Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

In vivo selection in non-human primates identifies AAV capsids for on-target CSF delivery to spinal cord.

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal (IT) delivery of AAV vectors into cerebral spinal fluid can avoid many issues, although distribution of the vector throughout the spinal cord is limited, and vector entry to the periphery sometimes initiates hepatotoxicity. Here we performed biopanning in non-human primates (NHPs) with an IT injected AAV9 peptide display library. We identified top candidates by sequencing inserts of AAV DNA isolated from whole tissue, nuclei, or nuclei from transgene-expressing cells. These barcoded candidates were pooled with AAV9 and compared for biodistribution and transgene expression in spinal cord and liver of IT injected NHPs. Most candidates displayed increased retention in spinal cord compared with AAV9. Greater spread from the lumbar to the thoracic and cervical regions was observed for several capsids. Furthermore, several capsids displayed decreased biodistribution to the liver compared with AAV9, providing a high on-target/low off-target biodistribution. Finally, we tested top candidates in human spinal cord organoids and found them to outperform AAV9 in efficiency of transgene expression in neurons and astrocytes. These capsids have potential to serve as leading-edge delivery vehicles for spinal cord-directed gene therapies.

Myocardial strain is associated with adverse cardiac events in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

BACKGROUND: Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T-cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy-related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T-cell therapy. OBJECTIVES: To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. METHODS: Patients who had an echocardiogram within 6 months prior to receiving CAR T-cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. RESULTS: Among 75 CAR T-cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p = .021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p = .012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48-0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p = .024) was associated with a higher risk of CE. CONCLUSION: Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T-cell therapy.

Impact of Operative Approach on Acute Kidney Injury Risk Prediction Models for Colectomy.

INTRODUCTION: Acute kidney injury (AKI) is a serious postoperative complication associated with increased morbidity and mortality. Identifying patients at risk for AKI is important for risk stratification and management. This study aimed to develop an AKI risk prediction model for colectomy and determine if the operative approach (laparoscopic versus open) alters the influence of predictive factors through an interaction term analysis. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was analyzed from 2005 to 2019. Patients undergoing laparoscopic and open colectomy were identified and propensity score matched. Multivariable logistic regression identified significant preoperative demographic, comorbidity, and laboratory value predictors of AKI. The predictive ability of a baseline model consisting of these variables was compared to a proposed model incorporating interaction terms between operative approach and predictor variables using the likelihood ratio test, c-statistic, and Brier score. Shapley Additive Explanations values assessed relative importance of significant predictors. RESULTS: 252,372 patients were included in the analysis. Significant AKI predictors were hypertension, age, sex, race, body mass index, smoking, diabetes, preoperative sepsis, Congestive heart failure, preoperative creatinine, preoperative albumin, and operative approach (P < 0.001). The proposed model with interaction terms had improved predictive ability per the likelihood ratio test (P < 0.05) but had no statistically significant interaction terms. C-statistic and Brier scores did not improve. Shapley Additive Explanations analysis showed hypertension had the highest importance. The importance of age and diabetes showed some variation between operative approaches. CONCLUSIONS: While the inclusion of interaction terms collectively improved AKI prediction, no individual operative approach interaction terms were significant. Including operative approach interactions may enhance predictive ability of AKI risk models for colectomy.

A Comparison of Plastic Surgery Authorship Trends Under Single Versus Double-Blinded Review.

INTRODUCTION: Research is key to academic advancement in plastic surgery. However, access to publication opportunities may be inequitable as seen in other fields. We compared authorship trends of plastic surgery manuscripts that underwent single-blinded review (SBR) versus double-blinded review (DBR) to identify potential disparities in publication opportunities. METHODS: Publications from two plastic surgery journals using SBR and two using DBR from September 2019 to September 2021 were evaluated. Name and institution of the article's first and senior author and journal's editor-in-chief (EIC) were recorded. Chi-squared and Fisher's exact analyses were used to compare author characteristics between SBR and DBR articles. RESULTS: Of 2500 manuscripts, 65.7% underwent SBR and 34.3% underwent DBR. SBR articles had higher percentages of women as first authors (31.9% versus 24.3%, P < 0.001) but lower percentages of first (50.7% versus 71.2%, P < 0.001) and senior (49.6% versus 70.3%, P < 0.001) authors from international institutions. First (26.0% versus 12.9%, P < 0.001) and senior (27.9% versus 18.0%, P = 0.007) authors of SBR articles tended to have more plastic surgery National Institutes of Health funding. Journals using SBR tended to have higher rates of authorship by EICs or authors sharing institutions with the EIC (P ≤ 0.005). CONCLUSIONS: While associated with greater female first authorship suggesting potential efforts toward gender equity in academia, SBR of plastic surgery articles tends to favor authors from institutions with higher National Institutes of Health funding and disadvantage authors from international or lower-resourced programs. Careful consideration of current peer-review proceedings may make publication opportunities more equitable.

From lab bench to hope: a review of gene therapies in clinical trials for Parkinson's disease and challenges.

Parkinson's disease (PD) is a chronic neurological disorder that is identified by a characteristic combination of symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It is the second most common neurodegenerative disease after Alzheimer's disease and is characterized by the progressive loss of dopamine-producing neurons in the brain. Currently, available treatments for PD are symptomatic and do not prevent the disease pathology. There is growing interest in developing disease-modifying therapy that can reduce disease progression and improve patients' quality of life. One of the promising therapeutic approaches under evaluation is gene therapy utilizing a viral vector, adeno-associated virus (AAV), to deliver transgene of interest into the central nervous system (CNS). Preclinical studies in small animals and nonhuman primates model of PD have shown promising results utilizing the gene therapy that express glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), aromatic L-amino acid decarboxylase (AADC), and glutamic acid decarboxylase (GAD). This study provides a comprehensive review of the current state of the above-mentioned gene therapies in various phases of clinical trials for PD treatment. We have highlighted the rationale for the gene-therapy approach and the findings from the preclinical and nonhuman primates studies, evaluating the therapeutic effect, dose safety, and tolerability. The challenges associated with gene therapy for heterogeneous neurodegenerative diseases, such as PD, have also been described. In conclusion, the review identifies the ongoing promising gene therapy approaches in clinical trials and provides hope for patients with PD.

Inhibition of the JAK/STAT Pathway With Baricitinib Reduces the Multiple Organ Dysfunction Caused by Hemorrhagic Shock in Rats.

OBJECTIVE: The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB, and NLRP3 caused by HS. BACKGROUND: Posttraumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown. METHODS: An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB, and NLRP3 pathways were analyzed by western blotting in the kidney and liver. RESULTS: We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB, and NLRP3 pathways caused by HS in the rat. CONCLUSIONS: Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.

Inhibition of Bruton's Tyrosine Kinase Activity Attenuates Hemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats.

OBJECTIVE: The aim of this study was to investigate (a) the potential of the Bruton's tyrosine kinase (BTK) inhibitors acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-κB and NLRP3 activation in HS. BACKGROUND: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. METHODS: Acute HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-κB and NLRP3 pathways were analyzed by western blot in the kidney. RESULTS: We demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute HS models and (c) reduced the activation of BTK, NF- kB and NLRP3 pathways in the kidney. CONCLUSION: Our results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage.

Association of Preoperative Blood Transfusion on Postoperative Outcomes in Emergency General Surgery.

INTRODUCTION: Emergency general surgery (EGS) patients often present with anemia, in which preoperative transfusions are performed to mitigate anemia-associated risks. However, transfusions have also been noted to cause worse postoperative outcomes. This study examined how transfusion-associated outcomes vary at different levels of anemia. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2019 was used to identify patients who had undergone any of 12 major EGS procedures using Current Procedural Terminology codes. Patients were divided into two cohorts based on receipt of preoperative transfusion. Cohorts were subdivided into anemia severity levels and propensity score-matched within each using patient demographic and comorbidity variables. We analyzed 30-day postoperative outcomes, including morbidity, mortality, and return to odds ratio (OR), using univariate Chi-squared tests, Wilcoxon signed-rank tests, and multivariate logistic regression analyses. RESULTS: 595,407 EGS cases were identified. Receiving preoperative transfusion were 44.45% (n = 3058) of severely anemic, 10.94% (n = 9076) of moderately anemic, 1.34% (n = 1370) of mildly anemic, and 0.174% (n = 704) of no anemia patients. Transfusion resulted in an increased overall morbidity in the severe (OR 1.54), moderate (OR 1.50), mild (OR 1.71), and no anemia (OR 1.85) groups. Mortality increased in the moderate (OR 1.27), mild (OR 1.61), and no anemia (OR 1.76) subgroups. In severe anemia, transfusion status and mortality were not significantly associated. CONCLUSIONS: Transfusion is associated with higher morbidity and mortality rates in those with higher hematocrit levels, even after controlling for pre-existing comorbidities. A restrictive transfusion strategy should be considered to avoid risks for those with a hematocrit level more than 24%.

Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.

Fluorescence Lifetime Imaging of Human Sub-RPE Calcification In Vitro Following Chlortetracycline Infusion.

We have shown that all sub-retinal pigment epithelial (sub-RPE) deposits examined contain calcium phosphate minerals: hydroxyapatite (HAP), whitlockite (Wht), or both. These typically take the form of ca. 1 µm diameter spherules or >10 µm nodules and appear to be involved in the development and progression of age-related macular degeneration (AMD). Thus, these minerals may serve as useful biomarkers the for early detection and monitoring of sub-RPE changes in AMD. We demonstrated that HAP deposits could be imaged in vitro by fluorescence lifetime imaging microscopy (FLIM) in flat-mounted retinas using legacy tetracycline antibiotics as selective sensors for HAP. As the contrast on a FLIM image is based on the difference in fluorescence lifetime and not intensity of the tetracycline-stained HAP, distinguishing tissue autofluorescence from the background is significantly improved. The focus of the present pilot study was to assess whether vascular perfusion of the well tolerated and characterized chlortetracycline (widely used as an orally bioavailable antibiotic) can fluorescently label retinal HAP using human cadavers. We found that the tetracycline delivered through the peripheral circulation can indeed selectively label sub-RPE deposits opening the possibility for its use for ophthalmic monitoring of a range of diseases in which deposit formation is reported, such as AMD and Alzheimer disease (AD).

Cardiac Investigation Trends Among Primary Care Physicians: A Paradigm Shift.

OBJECTIVE: While numerous recent guidelines support coronary computed tomography angiography (CTA) as a first-line test for stable chest pain, it remains underutilized by primary care physicians (PCPs). We aimed to evaluate cardiac investigation ordering practices following education sessions, as well as the total number of downstream tests and time to diagnosis for patients presenting with stable chest pain. METHODS: A retrospective chart review was completed for eligible patients assessed at the Women's College Hospital Family Practice Health Centre between 2017 and 2019 following the education sessions. The outcome measures were first-choice cardiac investigation, additional downstream testing, time from presentation to first investigation, and time to final diagnosis. RESULTS: 419 patients were included in the final analysis (74.70% female; mean age 61 ± 11 years). Coronary CTA requests by PCPs increased between 2017 and 2019 (18 vs 72 tests; P < .0001). When coronary CTA was the first-line test, patients were less likely to receive additional downstream testing when compared to those receiving other first-line investigations (P < .0001). Coronary CTA was associated with longer time to diagnosis than stress echocardiography (47 ± 45 vs 27 ± 36 days; P = .0068) due to limited availability of coronary CTA appointment times. There was no significant difference in time to final diagnosis among the cardiac imaging modalities observed in the cohort (P = .0623). CONCLUSION: Utilization of coronary CTA as the first-line test for stable chest pain increased following our education sessions targeting PCPs. Coronary CTA was associated with less downstream testing compared to other non-invasive cardiac investigations.

Diversity in Plastic Surgery: Analysis of Representation of Sex and Ethnic Diversity in Plastic Surgery Residency Social Media Accounts.

BACKGROUND: Increasing health care diversity is critical to overcoming disparities. Plastic surgery has been working to improve diversity through various efforts, including social media movements like Diversify PRS and #ilooklikeasurgeon. Because residency programs' social media sites serve as a public symbol of the programs' values and can attract potential applicants, we sought to analyze such platforms for content highlighting sex and ethnic diversity. METHODS: Integrated plastic surgery residency programs during the 2020 to 2021 academic year were found on the American Council of Academic Plastic Surgeons website, and their associated social media accounts were identified. The authors reviewed each program's account for all posts published by November 8, 2021, for content promoting sex or ethnic diversity. Any hashtags related to diversity were also recorded. Nonparametric Mann-Whitney U and Kruskal-Wallis tests were used to compare percentages of total social media posts related to sex and ethnic diversity between programs (α = 0.05). RESULTS: Of 82 programs, 76 (92.7%) had active Instagram accounts, 29 (35.4%) had active Facebook accounts, and 29 (35.4%) had active Twitter accounts. Across all platforms, 19.0% of all posts were promoting sex diversity and 3.3% were promoting ethnic diversity. Of 4651 posts promoting sex diversity, 4067 (87.4%) highlighted women, 1017 (21.9%) featured all-women teams, 779 (16.7%) used sex diversity-related hashtags, and 300 (6.5%) included purposeful statements. Of 808 posts promoting ethnic diversity, 527 (65.2%) used ethnic diversity-related hashtags, 224 (27.7%) included purposeful statements, 199 (24.6%) mentioned ethnic background, and 36 (4.5%) used different skin-toned emojis. Programs did not vary in percentages of posts related to diversity by geographic region, ranking, accreditation length, or engagement rate. The percentage of posts promoting sex diversity was greater than that promoting ethnic diversity (P < 0.001). The most used diversity hashtag was #ilooklikeasurgeon. CONCLUSIONS: Despite the importance of increasing recruitment of trainees from diverse backgrounds to plastic surgery and the global reach of social media movements like #ilooklikeasurgeon, sex and ethnic diversity are still poorly promoted on residency social media accounts. Increasing such content is a simple yet powerful way to create a culture of inclusivity for all applicants.

Utilizing Teledentistry to Manage Cleft Lip and Palate Patients in an Outpatient Setting.

BACKGROUND: As a result of the current global pandemic, the dental profession has utilized teledentistry to reduce footfall in the hospitals and clinics where possible. Pediatric dental consultants form a vital part of a multidisciplinary team and regularly monitor the dental growth and development of patients with cleft lip and palate. OBJECTIVE: To assess the effectiveness of the service provided by pediatric dental consultants in the South Thames Cleft Service at Evelina Children's Hospital during the COVID-19 pandemic through virtual clinics. DESIGN: Data were collected retrospectively and include all cleft patients contacted via the virtual clinic during May to July 2020. Patients were prioritized by the Red, Amber, Green (RAG) scale to highlight the urgency of their next face-to-face appointment. RESULTS: A total of 215 patients were contacted during this period with a 97% response rate. Patients given a RAG score of GREEN (86%) meant no urgent requirement for a face-to-face consultation and AMBER (8%) patients required treatment that was deemed nonurgent. However, 3% of patients received a RED rating as they required urgent input. CONCLUSION: Through these virtual clinics, the pediatric team was able to reach 208 patients and provided advice and reassurance. The need for face-to-face appointment was eliminated for 11% of patients who were discharged to their local dental practitioners, thereby reducing the risk of spreading COVID-19.

Impact of the COVID-19 Pandemic on Long-term Recovery From Traumatic Injury.

OBJECTIVE: Determine the proportion and characteristics of traumatic injury survivors who perceive a negative impact of the COVID-19 pandemic on their recovery and to define post-injury outcomes for this cohort. BACKGROUND: The COVID-19 pandemic has precipitated physical, psychological, and social stressors that may create a uniquely difficult recovery and reintegration environment for injured patients. METHODS: Adult (≥18 years) survivors of moderate-to-severe injury completed a survey 6 to 14 months post-injury during the COVID-19 pandemic. This survey queried individuals about the perceived impact of the COVID-19 pandemic on injury recovery and assessed post-injury functional and mental health outcomes. Regression models were built to identify factors associated with a perceived negative impact of the pandemic on injury recovery, and to define the relationship between these perceptions and long-term outcomes. RESULTS: Of 597 eligible trauma survivors who were contacted, 403 (67.5%) completed the survey. Twenty-nine percent reported that the COVID-19 pandemic negatively impacted their recovery and 24% reported difficulty accessing needed healthcare. Younger age, lower perceived-socioeconomic status, extremity injury, and prior psychiatric illness were independently associated with negative perceived impact of the COVID-19 pandemic on injury recovery. In adjusted analyses, patients who reported a negative impact of the pandemic on their recovery were more likely to have new functional limitations, daily pain, lower physical and mental component scores of the Short-Form-12 and to screen positive for PTSD and depression. CONCLUSIONS: The COVID-19 pandemic is negatively impacting the recovery of trauma survivors. It is essential that we recognize the impact of the pandemic on injured patients while focusing on directed efforts to improve the long-term outcomes of this already at-risk population.

Traumatic Brain Injury: Does Admission Service Matter?

BACKGROUND: Traumatic brain injury (TBI) is common, and significant institutional variation exists with regards to structure and processes of care. Affected patients may be admitted to one of several different services, and this may drive differential care and outcomes. We sought to evaluate differential care and outcomes for patients with isolated mild-to-moderate traumatic brain injury based on admission service. MATERIALS AND METHODS: This is a single-institution retrospective study of all adult (≥18 y old) patients admitted with isolated TBI (AIS ≤1 in all other body regions) over a 3-year period (6/2015-6/2018). Patients who underwent neurosurgical intervention (craniectomy/craniotomy) and those with a head AIS ≥4 were excluded. Patients were assigned to one of three groups based upon admission service: Trauma Surgery, Neurology/Medicine or Neurosurgery. Outcomes evaluated included in-hospital mortality and markers of differential care. We performed multivariate analyses adjusting for patient demographics and clinical characteristics. RESULTS: A total of 401 isolated mild-to-moderate TBI patients were identified. Overall mortality was 1.7%. Adjusted multivariate logistic regression analysis demonstrated no difference in mortality. Patients admitted to Neurosurgery underwent more repeat head CTs and were more likely to receive antiseizure medication in the absence of seizure activity, and those admitted to Neurology/Medicine were less likely to receive venous thromboembolism chemoprophylaxis compared to those admitted to Trauma Surgery. CONCLUSIONS: We identify several important metrics of variation in care received by patients with an isolated mild-to-moderate TBI based upon admission service. These findings deserve further study, and this study may lay the foundation for future efforts at protocolizing care in an evidence-based fashion for this patient cohort.

Cardiovascular Toxicities of CAR T-cell Therapy.

PURPOSE OF REVIEW: This review provides a contemporary overview of current studies outlining the incidence and characteristics of CAR T-cell cardiotoxicity in an effort to identify future directions for research and potential opportunities for prevention and intervention. RECENT FINDINGS: Cardiovascular events occurred in anywhere between 10 and 36% of patients in CAR T-cell clinical trials, ranging from tachycardia, hypotension, arrhythmia, decreased left ventricular systolic function to cardiogenic shock and death. Cardiac events are more often associated higher grades (> 2) of cytokine release syndrome and frequently proceeded by an elevated troponin. There is a growing recognition of cardiotoxicities of CAR T-cell therapy but has a limited study in this area. The mechanism of left ventricular dysfunction due to CAR T-cell therapy is also unknown. As CAR T-cell use expands, it becomes imperative to truly understand the mechanism behind cardiac injury and to assess long-term follow-up data as this will allow for surveillance, early intervention, and potentially prevention of cardiotoxicity.

Frailty Interdisciplinary Pathway: Compliance and Sustainability in a Level I Trauma Center.

BACKGROUND: Frailty is a state of physiological vulnerability that predisposes many older adult trauma patients to poor health outcomes. Specialized care pathways for frail trauma patients have been shown to improve outcomes, but the compliance and sustainability of these pathways have not been reported (Bryant et al., 2019; Engelhardt et al., 2018). METHODS: We retrospectively measured compliance and sustainability during the first 2 years of a frailty pathway for patients 65 years or older at an urban Level I trauma center. Compliance to 19 pathway elements was collected for 279 pathway patients between October 1, 2016, and September 30, 2018. Compliance was analyzed and reported as a percentage of the total possible times each element could have been completed per pathway guidelines. Benchmark compliance was 75% or more. RESULTS: Retrospective 2-year mean overall compliance to all pathway elements was 68.2% and improved from Year 1 (65.0%) to Year 2 (71.4%). Seven elements achieved a mean 75% or more compliance over the 2-year period: frailty screening on admission (92.8%), consultation requests for physical therapy (97.9%), geriatrics (96.2%), and nutrition (92.3%), consultant care within 72 hr of admission (78.0%), delirium screening 3 times daily (76.3%), and daily senna administration (76.0%). Compliance to 10 elements significantly improved from Year 1 to Year 2 and significantly worsened in 2 elements. CONCLUSION: Many standardized geriatric care processes for frail older adult trauma patients can be successfully integrated into routine daily inpatient practice and sustained over time. Multicenter studies are needed to demonstrate how to improve compliance and to understand better which pathway elements are most effective.

Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients.

Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients' responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non-small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1-targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients' responses to PD-1-targeted therapies.