) for two years following the date of return to care. RESULTS: Care retention was common: 70.2% of Veterans had at least one encounter in each year of the two-year follow-up period and an additional 22.7% had at least one encounter during one of the two years. During the two-year follow-up period, 72.4% of Veterans had at least one primary care encounter and 70.7% of Veterans had at least one mental health care encounter. Adjusted binomial logistic regression analyses found a return-to-care encounter in primary care (OR = 2.70; 95% CI: 1.34, 5.42) predicted primary care retention, and a return-to-care encounter in mental health care (OR = 4.01; 95% CI: 2.38, 6.75) predicted mental health care retention. CONCLUSION: Most Veterans who return to care via the SMI Re-Engagement program remain in VHA care for the subsequent two years.

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer.

PURPOSE: Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. PATIENTS AND METHODS: KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. RESULTS: KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. CONCLUSION: Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

Outcomes of a peer-led navigation program, PARTNER-MH, for racially minoritized Veterans receiving mental health services: a pilot randomized controlled trial to assess feasibility and acceptability.

This pilot study explored the feasibility and acceptability of PARTNER-MH, which aimed to engage racially diverse Veterans in mental health services, facilitate their active participation in care, and improve their communication with providers. Fifty participants were randomized to the intervention or a waitlist control group. For primary outcomes, we assessed the feasibility of the study design and PARTNER-MH's feasibility and acceptability. For secondary outcomes, we explored preliminary effects on patient engagement, patient activation, shared decision-making, and health-related outcomes. The study had a recruitment rate of 68%, enrollment rate of 91%, and a follow-up retention rate of 72%. For intervention feasibility and acceptability, fidelity scores were satisfactory and improved over time, session attendance was modest with 33% of participants completing ≥6 sessions, and 89% of participants were satisfied with the intervention. For secondary outcomes, patients in the intervention arm showed significant improvement on self-reported mental health and depression, compared with those in the control group at both 6- and 9-month follow-ups. However, there were no significant differences between study arms on the other measures. Pilot results provide support for future testing of PARTNER-MH in a larger trial, although modifications are needed to increase session attendance and follow-up retention rate. CLINICAL TRIAL INFORMATION: The study was preregistered at Clinical Trials.gov. The study Trial registration number is ClinicalTrials.gov NCT04515771.

This study tested whether a peer-led navigation program, PARTNER-MH, can be delivered effectively by peer specialists in the Veterans Health Administration (VHA) healthcare system to racially minoritized Veterans who are receiving mental healthcare. The study evaluated our ability to recruit and retain participants, deliver the intervention, and examined satisfaction with the program. We also explored preliminary effects of the program. Participants were successfully recruited for the study and peers were able to deliver the program effectively. Participants reported high satisfaction with the program and significant improvements in mental health outcomes, although completion rate of the program was low. Results provide support for future testing of PARTNER-MH in a larger trial, with modifications to increase program session attendance and retention.

eHealth Use on Acute Inpatient Mental Health Units: Implementation Processes, Common Practices, and Barriers to Use.

Information technology to promote health (eHealth) is an important and growing area of mental healthcare, yet little is known about the use of patient-facing eHealth in psychiatric inpatient settings. This quality improvement project examined the current practices, barriers, implementation processes, and contextual factors affecting eHealth use across multiple Veteran Health Administration (VHA) acute mental health inpatient units. Staff from units serving both voluntary and involuntary patients (n = 49 from 37 unique sites) completed surveys regarding current, desired, and barriers to use of Veteran-facing eHealth technologies. Two subsets of respondents were then interviewed (high success sites in eHealth use, n = 6; low success sites, n = 4) to better understand the context of their eHealth use. Survey responses indicated that 20% or less of Veterans were using any type of eHealth technology while inpatient. Tablets and video chat were the most desired overall and most successfully used eHealth technologies. However, many sites noted difficulty implementing these technologies (e.g., limited Wi-Fi access). Qualitative analysis of interviews revealed differences in risk/benefit analysis and implementation support between high and low success eHealth sites. Despite desired use, patient-facing eHealth technology is not regularly implemented on inpatient units due to multiple barriers (e.g., limited staffing, infrastructure needs). Successful implementation of patient-facing eHealth may require an internal champion, guidance from external supports with experience in successful eHealth use, workload balance for staff, and an overall perspective shift in the benefits to eHealth technology versus the risks.

Remdesivir improves biomarkers associated with disease severity in COVID-19 patients treated in an outpatient setting.

BACKGROUND: Remdesivir (RDV) is an intravenous antiviral with activity against SARS-CoV-2 for treatment of hospitalized COVID-19 patients with moderate-to-severe disease. Biomarkers associated with clinical outcomes have been identified for COVID-19, but few evaluated in context of antiviral treatment. Here, we assessed baseline (day 1, prior to first RDV dose) biomarkers and the impact of RDV treatment on longitudinal biomarker readouts. METHODS: Recently, RDV was evaluated in high-risk, non-hospitalized patients with confirmed SARS-CoV-2 infection and was highly effective at preventing disease progression. The randomized, double-blind, placebo-controlled Phase 3 study included 562 participants who received at least 1 dose of study drug, of which 312 consented for longitudinal biomarker assessments at baseline, day 3, and day 14. We assessed sixteen baseline biomarkers and the impact of RDV treatment on longitudinal biomarker readouts. RESULTS: Six well-known, inflammation-associated biomarkers are elevated at baseline in participants meeting the primary endpoint of hospitalization or death by day 28. Moreover, in comparison to placebo, biomarkers in RDV-treated participants show accelerated improvement, including reduction of soluble angiopoietin-2, D-dimer, and neutrophil-to-lymphocyte ratio, as well as an increase in lymphocyte counts. CONCLUSIONS: Overall, the findings in this study suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection. These findings have implications for better understanding the activity of antiviral treatments in COVID-19.

Certain cells and proteins in the blood can act as markers of COVID-19 severity. However, little is known about the impact of antiviral treatments on these markers. Here, we measured protein and cell markers in patient samples before treatment and those taken during the course of COVID-19 in high-risk non-hospitalized patients treated with or without the antiviral remdesivir (RDV). Several markers were improved with RDV treatment, including those associated with normal responses from the immune system and factors involved in blood clotting. These findings further our understanding of the activity of antivirals in COVID-19 and inform future studies to understand how patients with an increased risk of COVID-19 disease progression respond to these treatments.

NAFLD and NASH biomarker qualification in the LITMUS consortium - Lessons learned.

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Sharing knowledge of such interactions with the scientific community is of paramount importance to increase the chances of qualification of relevant biomarkers that may accelerate drug development, and thereby help patients, across disease indications. A qualified biomarker enables a decision to be made that all understand and support in a common framework.

Defining A Liquid Biopsy Profile of Circulating Tumor Cells and Oncosomes in Metastatic Colorectal Cancer for Clinical Utility.

Metastatic colorectal cancer (mCRC) is characterized by its extensive disease heterogeneity, suggesting that individualized analysis could be vital to improving patient outcomes. As a minimally invasive approach, the liquid biopsy has the potential to longitudinally monitor heterogeneous analytes. Current platforms primarily utilize enrichment-based approaches for epithelial-derived circulating tumor cells (CTC), but this subtype is infrequent in the peripheral blood (PB) of mCRC patients, leading to the liquid biopsy's relative disuse in this cancer type. In this study, we evaluated 18 PB samples from 10 mCRC patients using the unbiased high-definition single-cell assay (HDSCA). We first employed a rare-event (Landscape) immunofluorescence (IF) protocol, which captured a heterogenous CTC and oncosome population, the likes of which was not observed across 50 normal donor (ND) samples. Subsequent analysis was conducted using a colorectal-targeted IF protocol to assess the frequency of CDX2-expressing CTCs and oncosomes. A multi-assay clustering analysis isolated morphologically distinct subtypes across the two IF stains, demonstrating the value of applying an unbiased single-cell approach to multiple assays in tandem. Rare-event enumerations at a single timepoint and the variation of these events over time correlated with progression-free survival. This study supports the clinical utility of an unbiased approach to interrogating the liquid biopsy in mCRC, representing the heterogeneity within the CTC classification and warranting the further molecular characterization of the rare-event analytes with clinical promise.

Proactive, Recovery-Oriented Treatment Navigation to Engage Racially Diverse Veterans in Mental Healthcare (PARTNER-MH), a Peer-Led Patient Navigation Intervention for Racially and Ethnically Minoritized Veterans in Veterans Health Administration Mental Health Services: Protocol for a Mixed Methods Randomized Controlled Feasibility Study.

BACKGROUND: Mental health care disparities are persistent and have increased in recent years. Compared with their White counterparts, members of racially and ethnically minoritized groups have less access to mental health care. Minoritized groups also have lower engagement in mental health treatment and are more likely to experience ineffective patient-provider communication, which contribute to negative mental health care experiences and poor mental health outcomes. Interventions that embrace recovery-oriented practices to support patient engagement and empower patients to participate in their mental health care and treatment decisions may help reduce mental health care disparities. Designed to achieve this goal, the Proactive, Recovery-Oriented Treatment Navigation to Engage Racially Diverse Veterans in Mental Healthcare (PARTNER-MH) is a peer-led patient navigation intervention that aims to engage minoritized patients in mental health treatment, support them to play a greater role in their care, and facilitate their participation in shared treatment decision-making. OBJECTIVE: The primary aim of this study is to assess the feasibility and acceptability of PARTNER-MH delivered to patients over 6 months. The second aim is to evaluate the preliminary effects of PARTNER-MH on patient activation, patient engagement, and shared decision-making. The third aim is to examine patient-perceived barriers to and facilitators of engagement in PARTNER-MH as well as contextual factors that may inhibit or promote the integration, sustainability, and scalability of PARTNER-MH using the Consolidated Framework for Implementation Research. METHODS: This pilot study evaluates the feasibility and acceptability of PARTNER-MH in a Veterans Health Administration (VHA) mental health setting using a mixed methods, randomized controlled trial study design. PARTNER-MH is tested under real-world conditions using certified VHA peer specialists (peers) selected through usual VHA hiring practices and assigned to the mental health service line. Peers provide PARTNER-MH and usual peer support services. The study compares the impact of PARTNER-MH versus a wait-list control group on patient activation, patient engagement, and shared decision-making as well as other patient-level outcomes. PARTNER-MH also examines organizational factors that could impact its future implementation in VHA settings. RESULTS: Participants (N=50) were Veterans who were mostly male (n=31, 62%) and self-identified as non-Hispanic (n=44, 88%) and Black (n=35, 70%) with a median age of 45 to 54 years. Most had at least some college education, and 32% (16/50) had completed ≥4 years of college. Randomization produced comparable groups in terms of characteristics and outcome measures at baseline, except for sex. CONCLUSIONS: Rather than simply documenting health disparities among vulnerable populations, PARTNER-MH offers opportunities to evaluate a tailored, culturally sensitive, system-based intervention to improve patient engagement and patient-provider communication in mental health care for racially and ethnically minoritized individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT04515771; https://clinicaltrials.gov/ct2/show/NCT04515771. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37712.

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival.

BACKGROUND: Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer. METHODS: Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers. RESULTS: 144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-ß fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-ß fibrosis, and HER2, TMB was the main driver of survival in this patient population. CONCLUSION: Combination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-ß were associated with improved outcomes. TRIAL REGISTRATION NUMBER: NCT02864381 or GS-US-296--2013.

Liver failure from delayed hepatitis B reactivation in anti-HBc-positive patient following rituximab for B-cell lymphoma.

A 93-year-old man was admitted with 1 week of frank jaundice and abdominal pain. His medical history included diffuse large B-cell lymphoma treated with rituximab and cyclophosphamide, hydroxydaunomycin, oncovin and prednisolone (R-CHOP) chemotherapy 10 months prior. His investigations revealed marked hyperbilirubinemia with a total bilirubin of 355 µmol/L, along with a 17-fold elevation in alanine transaminase and impaired hepatic synthetic function. He tested hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) negative, hepatitis B core antibody (HBcAb) positive and had elevated hepatitis B virus DNA level at 13 691 IU/L. This was in the setting of radiological evidence of suspected cirrhosis. He was later found to have tested positive for HBcAb and negative for HBsAg and HBsAb prior to chemotherapy, but had not received antiviral prophylaxis. He was diagnosed with fulminant hepatitis secondary to delayed hepatitis B reactivation in the setting of rituximab. Hepatitis B reactivation and the role of screening and antiviral prophylaxis in isolated HBcAb-positive patients is reviewed.

Pre-implementation Evaluation of PARTNER-MH: A Mental Healthcare Disparity Intervention for Minority Veterans in the VHA.

To design PARTNER-MH, a peer-led, patient navigation program for implementation in Veterans Health Administration (VHA) mental health care settings, we conducted a pre-implementation evaluation during intervention development to assess stakeholders' views of the intervention and to explore implementation factors critical to its future adoption. This is a convergent mixed-methods study that involved qualitative semi-structured interviews and survey data. Data collection was guided by the Consolidated Framework for Implementation Research (CFIR). We interviewed and administered the surveys to 23 peers and 10 supervisors from 12 midwestern VHA facilities. We used deductive and inductive approaches to analyze the qualitative data. We also conducted descriptive analysis and Fisher Exact Test to compare peers and supervisors' survey responses. We triangulated findings to refine the intervention. Overall, participants viewed PARTNER-MH favorably. However, they saw the intervention's focus on minority Veterans and social determinants of health framework as potential barriers, believing this could negatively affect the packaging of the intervention, complicate its delivery process, and impact its adoption. They also viewed clinic structures, available resources, and learning climate as potential barriers. Peers and supervisors' selections and discussions of CFIR items were similar. Our findings informed PARTNER-MH development and helped identify factors that could impact its implementation. This project is responsive to the increasing recognition of the need to incorporate implementation science in healthcare disparities research. Understanding the resistance to the intervention's focus on minority Veterans and the potential barriers presented by contextual factors positions us to adjust the intervention prior to testing, in an effort to maximize implementation success.

Risk factors for disease progression in idiopathic pulmonary fibrosis.

In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.

Blinded Comparative Review of Lubricants Commonly Used for Split-Thickness Skin Graft Harvest.

Lubricating agents facilitate effective harvesting of split-thickness skin grafts. Multiple agents, including water-based gel, mineral oil, glycerin, and poloxamer 188, have been utilized in this capacity. The agent selected is typically at the discretion of the provider and institution, as a single "ideal" lubricant remains to be objectively established. Furthermore, a recent discontinuation of Shur-Clens® Skin Wound Cleanser1 (a wound cleansing solution consisting of the surfactant poloxamer 188) has prompted the search for a suitable substitute for many providers. The purpose of this study is to directly compare five lubricants (including a novel surgical lubricant-based solution) to select a preferred agent. Four practitioners blindly tested five lubricants while harvesting a split-thickness skin graft on a porcine skin model (glycerin, mineral oil, saline, poloxamer 188, and a novel lubricant solution created with surgical lube and sterile water). The results were recorded on a Likert scale where 1 indicated poor performance and 5 indicated excellent performance. Data were pooled, and means were compared with analysis of variance and post hoc Tukey test. The cost of each lubricating solution was also reported. Mean scores for each of the solutions were as follows: dry control = 1.1 ± 0.1; glycerin = 2.62 ± 1.02, saline = 3.88 ± 0.81, mineral oil = 3.75 ± 1.00, novel water-based lubricant solution = 4.63 ± 0.71, and poloxamer 188 = 3.88 ± 0.81. All solutions were superior to dry control (P < .01). Glycerin was noted to have statistically lower scores than all of the other solutions (P < .01). The novel water-based surgical lubricant solution had significantly higher mean scores than both glycerin (P < .01) and mineral oil (P < .05). Each solution was compared according to dollars per 100cc with glycerin and Shur-Clens® representing the most expensive options at almost $3/100cc and saline the least expensive at less than $0.15/100cc. In a porcine skin model, the novel water-based surgical lubricant solution had the best performance. It was statistically superior to glycerin and mineral oil and was also found to be the most cost-effective option in terms of overall performance compared with relative cost. Glycerin had the worst performance with statistically lower scores than all other solutions. Glycerin was also found to be the least cost-effective due to a large discrepancy between high cost and low overall performance. Saline performed better than expected. These results may be skewed due to the inherently greasy nature of the butcher shop porcine skin, creating limitations and decreasing the fidelity of the model. In a search for the "ideal" lubricant, other models should be further studied.

Coadministration of 13-valent pneumococcal conjugate and quadrivalent inactivated influenza vaccines in adults previously immunized with polysaccharide pneumococcal vaccine 23: a randomized clinical trial.

Immune responses to 13-valent pneumococcal conjugate vaccine (PCV13) and quadrivalent inactivated influenza vaccine (QIV) in older adults may vary with coadministration and previous pneumococcal polysaccharide vaccination. This study assessed safety and noninferiority of immune responses to coadministered PCV13 and QIV compared with each vaccine given alone. Adults ≥50 years old preimmunized with ≥1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) ≥1 year before enrollment were randomized 1:1 to receive PCV13+QIV then placebo 1 month later or placebo+QIV then PCV13 1 month later. Administration of PCV13 and placebo was blinded; QIV was administered open-label. Pneumococcal serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after PCV13, and influenza hemagglutination inhibition assay GMTs 1 month after QIV were measured. Prespecified noninferiority was demonstrated by a lower bound of the 2-sided 95% CI for geometric mean ratios >0.5. Safety endpoints included proportions of subjects with adverse and serious adverse events. Of 882 randomized subjects, 846 comprised the evaluable immunogenicity population. Immune responses to all 13 pneumococcal serotypes and all 4 influenza strains 1 month after PCV13+QIV were noninferior to responses 1 month after each vaccine given alone. No safety concerns were identified. Immune responses to coadministered PCV13 and QIV were noninferior to responses after each vaccine given alone, although generally lower for coadministered PCV13. PCV13 and QIV can be administered concomitantly to adults ≥50 years of age preimmunized with PPSV23.

Homogeneous BTK Occupancy Assay for Pharmacodynamic Assessment of Tirabrutinib (GS-4059/ONO-4059) Target Engagement.

Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation. We developed a novel duplex homogeneous BTK occupancy assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to measure free and total BTK levels in a multiplexed format. The dual-wavelength emission property of terbium-conjugated anti-BTK antibody served as the energy donor for two fluorescent energy acceptors with distinct excitation and emission spectra. The assay was characterized and qualified using full-length purified recombinant human BTK protein and peripheral blood mononuclear cells derived from healthy volunteers and patients with CLL. We demonstrated assay utility using cells derived from lymph node and bone marrow samples from patients with CLL and DLBCL. Our TR-FRET-based BTK occupancy assay provides accurate, quantitative assessment of BTK occupancy in the clinical trial program for tirabrutinib and is in use in ongoing clinical studies.

Avulsion fracture of the tibial eminence in an adult with a unique mechanism of injury.

Tibial eminence avulsion fractures are not infrequent in the pediatric population; however, they are rare in the adult population. These injuries typically occur in skeletally immature patients between the ages of 8 and 14 years. We report the unique clinical history, imaging findings, and operative results of a 48-year-old female who presented with severe knee pain. Imaging findings revealed an anterior tibial eminence fracture with an intact anterior cruciate ligament tendon attached to the avulsed fragment. The patient underwent knee arthroscopy, with direct repair of the tibial eminence fracture.

Late onset of injection site reactions after vaccination with the 13-valent pneumococcal conjugate vaccine in adult study populations.

Injection site reactions (ISRs; redness, swelling and pain) commonly occur within 1-2 days after vaccination. After administration of toxoid vaccines including diphtheria toxoid, a later onset of ISRs has also been observed. As the serotype capsular polysaccharides in the 13-valent pneumococcal conjugate vaccine (PCV13) are conjugated to cross-reactive material 197 (CRM197), a nontoxic variant of diphtheria toxin, the onset of ISRs over 14 days was explored in 8 adult studies with 19 cohorts. Subjects received PCV13 with aluminum phosphate (AlPO4, n = 5667) or without AlPO4 (n = 304); 1097 subjects received 23-valent pneumococcal polysaccharide vaccine (PPSV23). Late ISRs with onset between days 6-14 were observed in 8/8 cohorts aged ≥65 years after PCV13 with AlPO4 (incidence across cohorts for redness, 2.3%-19.6%; swelling, 0.9%-10.8%; pain, 1.6%-10.0%) and in 1/1 cohort after PCV13 without AlPO4 (redness 10.5%; swelling 7.5%; pain 12.3%); and in 2/4 cohorts aged 50 to 64 years after PCV13 (redness 3.1%-4.8%; swelling 1.0%-3.2%; pain 3.7%-5%). Late ISRs were not generally observed in 1/1 cohort aged 18 to 49 years after PCV13; in 2/2 cohorts aged ≥53 years after PCV13 revaccination; and in 3/3 cohorts aged ≥60 years who received PPSV23, which does not contain CRM197. Post hoc analysis demonstrated numerically higher pneumococcal immune responses in subgroups with late ISRs versus those without. In conclusion, causality of late ISRs is likely multifactorial, with age and the PCV13 carrier protein CRM197 potentially associated. AlPO4, a vaccine adjuvant, did not appear causally related. Observations do not affect the favorable risk-benefit profile of PCV13.