A novel outpatient regimen in management of fluoropyrimidine-induced cardiotoxicity.

INTRODUCTION: Fluoropyrimidines (FP) are cornerstone drugs in the treatment of gastrointestinal (GI) malignancies. Cardiotoxicity secondary to an FP chemotherapy is a serious complication. There are no standardized guidelines on the treatment of FP induced cardiotoxicity which may result in interruption and even discontinuation of life saving treatment. We present our experience in FP rechallenge using a novel outpatient regimen based on our "up-front" triple agent antianginal protocol. METHODS: We report the retrospective study of the patients with suspected FP induced cardiotoxicity. Patients meeting the criteria were selected by C3OD (curated cancer clinical outcomes database) at Kansas University Medical Center (KUMC). We identified all patients with gastrointestinal malignancies who had suspected FP induced cardiotoxicity from January 2015 to March 2022. We then included the patients who were rechallenged with planned fluoropyrimidine regimen utilizing the three drug KU-protocol. We utilized a novel regimen by repurposing the already FDA-approved anti-anginal drugs in a manner that minimizes the risk of hypotension and bradycardia. RESULTS: In this retrospective study, 10 patients with suspected fluoropyrimidine induced cardiotoxicity were included from January-2015 to March-2022 at KUMC. Out of 10 patients who were rechallenged utilizing KU-protocol, eight patients (80%) were able to complete the previously planned fluoropyrimidine regimen. None of the patients required ER visits or hospital admission due to cardiac symptoms during the rechallenge utilizing the KU-protocol. CONCLUSIONS: Utilizing our novel outpatient regimen, we have successfully and safely allowed re-challenge of FP chemotherapy with good tolerability and completion of the intended course of chemotherapy without recurrent morbidity.

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.

Permissive Cardiotoxicity: The Clinical Crucible of Cardio-Oncology.

The field of cardio-oncology was born from the necessity for recognition and management of cardiovascular diseases among patients with cancer. This need for this specialty continues to grow as patients with cancer live longer as a result of lifesaving targeted and immunologic cancer therapies beyond the usual chemotherapy and/or radiation therapy. Often, potentially cardiotoxic anticancer treatment is necessary in patients with baseline cardiovascular disease. Moreover, patients may need to continue therapy in the setting of incident cancer therapy-associated cardiotoxicity. Herein, we present and discuss the concept of permissive cardiotoxicity as a novel term that represents an essential concept in the field of cardio-oncology and among practicing cardio-oncology specialists. It emphasizes a proactive rather than reactive approach to continuation of lifesaving cancer therapies in order to achieve the best oncologic outcome while mitigating associated and potentially off-target cardiotoxicities.

Emergency department use and hospital admissions among adult orthotopic heart transplant patients.

Objective: To study the demographics, clinical presentations, and outcomes of emergency department (ED) visits of patients with heart transplantation (HT) in the United States. Methods: We performed a secondary analysis of the National Emergency Department Sample database from 2016 to 2018. All ED visits of patients with HT aged ≥ 18 years were identified using International Classification of Diseases, Tenth Revision codes. Results: Out of a total 308,182,495 national ED visits, 55,583 were HT-related visits. The median age was 61.07 years (interquartile range [IQR]: 46.91-69.38) and 69.44% were males. The hospital admission rate was 54.3% and median inpatient length of stay was 3.19 days (IQR: 1.63-5.92). The mortality rate during inpatient stay was 1.16%. Median inpatient and ED charges among admitted patients were $37,911 (IQR: $21,487-$71,262). The most common primary diagnosis of HT-related ED visits was sepsis (4.3%) followed by acute kidney injury (3.57%) and chest pain (3%). Conclusion: More than half of total ED visits among HT patients resulted in hospital admission. The most common cause for ED visit in these patients was sepsis followed by acute kidney injury and chest pain.

Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement.

The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

Prognostic Role of Cardiopulmonary Exercise Testing in Wild-Type Transthyretin Amyloid Cardiomyopathy Patients Treated With Tafamidis.

BACKGROUND: The prognostic value of cardiopulmonary exercise testing (CPET) in patients with wild-type transthyretin cardiac amyloidosis treated with tafamidis is unknown. METHODS AND RESULTS: This retrospective study included patients with wtATTR who underwent baseline cardiopulmonary exercise testing and were treated with tafamidis from August 31, 2018, until March 31, 2020. Univariate logistic and multivariate cox-regression models were used to predict the occurrence of the primary outcome (composite of mortality, heart transplant, and palliative inotrope initiation). A total of 33 patients were included (median age 82 years, interquartile range [IQR] 79-84 years), 84% were Caucasians and 79% were males). Majority of patients had New York Heart Association functional class III disease at baseline (67%). The baseline median peak oxygen consumption (VO2) and peak circulatory power (CP) were 11.35 mL/kg/min (IQR 8.5-14.2 mL/kg/min) and 1485.8 mm Hg/mL/min (IQR 988-2184 mm Hg/mL/min), respectively, the median ventilatory efficiency was 35.7 (IQR 31-41.2). After 1 year of follow-up, 11 patients experienced a primary end point. Upon multivariate analysis, the low peak VO2 (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.79, P = .007], peak CP (HR 0.98, 95% CI 0.98-0.99, P = .02), peak oxygen pulse (HR 0.62, 95% CI 0.39-0.97, P = .03), and exercise duration of less than 5.5 minutes (HR 5.82, 95% CI 1.29-26.2, P = .02) were significantly associated with the primary outcome. CONCLUSIONS: Tafamidis-treated patients with wtATTR who had baseline low peak VO2, peak CP, peak O2 pulse, and exercise duration of less than 5.5 minutes had worse outcomes.

Vitamin D3 attenuates doxorubicin-induced senescence of human aortic endothelial cells by upregulation of IL-10 via the pAMPKα/Sirt1/Foxo3a signaling pathway.

The toxicity of doxorubicin to the cardiovascular system often limits its benefits and widespread use as chemotherapy. The mechanisms involved in doxorubicin-induced cardiovascular damage and possible protective interventions are not well-explored. Using human aortic endothelial cells, we show vitamin D3 strongly attenuates doxorubicin-induced senescence and cell cycle arrest. We further show the protective effects of vitamin D3 are mediated by the upregulation of IL-10 and FOXO3a expression through fine modulation of pAMPKα/SIRT1/FOXO3a complex activity. These results have great significance in finding a target for mitigating doxorubicin-induced cardiovascular toxicity.

Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers (Breast and Prostate) on the Cardiovascular System: Effects and Modifications: A Scientific Statement From the American Heart Association.

Cardiovascular disease and cancer are the leading causes of death in the United States, and hormone-dependent cancers (breast and prostate cancer) are the most common noncutaneous malignancies in women and men, respectively. The hormonal (endocrine-related) therapies that serve as a backbone for treatment of both cancers improve survival but also increase cardiovascular morbidity and mortality among survivors. This consensus statement describes the risks associated with specific hormonal therapies used to treat breast and prostate cancer and provides an evidence-based approach to prevent and detect adverse cardiovascular outcomes. Areas of uncertainty are highlighted, including the cardiovascular effects of different durations of hormonal therapy, the cardiovascular risks associated with combinations of newer generations of more intensive hormonal treatments, and the specific cardiovascular risks that affect individuals of various races/ethnicities. Finally, there is an emphasis on the use of a multidisciplinary approach to the implementation of lifestyle and pharmacological strategies for management and risk reduction both during and after active treatment.

Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

Intraspecific phylogeny of Anopheles (Kerteszia) neivai Howard, Dyar & Knab 1913, based on mitochondrial and nuclear ribosomal genes.

Three mitochondrial regions and a fragment of a large nuclear ribosomal subunit was used to study the evolutionary patterns of An. neivai, a mosquito inhabiting mangroves and tropical forest in the lowland and coastal areas of the Yucatan Peninsula through the Pacific Ecuadorian coast. This species exhibits epidemiological importance regarding Malaria transmission in natural ecosystems, particularly in rural areas of the Pacific Colombian coast. The results based on phylogenetic networks and Bayesian inference showed no robust evidence supporting the existence of previously suggested cryptic species. Diversification patterns in geographically widespread species such as this one, are complex and therefore could impact malaria control strategies. Further studies focused on behavior, morphology, and phylogenomics will improve the understanding of the evolutionary patterns within An. neivai and its role as a disease vector.

[Phylogenetic signal at the Cytb-SertRNA-IG1-ND1 mitochondrial region in Anopheles (Kerteszia) neivai Howard, Dyar & Knab, 1913].

INTRODUCTION: Mitochondrial DNA has proven its utility for the study of insect evolution. Genes such as cytochrome b (Cytb) and the transfer gene for serine (SertRNA) can be used to compare closely related organisms. OBJECTIVE: The phylogenetic utility of Cytb-SertRNA-IG1-ND1 was tested for polymorphisms, and secondary structure modeling in SertRNA was done to detect possible cryptic species in Anopheles neivai. MATERIALS AND METHODS: Specimens from Colombia, Guatemala, and the type locality in Panamá were collected and sequenced for specimen comparison based on DNA polymorphisms, and secondary structure modeling for the SertRNA gene. RESULTS: Thirty-six sequences for A. neivai and A. pholidotus were obtained. CONCLUSIONS: Polymorphic variants were detected in A. neivai for Cytb-SertRNA-IG1- ND1. Despite this variation in A. neivai, cryptic species could not be detected.

Species of sand flies (Diptera: Psychodidae) collected from natural reserves in the Pacific and Darien regions of Colombia.

INTRODUCTION: The departments of Chocó and Antioquia in Colombia show climatic and vegetation conditions favoring the establishment of vector species of the genus Lutzomyia and the transmission of Leishmania spp. to human populations entering conserved forest environments. OBJECTIVE: To report the species of Phlebotomine sandflies present in three natural reserves in the Darien and Pacific regions of Colombia. MATERIALS AND METHODS: Sand flies were collected specifically in the natural reserves El Aguacate (Acandí, Chocó), Nabugá (Bahía Solano, Chocó) and Tulenapa (Carepa, Antioquia). Sand flies were collected with CDC light traps, active search in resting places and Shannon traps. The taxonomic determination of species was based on taxonomic keys. For some species of taxonomic interest, we evaluated the partial sequences of the 5' region of COI gene. RESULTS: A total of 611 adult sand flies were collected: 531 in Acandí, 45 in Carepa and 35 in Bahía Solano. Seventeen species of the genus Lutzomyia, three of the genus Brumptomyia and one of the genus Warileya were identified. The genetic distances (K2P) and grouping supported (>99%) in the neighbor joining dendrogram were consistent for most established molecular operational taxonomic units (MOTU) of the Aragaoi group and clearly confirmed the identity of Lu. coutinhoi. CONCLUSION: Species that have importance in the transmission of leishmaniasis in Acandí, Bahía Solano and Carepa were identified. The presence of Lu. coutinhoi was confirmed and consolidated in Colombia.

Phylogenetic signal at the Cytb-SertRNA-IG1-ND1 mitochondrial region in Anopheles (Kerteszia) neivai Howard, Dyar & Knab, 1913 / Señal filogenética de la región Cytb- SertRNA -IG1-ND1 en Anopheles (Kerteszia) neivai Howard, Dyar & Knab, 1913

Abstract Introduction: Mitochondrial DNA has proven its utility for the study of insect evolution. Genes such as cytochrome b (Cytb) and the transfer gene for serine (SertRNA) can be used to compare closely related organisms. Objective: The phylogenetic utility of Cytb-SertRNA-IG1-ND1 was tested for polymorphisms, and secondary structure modeling in SertRNA was done to detect possible cryptic species in Anopheles neivai. Materials and methods: Specimens from Colombia, Guatemala, and the type locality in Panamá were collected and sequenced for specimen comparison based on DNA polymorphisms, and secondary structure modeling for the SertRNA gene. Results: Thirty-six sequences for A. neivai and A. pholidotus were obtained. Conclusions: Polymorphic variants were detected in A. neivai for Cytb-SertRNA-IG1- ND1. Despite this variation in A. neivai, cryptic species could not be detected.

Resumen Introducción. El ADN mitocondrial ha demostrado su utilidad para el estudio de la evolución en los insectos. Existen algunos genes mitocondriales como el citocromo b (Cytb) y el gen de transferencia para el aminoácido serina (SertRNA) que pueden usarse en el diagnóstico de especies estrechamente relacionadas. Objetivo. Explorar la utilidad filogenética de la región Cytb-SertRNA-IG1-ND1 para detectar posibles especies crípticas en Anopheles neivai. Materiales y métodos. Se recolectaron especímenes en Colombia, Guatemala y en la localidad tipo en Panamá, los cuales se secuenciaron y se compararon mediante el polimorfismo de ADN en toda la región y mediante la simulación de estructuras secundarias del gen SertRNA. Resultados. Se obtuvieron las secuencias de especímenes de A. neivai (34) y A. pholidotus (2). Conclusiones. Se detectaron algunos polimorfismos para la regiónCytb-SertRNA-IG1-ND1 en A. neivai, pero no así especies crípticas.

Especies de flebotomíneos (Diptera: Psychodidae) recolectados en reservas naturales de las regiones del Darién y del Pacífico en Colombia / Species of sand flies (Diptera: Psychodidae) collected from natural reserves in the Pacific and Darien regions of Colombia

Resumen Introducción. Los departamentos de Chocó y Antioquia en Colombia presentan condiciones climáticas y de vegetación que favorecen el establecimiento de especies de vectores del género Lutzomyia y la transmisión de Leishmania spp. a poblaciones humanas que ingresan a ambientes selváticos conservados. Objetivo. Reportar las especies de flebotomíneos presentes en tres reservas naturales de las regiones del Darién y del Pacífico en Colombia. Materiales y métodos. Los flebotomíneos se recolectaron en las reservas naturales El Aguacate (Acandí, Chocó), Nabugá (Bahía Solano, Chocó) y Tulenapa (Carepa, Antioquia). La recolección se hizo con trampas de luz CDC, mediante búsqueda activa en sitios de reposo y con trampas Shannon. La determinación taxonómica de especies se basó en las claves taxonómicas. En algunas especies de interés taxonómico, se evaluó el uso de secuencias parciales de la región 5' del gen COI. Resultados. Se recolectaron 611 flebotomíneos adultos: 531 en Acandí, 45 en Carepa y 35 en Bahía Solano. Se identificaron 17 especies del género Lutzomyia, tres del género Brumptomyia y una del género Warileya. Las distancias genéticas (K2P) y los soportes de agrupación (>99 %) en el dendrograma de neighbor joining correspondieron a la mayoría de unidades taxonómicas operacionales moleculares (Molecular Operational Taxonomic Units, MOTU) establecidas para el grupo Aragaoi y confirmaron claramente la identidad de Lu. coutinhoi. Conclusión. Se identificaron especies que tienen importancia en la transmisión de la leishmaniasis en Acandí, Bahía Solano y Carepa. Se confirmó la presencia de Lu. coutinhoi en Colombia.

Abstract Introduction: The departments of Chocó and Antioquia in Colombia show climatic and vegetation conditions favoring the establishment of vector species of the genus Lutzomyia and the transmission of Leishmania spp. to human populations entering conserved forest environments. Objective: To report the species of Phlebotomine sandflies present in three natural reserves in the Darien and Pacific regions of Colombia. Materials and methods: Sand flies were collected specifically in the natural reserves El Aguacate (Acandí, Chocó), Nabugá (Bahía Solano, Chocó) and Tulenapa (Carepa, Antioquia). Sand flies were collected with CDC light traps, active search in resting places and Shannon traps. The taxonomic determination of species was based on taxonomic keys. For some species of taxonomic interest, we evaluated the partial sequences of the 5' region of COI gene. Results: A total of 611 adult sand flies were collected: 531 in Acandí, 45 in Carepa and 35 in Bahía Solano. Seventeen species of the genus Lutzomyia, three of the genus Brumptomyia and one of the genus Warileya were identified. The genetic distances (K2P) and grouping supported (>99%) in the neighbor joining dendrogram were consistent for most established molecular operational taxonomic units (MOTU) of the Aragaoi group and clearly confirmed the identity of Lu. coutinhoi. Conclusion: Species that have importance in the transmission of leishmaniasis in Acandí, Bahía Solano and Carepa were identified. The presence of Lu. coutinhoi was confirmed and consolidated in Colombia.

Molecular operational taxonomic units of mosquitoes (Diptera: Culicidae) collected in high Andean mountain ecosystems of Antioquia, Colombia.

Accurate taxonomic identification of highland mosquito species may be complicated because of the lack of comprehensive regional morphological keys and taxonomic specialists, particularly for mosquitoes of medical or ecological importance. We applied a multi-locus approach to explore the diversity of genera/species collected, to define the Molecular Operational Taxonomic Units (MOTUs) and to perform phylogenetic clustering. Twenty MOTUs and three single sequences were revealed from 78 concatenated cox1 + ITS2 sequences, and the species name was allocated for five of these. This study provides molecular taxonomic information of culicid fauna present in high Andean mountain ecosystems in Antioquia, Colombia. However, future morphological and integrative taxonomic studies should be conducted to achieve the specific identity of all detected MOTUs.

Use of DNA barcoding to distinguish the malaria vector Anopheles neivai in Colombia.

A reference 535 bp barcode sequence from a fragment of the mitochondrial gene cytochrome oxidase I (COI), acquired from specimens of An. neivai Howard, Dyar & Knab, 1913 from its type locality in Panama, was used as a tool for distinguishing this species from others in the subgenus Kerteszia. Comparisons with corresponding regions of COI between An. neivai and other species in the subgenus (An. bellator Dyar & Knab 1906, An. homunculus Komp 1937, An cruzii Dyar & Knab, 1908 and An. laneanus Corrêa & Cerqueira, 1944) produced K2P genetic distances of 8.3-12.6%, values well above those associated with intraspecific variation. In contrast, genetic distances among 55 specimens from five municipalities in the Colombian Pacific coastal state of Chocó were all within the range of 0-2.5%, with an optimized barcode threshold of 1.3%, the limit for unambiguous differentiation of An. neivai. Among specimens from the Chocó region, 18 haplotypes were detected, two of which were widely distributed over the municipalities sampled. The barcode sequence permits discrimination of An. neivai from sympatric species and indicates genetic variability within the species; aspects key to malaria surveillance and control as well as defining geographic distribution and dispersion patterns.

Partial Brain Tissue Oxygen Levels Predict Arrhythmia and Prognosis in Patients With Brain Injury.

The objective of this study was to examine the clinical determinants of incidence and prognosis of arrhythmias in the setting of acute brain injury. Acute brain injury is known to cause electrocardiographic abnormalities and cardiac arrhythmias. The relation between partial brain tissue oxygen (PBTO) and intracranial pressure (ICP) with arrhythmia incidence and prognosis remains unknown. Consecutive patients with acute brain injury and intracranial bleed admitted to the neurosurgical intensive care unit were enrolled in the study. Baseline characteristics [demographics, medical history, etiology of brain injury, Glasgow Coma Scale (GCS) score, blood pressure, and respiratory rate] were documented. Patient's telemetry recordings were reviewed for daily mean heart rates and arrhythmias. If arrhythmia was noted, PBTO levels at the beginning of arrhythmia, ICP, brain tissue temperature, and outcomes were recorded. A total of 106 subjects (53% men, age 39 ± 18 years, 65 traumatic and 41 nontraumatic brain injuries) were studied. Overall, 62% of subjects developed a total of 241 arrhythmia episodes. Ventricular arrhythmias were associated with significantly higher daily mean heart rates, low PBTO levels, and low GCS scores, whereas atrial arrhythmias were associated with lower daily mean heart rates, normal PBTO levels, and higher GCS and ICP. Three or more episodes of arrhythmia predicted worse outcomes, including mortality (P = 0.001). In patients with acute brain injury, poor PBTO levels are associated with higher incidence of ventricular tachyarrhythmias. In contrast, atrial tachyarrhythmias occur in patients with normal PBTO levels and higher ICP. Incidence of ventricular arrhythmia in those with poor PBTO is associated with increased mortality.

Cardio-Oncology Training: A Proposal From the International Cardioncology Society and Canadian Cardiac Oncology Network for a New Multidisciplinary Specialty.

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field.