Ultrasensitive detection of aromatic water pollutants through protein immobilization driven organic electrochemical transistors.

Xenobiotic aromatic water pollutants pose an extreme threat to environmental sustainability. Due to the lack of detectable functional groups in these compounds and scarcity of selective bio-recognition scaffolds, easy-to-use sensing strategies capable of on-site detection remain unavailable. Herein, to address this lacune, we entail a strategy that combines biosensor scaffolds with organic electronics to create a compact device for environmental aromatic pollution monitoring. As proof of principle, a sensor module capable of rapid, economic, reliable, and ultrasensitive detection of phenol down to 2 ppb (0.02 µM) was designed wherein biosensing protein MopR was coupled with an organic electrochemical transistor (OECT). For effective interfacing of the sensing scaffold MopR, graphene oxide (GO) nanosheets were optimized as a host immobilization matrix. The MopR-GO immobilized sensor module was subsequently substituted as the gate electrode with PEDOT:PSS serving as an organic semiconductor material. The resulting OECT sensor provided a favourable microenvironment for protein activity, maintaining high specificity. Exclusive phenol detection with minimal loss of sensitivity (<5% error) could be achieved in both complex pollutant mixtures and real environmental samples. This fabrication strategy that amalgamates biological biosensors with organic electronics harnesses the potential to achieve detection of a host of emerging pollutants.

Inkjet-printed sub-zero temperature sensor for real-time monitoring of cold environments.

Real-time monitoring of low temperatures (usually below 0 °C) or cold environments is a specific requirement that finds its high demand in the aerospace, pharmaceutical, food, and beverage industries to maintain the temperature at high altitudes or in refrigerators and cold storage. In general, this purpose is achieved by using a sub-zero temperature sensor coupled with a control system. However, the market available such temperature sensors are very expensive, and bulky, thus not being suitable for portable operation, and also they suffer from poor accuracy. Therefore, the development of high-performance, low-cost, lightweight, and portable sub-zero temperature sensors is highly desired. In our recent work, we developed such sensors and integrated them with auxiliary electronics to demonstrate their wireless operation for the continuous and real-time monitoring of cold environments. So, in order to obtain low-cost sensors a cost-effective inkjet printing technology was employed for the fabrication of devices. A lightweight polydimethylsiloxane (PDMS) was used as the substrate and an electrically conducting graphene nanocomposite was used as the temperature-sensing material. To obtain a functional graphene nanocomposite film with a thickness of 530 nm and a conductivity of ~189 S m-1, the printed graphene nanocomposite was photonically sintered using a xenon flash lamp. This step was crucial for obtaining a sensor on the soft PDMS platform. The graphene nanocomposite film exhibited a positive temperature coefficient resistance value of approximately 0.119 %/°C, and its resistance values varied almost linearly (with an Adjusted R2 value (model accuracy) of 0.99) with temperature within the operating range of -30 °C to 80 °C. The sensor was properly encapsulated for protection without significantly affecting its performance. The sensors demonstrated sufficient flexibility, with a bending radius of 20 mm, and sustained 500 continuous bending cycles. Finally, the real-time operation of the sensors was demonstrated by wirelessly transmitting and monitoring the temperature over a smartphone platform.

Intratympanic Dexamethasone Role in Hearing Protection in Cancer Patients.

Introduction The study aims to determine the role of intratympanic dexamethasone (ITD) on the hearing profile of patients with head and neck cancer post-chemoradiotherapy. Study design This study employs a prospective case-control design. Subjects and methods In total 834 patients were evaluated for eligibility. Seven hundred and eleven were excluded because they didn't meet the inclusion criteria. A hundred cases out of 123 were diagnosed with head and neck cancer for which the treatment protocol included cisplatin concurrent to radiotherapy recruited. Before each cisplatin treatment session, ITD was injected into one ear (experimental ear) while the other ear of the same patient served as the control. Pure-tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAE) test results of the baseline and follow-up examinations in the sixth and 12th weeks were compared within and between the study and control ears. Results For pure tone thresholds, significant hearing threshold change was noticed at 8 kHz in the experimental group at six weeks and at ≥ 6 kHz in the control group. At 12 weeks, high frequencies were significantly affected at ≥ 4 kHz in the control group. When the baseline was compared across the groups in the 12th week, for otoacoustic emissions, high frequencies showed a loss in the control group more compared to the experimental side (Wilcoxon signed-rank test). Conclusion ITD functions less effectively at higher frequencies because the basal turn of the cochlea is more susceptible to cisplatin ototoxicity. ITD might have potential in the reduction of cisplatin-induced hearing loss.

Intrinsically Stretchable Conductive Self-Healable Organogels for Strain, Pressure, Temperature, and Humidity Sensing.

Intrinsically stretchable conductive self-healable organogels containing poly(lipoic acid), Al3+ ion, tannic acid, and reduced graphene oxide are produced in this report. These noncovalent networks interlocked through physical (hydrogen and coordination) bonds offered high stretchabilities and mechanical strengths as well as fast self-healing behaviors. The optimum organogel-based sensor showed outstanding pressure sensitivities (0.94 kPa-1 up to 10 and 1.07 kPa-1 for 10-50 kPa) and high strain responses (corresponding gauge factors of 1.1 and 0.4 for 0-50 and 50-100% stretching ratios). This organogel also revealed high stabilities at ambient atmosphere due to the presence of binary solvents of dimethyl sulfoxide and glycerol. Additionally, this stretchable thermistor displayed remarkable two-stage sensitivities of -2.6 and -0.4%/°C ranging over 0-30 and 30-80 °C, respectively. Besides, the signal variations of water droplet addition and removal with different temperatures were recorded by the organogel sensor to elucidate the practical applicabilities as a temperature sensor. Moreover, the organogel was utilized to demonstrate humidity sensing, where individual sensitivities of 0.89 and 0.55 were obtained in the respective relative humidity ranges of 10-30 and 40-90%. In the meanwhile, the sensor device illustrated distinct humidity signals during respiration monitoring of nose and mouth breathing detection. Accordingly, these quad-functional sensor applications in strain, pressure, temperature, and humidity detection enable this gel to act as a promising material for future multifunctional flexible electronics.

Tumor Genomic Profile Is Associated With Arterial Thromboembolism Risk in Patients With Solid Cancer.

Background: Patients with cancer have an increased risk for arterial thromboembolism (ATE). Scant data exist about the impact of cancer-specific genomic alterations on the risk for ATE. Objectives: The aim of this study was to determine whether individual solid tumor somatic genomic alterations influence the incidence of ATE. Methods: A retrospective cohort study was conducted using tumor genetic alteration data from adults with solid cancers who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets testing between 2014 and 2016. The primary outcome, ATE, was defined as myocardial infarction, coronary revascularization, ischemic stroke, peripheral arterial occlusion, or limb revascularization and identified through systematic electronic medical record assessments. Patients were followed from date of tissue-matched blood control accession to first ATE event or death, for up to 1 year. Cause-specific Cox proportional hazards regression was used to determine HRs of ATE for individual genes adjusted for pertinent clinical covariates. Results: Among 11,871 eligible patients, 74% had metastatic disease, and there were 160 ATE events. A significantly increased risk for ATE independent of tumor type was noted for the KRAS oncogene (HR: 1.98; 95% CI: 1.34-2.94; multiplicity-adjusted P = 0.015) and the STK11 tumor suppressor gene (HR: 2.51; 95% CI: 1.44-4.38; multiplicity-adjusted P = 0.015). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS and STK11 were associated with an increased risk for ATE independent of cancer type. Further investigation is needed to elucidate the mechanism by which these mutations contribute to ATE in this high-risk population.

Long-Term Prognostic Value of 82Rb PET/CT-Determined Myocardial Perfusion and Flow Reserve in Cancer Patients.

Myocardial flow reserve (MFR), derived from quantitative measurements of myocardial blood flow during PET imaging, provides prognostic information on patients with coronary artery disease (CAD), but it is not known if this also applies to cancer patients with a competing risk for mortality. Methods: To determine the prognostic value of MFR in patients with cancer, we designed a retrospective cohort study comprising 221 patients with known or suspected CAD (median age, 71 y; range, 41-92 y) enrolled between June 2009 and January 2011. Most patients were referred for perioperative risk assessment. Patients underwent measurement of myocardial blood flow at rest and during pharmacologic stress, using quantitative 82Rb PET imaging. They were divided into early-stage versus advanced-stage cancer groups based on cancer histopathology and clinical state and were further stratified by myocardial perfusion summed stress score, summed difference score, and calculated MFR. Overall survival (OS) was assessed using the Kaplan-Meier estimator, and Cox proportional-hazards regression helped identify independent predictors for OS. Results: During a follow-up of 85.6 mo, 120 deaths occurred. MFR, summed difference score, and cancer stage were significantly associated with OS. In the age-adjusted Cox hazard multivariable analysis, MFR and cancer stage remained independent prognostic factors. MFR combined with cancer stage enhanced OS discrimination. The groups had significantly different outcomes (P < 0.001), with 5-y OS of 88% (MFR ≥ 1.97 and early-stage), 53% (MFR < 1.97 and early-stage), 33% (MFR ≥ 1.97 and advanced-stage), and 13% (MFR < 1.97 and advanced-stage). Conclusion: Independent of cancer stage, MFR derived from quantitative PET was prognostic of OS in our cohort of cancer patients with known or suspected CAD. Combining these 2 parameters enhanced discrimination of OS, suggesting that MFR improves risk stratification and may serve as a treatment target to increase survival in cancer patients.

Pathologic Outcomes in Single Versus Multiple Areas of Architectural Distortion on Digital Breast Tomosynthesis.

BACKGROUND. Digital breast tomosynthesis (DBT) has led to increased detection of architectural distortion (AD). Management of patients with multiple areas of AD is not established. OBJECTIVE. The purpose of this article is to compare pathologic outcomes between single and multiple areas of AD identified on DBT. METHODS. This retrospective study included 402 patients (mean age, 56 years) who underwent image-guided core needle biopsy of AD visualized on DBT between April 7, 2017, and April 16, 2019. Patients were classified as having a single or multiple areas of AD according to the presence of distinct areas of AD described in the clinical radiology reports. The pathologic diagnosis for each AD was on the basis of the most aggressive pathology identified on either biopsy or surgical excision, if performed. Patients with single and multiple areas of AD were compared. RESULTS. The sample included 372 patients with a single AD (145 benign, 121 high risk, 105 malignant, one other) and 30 patients with multiple visualized ADs, including 66 biopsied ADs (10 benign, 35 high risk, 21 malignant). At pathologic assessment on a per-lesion basis, multiple compared with single ADs showed higher frequency of high-risk pathology (53.0% vs 32.5%, p = .002) but no difference in frequency of malignancy (31.8% vs 28.2%, p = .56). In multivariable analysis of a range of patient-related characteristics, the presence of single versus multiple areas of AD was not independently associated with malignancy (p = .51). In patients with multiple areas of AD, the most aggressive pathology (benign, high risk, or malignant) across all ADs was not associated with the number of ADs (p = .73). In 8 of 24 patients with at least two ipsilateral biopsied ADs, the ipsilateral areas varied in terms of most aggressive pathology; in 5 of 10 patients with contralateral biopsied ADs, the contralateral areas varied in most aggressive pathology. CONCLUSION. The presence of multiple areas of AD, compared with a single AD, was significantly more likely to yield high-risk pathology but was not significantly different in yield of malignancy. In patients with multiple ADs, multiple ipsilateral or contralateral ADs commonly varied in pathologic classification (benign, high risk, or malignant). CLINICAL IMPACT. These findings may help guide management of AD visualized by DBT, including multiple ADs. For patients with multiple areas of AD, biopsy of all areas may be warranted given variation in pathologic diagnoses.

Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS. OBJECTIVES: This study aimed to detail the role of GCS and GRS in ICI myocarditis. METHODS: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death. RESULTS: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002). CONCLUSIONS: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

Impact of Social Vulnerability on Comorbid Cancer and Cardiovascular Disease Mortality in the United States.

Background: Racial and social disparities exist in outcomes related to cancer and cardiovascular disease (CVD). Objectives: The aim of this cross-sectional study was to study the impact of social vulnerability on mortality attributed to comorbid cancer and CVD. Methods: The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database (2015-2019) was used to obtain county-level mortality data attributed to cancer, CVD, and comorbid cancer and CVD. County-level social vulnerability index (SVI) data (2014-2018) were obtained from the CDC's Agency for Toxic Substances and Disease Registry. SVI percentiles were generated for each county and aggregated to form SVI quartiles. Age-adjusted mortality rates (AAMRs) were estimated and compared across SVI quartiles to assess the impact of social vulnerability on mortality related to cancer, CVD, and comorbid cancer and CVD. Results: The AAMR for comorbid cancer and CVD was 47.75 (95% CI: 47.66-47.85) per 100,000 person-years, with higher mortality in counties with greater social vulnerability. AAMRs for cancer and CVD were also significantly greater in counties with the highest SVIs. However, the proportional increase in mortality between the highest and lowest SVI counties was greater for comorbid cancer and CVD than for either cancer or CVD alone. Adults <45 years of age, women, Asian and Pacific Islanders, and Hispanics had the highest relative increase in comorbid cancer and CVD mortality between the fourth and first SVI quartiles, without significant urban-rural differences. Conclusions: Comorbid cancer and CVD mortality increased in counties with higher social vulnerability. Improved education, resource allocation, and targeted public health interventions are needed to address inequities in cardio-oncology.

Anti-cancer Drugs Associated Atrial Fibrillation-An Analysis of Real-World Pharmacovigilance Data.

Background: Several anti-cancer drugs have been linked to new onset atrial fibrillation (AF) but the true association of these drugs with AF is unknown. The FDA Adverse Event Reporting System (FAERS), a publicly available pharmacovigilance mechanism provided by the FDA, collects adverse event reports from the United States and other countries, thus providing real-world data. Objectives: To identify anti-cancer drugs associated with AF using the FAERS database. Methods: The FAERS database was searched for all drugs reporting AF as an adverse event (AE). The top 30 anti-cancer drugs reporting AF cases were shortlisted and analyzed. Proportional reporting ratio (PRR) was used to measure disproportionality in reporting of adverse events for these drugs. Results: When analyzed for AF as a percentage of all reported AE for a particular drug, Ibrutinib had the highest percentage (5.3%) followed distantly by venetoclax (1.6%), bortezomib (1.6%), carfilzomib (1.5%), and nilotinib (1.4%). The percentage of cardiac AE attributable to AF was also highest for ibrutinib (41.5%), followed by venetoclax (28.4%), pomalidomide (23.9%), bortezomib (18.2%), and lenalidomide (18.2%). Drugs with the highest PRR for AF included ibrutinib (5.96, 95% CI= 5.70-6.23), bortezomib (1.65, 95% CI = 1.52-1.79), venetoclax (1.65, 95% CI = 1.46-1.85), carfilzomib (1.53, 95% CI = 1.33-1.77), and nilotinib (1.46, 95% CI = 1.31-1.63). Conclusions: While newer anti-cancer drugs have improved the prognosis in cancer patients, it is important to identify any arrhythmias they may cause early on to prevent increased morbidity and mortality. Prospective studies are needed to better understand the true incidence of new onset AF associated with anti-cancer drugs.

A multidisciplinary approach to axillary lymph node staging with ultrasound in the setting of a highly suggestive or suspicious breast mass.

The radiologists' role in axillary imaging in the setting of a suspicious breast mass is evolving in light of the Z0011 trial leading to expected practice variation. The purpose of our project was to generate a standardized algorithm guiding the utilization of axillary ultrasound in the setting of a highly suggestive or highly suspicious breast mass (BI-RADS 4C or 5) without a known cancer diagnosis. The algorithm was created with Z0011 practices in mind while reflecting the clinical preferences of our radiology and surgical teams. The four breast surgeons at our academic institution were individually queried regarding their preferred axillary imaging and biopsy approach. The best practices for axillary imaging were then developed in a breast imaging intradepartmental meeting. There was agreement among the surgical group that the presence of suspicious axillary lymph node (s) on ultrasound could be used for treatment planning and patient discussion but would not be used for surgical planning in most cases. They also agreed that an ultrasound-guided core needle biopsy of a suspicious axillary lymph node should be deferred until after surgical consultation. Discussion among our breast radiologists resulted in the consensus that axillary ultrasound in the setting of a BIRADS 4 or 5 mass should be deferred at its initial presentation unless there is palpable lymphadenopathy, suspicious lymph node on mammography, or a tumor is at least stage T3, presumably excluding them from Z0011 criteria. The decision was also made to defer biopsies of suspicious axillary lymph nodes without prior surgical consultation/discussion.

A Single-Center Study of Adherence to Breast Cancer Screening Mammography Guidelines by Transgender and Non-Binary Patients.

BACKGROUND: Adherence to screening guidelines among transgender and non-binary (TGNB) populations is not well studied. This study examines breast cancer screening patterns among TGNB patients at an urban academic medical center. METHODS: Demographic information, risk factors, and screening mammography were collected. Mammography rates were calculated in populations of interest according to national guidelines, and mammogram person-years were also calculated. Univariate and multivariate logistic regression was performed. RESULTS: Overall, 253 patients were analyzed: 193 transgender women and non-binary people designated male at birth (TGNB DMAB) and 60 transgender men and non-binary people designated female at birth (TGNB DFAB). The median (interquartile range) age was 53.2 years (42.3-62.6). Most patients had no family history of breast cancer (n = 163, 64.4%) and were on hormone therapy (n = 191, 75.5%). Most patients where White (n = 164, 64.8%), employed (n = 113, 44.7%), and had public insurance (n = 128, 50.6%). TGNB DFAB breast screening rates were low, ranging from 2.0 to 50.0%, as were TGNB DMAB screening rates, ranging from 7.1 to 47.6%. The screening rates among the TGNB DFAB and TGNB DMAB groups did not significantly differ from one another. Among TGNB DFAB patients, univariate analyses showed no significant predictors for mammography. Among TGNB DMAB patients, not being on hormone therapy resulted in fewer odds of undergoing mammography. There were no significant findings on multivariate analyses. CONCLUSION: Mammography rates in the TGNB population are lower than institutional and national rates for cisgender patients, which are 77.3% and 66.7-78.4%, respectively. Stage of transition, organs present, hormone therapy, and risk factors should be considered to guide screening.

Self-healable and anti-freezing ion conducting hydrogel-based artificial bioelectronic tongue sensing toward astringent and bitter tastes.

Numerous efforts have been attempted to mimic human tongue since years. However, they still have limitations because of damages, temperature effects, detection ranges etc. Herein, a self-healable hydrogel-based artificial bioelectronic tongue (E-tongue) containing mucin as a secreted protein, sodium chloride as an ion transporting electrolyte, and chitosan/poly(acrylamide-co-acrylic acid) as the main 3D structure holding hydrogel network is synthesized. This E-tongue is introduced to mimic astringent and bitter mouth feel based on cyclic voltammetry (CV) measurements subjected to target substances, which permits astringent tannic acid (TA) and bitter quinine sulfate (QS) to be detected over wide corresponding ranges of 29.3 mM-0.59 µM and 63.8 mM-6.38 µM with remarkable respective sensitivities of 0.2 and 0.12 wt%-1. Besides, the taste selectivity of this E-tongue is performed in the presence of various mixed-taste chemicals to show its high selective behavior toward bitter and astringent chemicals. The electrical self-healability is shown via CV responses to illustrate electrical recovery within a short time span. In addition, cytotoxicity tests using HeLa cells are performed, where a clear viability of ≥95% verified its biocompatibility. The anti-freezing sensing of E-tongue tastes at -5 °C also makes this work to be useful at sub-zero environments. Real time degrees of tastes are detected using beverages and fruits to confirm future potential applications in food taste detections and humanoid robots.

Cardio-oncology Training in the COVID-19 Era.

OPINION STATEMENT: Cardio-oncology is a field dedicated to the prevention, diagnosis, and management of cardiovascular disease in cancer patients before, during, and after cancer therapy. It is an emerging field with limited opportunities for structured education and training. In the year 2021, we cannot define the requirements of cardio-oncology training without acknowledging the impact of the global coronavirus disease 19 (COVID-19) pandemic. While this pandemic poses significant health risks to patients with cancer and cardiovascular disease as well as the providers who care for them, it also allows novel opportunities for the nascent field of cardio-oncology to readily adapt. In this article, we detail how the COVID-19 pandemic has impacted all aspects of cardio-oncology training, how programs and trainees can adapt to these challenges, and how lessons learned from the COVID-19 era can continue to positively impact cardio-oncology training for the foreseeable future.

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

BACKGROUND: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. OBJECTIVES: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. METHODS: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. RESULTS: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. CONCLUSIONS: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

BACKGROUND: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. METHODS: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. RESULTS: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). CONCLUSIONS: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease.

Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and ßS-globin. Kinetic studies with MetAP2 show that ßS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood-derived erythroid progenitor 2 cells shows more extensive modification of α-globin than ß-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on ßS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor-treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2-affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.