Auswahl der wissenschaftlichen Literatur zum Thema „Time-Of-Day administration of immunotherapy“

e16537 Background: Circadian rhythm influences adaptive immune response. In recent years, some studies have suggested a relationship between the time of day of immune checkpoint inhibitor (ICI) infusions and disease outcomes among cancer patients. Evening infusions (after 4:30 pm) are associated with shorter overall survival. This study aims to determine whether the time of day of immunotherapy infusion affects the efficacy of treatment in patients with metastatic renal cell cancer (mRCC) in a Mexican population. Methods: This is an observational, retrospective, single-center study that included patients with mCRC treated with Nivolumab plus Ipilimumab in first line diagnosed between 2018 and 2023. Patients who received <20% of infusions after 4:30 pm were assigned to early time of infusion (TOI) group, while patients who received ≥20% of infusions after that time were assigned to late TOI group. The primary end point was overall survival (OS), and the secondary end point was overall response rate (ORR). Both groups were compared using Kaplan-Meier analysis and Cox regression model. Results: 127 patients were included in the analysis. Most of the population were men (70.1%). Median age was 62 years. In addition, 100% had clear cell histology and 96% had intermediate/poor-risk disease. The early TOI group included 84 (66%) patients, while 43 patients were assigned to the late TOI group. In the overall population, median OS in the early TOI group was 64.8 months (95% CI, 53.4-68.8) versus 46.3 months (95% CI, 22.5-61.4) in the late TOI group, with a hazard ratio (HR) of 0.67 (95% CI, 0.51-0.83; p=0.03). Improvement in OS with early administration of therapy was seen across all subgroups that were evaluated. The impact of time of day of ICI administration was greater in patients with intermediate/poor-risk disease (median OS 56.4 months [95% CI 41.4-67.2] in the early TOI group versus 36.8 months [95% CI 18.9-51.3] in the late TOI group, HR 0.52 [95% CI 0.37-0.85]; p=0.002). In the overall population, the ORR was higher in the early TOI group (32.8% versus 22.4%; p= 0.04), with similar results in patients with intermediate and high-risk disease (34.5% versus 21.6%, and 30.5% versus 24.8% respectively). In the multivariate analysis, time-of-day administration of immunotherapy was an independent prognostic factor for death. Conclusions: Our results demonstrated improved OS and ORR in ICI-treated patients who received most infusions before 4:30 pm, particularly in patients with intermediate/poor-risk mRCC, in line with the findings of previous analyzes showing that chronomodulation influences the efficacy of immunotherapy. This is the first work in a Mexican population. Although larger prospective and controlled studies are necessary, early ICI infusion is a practical, safe and reasonable strategy that could be considered in the treatment of Mexican patients with metastatic renal cell cancer.

e16541 Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.

98 Background: With approvals across multiple cancer types and favorable toxicity profiles, oncologists may consider using immunotherapy (IMT) while their patients are hospitalized. Inpatient IMT may be cost-prohibitive to administer for most institutions due to high cost and inpatient payment structure, but little data are available to evaluate outcomes for IMT in hospitalized patients. We investigated the survival benefit of administering IMT to hospitalized patients with cancer at an NCI-designated cancer center. Methods: We conducted a retrospective chart review of all patients receiving ipilimumab, nivolumab, or pembrolizumab during inpatient admission at Dana-Farber Cancer Institute/Brigham & Women’s Hospital in 2017. For each patient, we assessed: total dose, indication for dosing, cancer type, time between dose and discharge, time between discharge and death, and total cost (average wholesale price). Study follow up was January 1, 2017 to July 1, 2018. Results: Fifty doses of IMT were administered to 44 patients. Most patients (40) received 1 dose, 2 patients received 3 doses, 1 patient received 2 doses, and 1 patient received a combination of ipilimumab/nivolumab. The most common cancer types were lung (41%), gastrointestinal (18%), and head and neck (16%). Indications for IMT administration were: patient due for next dose (48%), disease progression (42%), and new diagnosis (11%). The majority of doses (70%) were received within 7 days prior to discharge, with 32% of doses within 1 day of discharge. The majority of patients (86%) died in the study period; 14% of patients died during admission. Average survival between discharge and death was 54 days (range: 0-444 days). Total cost of inpatient IMT administration was $413,370, an average of $9,395 per patient. Conclusions: To our knowledge, this is the largest analysis of outcomes for patients receiving IMT during a hospitalization. Inpatient use of IMT in cancer patients is associated with high cost and poor clinical outcomes. Dosing within one week prior to hospital discharge was common. Clinical factors such as PD-L1 status, disease status, and reason for admission, which may be important to understand which patients may benefit most from inpatient IMT, should be examined.

e18225 Background: With approvals across multiple cancer types and favorable toxicity profiles, oncologists may consider using immunotherapy (IMT) while their patients are hospitalized. Inpatient IMT may be cost-prohibitive to administer for most institutions due to high cost and inpatient payment structure, but little data are available to evaluate outcomes for IMT in hospitalized patients. We investigated the survival benefit of administering IMT to hospitalized patients with cancer at an NCI-designated cancer center. Methods: We conducted a retrospective chart review of all patients receiving ipilimumab, nivolumab, or pembrolizumab during inpatient admission at Dana-Farber Cancer Institute/Brigham & Women’s Hospital in 2017. For each patient, we assessed: total dose, indication for dosing, cancer type, time between dose and discharge, time between discharge and death, and total cost (average wholesale price). Study follow up was January 1, 2017 to July 1, 2018. Results: Fifty doses of IMT were administered to 44 patients. Most patients (40) received 1 dose, 2 patients received 3 doses, 1 patient received 2 doses, and 1 patient received a combination of ipilimumab/nivolumab. The most common cancer types were lung (41%), gastrointestinal (18%), and head and neck (16%). Indications for IMT administration were: patient due for next dose (48%), disease progression (42%), and new diagnosis (11%). The majority of doses (70%) were received within 7 days prior to discharge, with 32% of doses within 1 day of discharge. The majority of patients (86%) died in the study period; 14% of patients died during admission. Average survival between discharge and death was 54 days (range: 0-444 days). Total cost of inpatient IMT administration was $413,370, an average of $9,395 per patient. Conclusions: To our knowledge, this is the largest analysis of outcomes for patients receiving IMT during a hospitalization. Inpatient use of IMT in cancer patients is associated with high cost and poor clinical outcomes. Dosing within one week prior to hospital discharge was common. Clinical factors such as PD-L1 status, disease status, and reason for admission, which may be important to understand which patients may benefit most from inpatient IMT, should be examined.

e18768 Background: Unplanned complications of outpatient chemotherapy can significantly affect patient oncologic outcomes, health, and increase cost of care. CMS rule OP-35 evaluates quality of care for Medicare patients by assessing the risk of emergency department (ED) visit within 30 days after outpatient chemotherapy administration. This study reviews this measure for all oncology patients treated in our community hospital setting. Methods: Patients treated between 02/2012 and 04/2021 were identified. Age at first chemotherapy administration, gender, cancer diagnosis, and chemotherapy regiment were evaluated. Chemotherapy was stratified into cytotoxic therapy, immunotherapy, targeted therapy, and endocrine therapy. ED visits were only those in our hospital system. 30-day risk of ED visit was calculated for individual chemotherapy administrations. Internal results were compared with our CMS OP-35 results for concordance. Results: There were 19,732 patients who received chemotherapy treatments between 02/2012 and 04/2021, with 262,379 chemotherapy administrations. Individual chemotherapy administration had 5.2% risk of a 30 day ED visit. Cumulative risk of a patient having a 30 day ED visit was 32.9%. From ED, patients had 61.2% rate of hospital admission, vs 24.8% rate for general ED population. By age at first chemotherapy administration, the risk of 30 day ED visit was 6.3% for age < 18, 5.4% for age 18-64, and 5.9% for age > = 65. Our rate was relatively stable between 2014 and 2020. Our corresponding CMS score was 5.5% in 2016, 5.5% in 2018, and 5.1% in 2019. By gender, the risk was 5.6% for male and 5.0% for female patients. By chemotherapy category, the risk was 5.9% for cytotoxic chemotherapy, 7.5% for immunotherapy, 4.2% for targeted therapy, and 5.2% for endocrine therapy. Carboplatin/paclitaxel was the most common drug combination administered, with 8.7% risk. Cytarabine/methotrexate combination had the highest risk at 57.0%. By ICD diagnosis, breast cancer accounted for most patients and most chemotherapy administrations, with 30 day ED visit risk of 3.6%. Multiple myeloma had the highest rate of chemotherapy administrations at 26.3 per patient and a risk of 4.0%, compared with 13.3 across the entire population. Stomach cancer had the highest risk of 30 day ED visit at 10.0%. Conclusions: The risk of 30 day unplanned ED visit was elevated in pediatric patients, and was similar in patients 18-64 and > = 65 years of age, and corresponded well to our CMS OP-35 metric, despite only tracking internal ED visits. Immunotherapy had significantly elevated risk compared with cytotoxic therapy, while targeted therapy had the lowest risk of ED visit. There were significant differences depending on disease site. We have established a baseline, and developed a live dashboard in our electronic medical record to monitor this metric globally, and to intervene in patients at high risk of 30 day ED visit.

Aims and Background The theraputic role of chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial because of its potentially detrimental action on host anticancer defenses. On the contrary, IL-2 would seem to prolong survival time by improving the immune status, even though it is generally less effective in determining tumor regression in NSCLC. Our previous studies have suggested the possibility of increasing tumor sensitivity to IL-2 by concomitant administration of immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On this basis, a study was carried out to evaluate the efficacy of immunotherapy with low-dose IL-2 plus MLT versus chemotherapy in advanced NSCLC. Methods The study included 60 patients with locally advanced or metastatic NSCLC, who were randomized to receive immunotherapy or chemotherapy. The immunotherapy consisted of IL-2 (3 million IU/day subcutaneously for 6 days/week for 4 weeks) and MLT (40 mg/day orally every day, starting 7 days before IL-2); in nonprogressing patients, a second cycle was repeated after a 21-day rest period, then they underwent a maintenance period consisting of one week of therapy every month until progression. Chemotherapy consisted of cisplatin (20 mg/m2) and etoposide (100 mg/m2)/day intravenously for 3 days; cycles of chemotherapy were repeated every 21 days until progression. Results No complete response was obtained. A partial response was achieved in 7/29 patients treated with chemotherapy and in 6/31 patients receiving chemotherapy. The difference was not significant. In contrast, the mean progression-free period and the percentage survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with chemotherapy. Toxicity was substantially lower in patients receiving immunotherapy than in those given chemotherapy. Conclusions This randomized study showed that immunotherapy with low-dose IL-2 plus MLT is a better tolerated and more effective therapy in terms of survival time than chemotherapy containing cisplatin in patients affected by advanced NSCLC.

Five years ago, on November 23, 2015, the US Food and Drug Administration (FDA) approved nivolumab for the treatment of metastatic renal cell carcinoma, thus ushering in a new era of immunotherapy for this tumor. The purpose of this review is to systematize the accumulated results of studies of nivolumab in monotherapy and in combinations.

The only causative treatment for IgE-mediated allergies is allergen-specific immunotherapy. However, fewer than 5% of allergy patients receive immunotherapy because of its long duration and risk of allergic side effects. We aimed at enhancing s.c. immunotherapy by direct administration of allergen into s.c. lymph nodes. The objective was to evaluate safety and efficacy compared with conventional s.c. immunotherapy. In a monocentric open-label trial, 165 patients with grass pollen-induced rhinoconjunctivitis were randomized to receive either 54 s.c. injections with pollen extract over 3 years [cumulative allergen dose 4,031,540 standardized quality units (SQ-U)] or 3 intralymphatic injections over 2 months (cumulative allergen dose 3,000 SQ-U). Patients were evaluated after 4 months, 1 year, and 3 years by nasal provocation, skin prick testing, IgE measurements, and symptom scores. Three low-dose intralymphatic allergen administrations increased tolerance to nasal provocation with pollen already within 4 months (P < 0.001). Tolerance was long lasting and equivalent to that achievable after standard s.c. immunotherapy (P = 0.291 after 3 years). Intralymphatic immunotherapy ameliorated hay fever symptoms (P < 0.001), reduced skin prick test reactivity (P < 0.001), decreased specific serum IgE (P < 0.001), caused fewer adverse events than s.c. immunotherapy (P = 0.001), enhanced compliance (P < 0.001), and was less painful than venous puncture (P = 0.018). In conclusion, intralymphatic allergen administration enhanced safety and efficacy of immunotherapy and reduced treatment time from 3 years to 8 weeks.

Abstract Background: Activated Targeted Killer (ATAK) cells are a cellular immunotherapy which protects neutropenic mice from invasive candidiasis and aspergillosis. However,the lifespan and distribution of ATAK cells into organs has not been determined in vivo. Methods: ATAK cells were stably transfected with a luminescence reporter system. Neutropenic mice were imaged by IVIS after administration of coelentrazine substrate. RT-PCR was used to confirm the luminescence results. Results: On day 1 after ATAK cell administration, livers, kidneys, and spleens were infiltrated by the ATAK cells. By day 3, cells had infiltrated more significantly into the spleen, and also spread into the lungs. By day 5, cell signal began to wane. By day 8, the day after neutrophil recovery, there was no detectable signal. By RT-PCR, viable cells were detected at 6 hours and 3 days after treatment. By day 5, no mRNA was detected. Mouse immunity to ATAK cells was detectable by ELISA and flow cytometry post-neutrophil recovery. Discussion: ATAK cells are viable and circulate widely into visceral organs in neutropenic mice, commensurate with their ability to protect mice from tissue invasive fungal infections. Hence the cells can provide protection during the critical neutropenic period yet the risk of engraftment is minimized by host-versus-graft affect after marrow recovery.

Mieux comprendre les mécanismes physiopathologiques et mieux cibler les traitements, selon les caractéristiques de la personne et de sa tumeur, font l'objet de recherches intensives , dans le cadre de la médecine cancérologique de précision et personnalisée. Celle-ci commence à intégrer les horloges circadiennes moléculaires, qui génèrent des oscillations périodiques d'environ 24 h du métabolisme, de la prolifération et de la mort cellulaire, ainsi que des réponses aux substances toxiques ou thérapeutiques. De nombreuses études expérimentales, cliniques et épidémiologiques ont montré le rôle important du système circadien dans toutes les étapes de la cancérogenèse, depuis l'initiation et la promotion jusqu'à la progression et la dissémination métastatique. Le système circadien influence aussi la tolérance et l'efficacité des traitements anticancéreux tant dans les modèles expérimentaux que chez les patients. Constatant une apparente grande homogénéité des réponses temporelles à l'immunothérapie des cancers dans ma pratique clinique, j'ai recherché le rôle du moment d'administration et des rythmes circadiens dans l'efficacité des inhibiteurs de points-de-contrôle immunologiques. En effet, cette dernière décade a vu émerger l'immunothérapie comme traitement de référence de plusieurs types de cancer. Cependant tous les patients n'en bénéficient pas, et la guérison ne concerne qu'un faible nombre d'entre eux. Mon travail de thèse a d'abord mis en évidence le rôle de l'heure d'administration des inhibiteurs de point de contrôle immunologique sur leur efficacité et leur tolérance chez des patients atteints de cancer du poumon non-à petites cellules, avec notamment un quadruplement de la survie des patients traités le matin en comparaison de l'après-midi ou la soirée. J'ai ensuite montré, dans une première méta-analyse puis dans une revue de synthèse, que l'administration matinale de l'immunothérapie doublait en moyenne la survie et la survie sans progression des patients atteints de huit types différents de cancer. J'ai alors proposé les mécanismes circadiens principaux capables d'influencer l'efficacité de l'immunothérapie au cours des 24 heures. Enfin, mon travail montre que l'administration matinale d'un inhibiteur de point de contrôle immunologique permet aussi de doubler son efficacité en comparaison d'une administration l'après-midi, malgré son association avec une chimiothérapie immunosuppressive. De plus, les horaires des quatre premiers cycles récapitulent de façon satisfaisante la quasi-intégralité de l'effet chrono-immunothérapeutique. En conclusion, la découverte d'un impact majeur de l'heure d'administration de l'immunothérapie anticancéreuse sur son efficacité est en faveur d'une synchronisation inter-patients des mécanismes circadiens de sa pharmacodynamie vis-à-vis des cellules du système immunitaire. La caractérisation des différences inter-patients de la synchronisation circadienne pourrait encore permettre l'optimisation personnalisée de cette chronoimmunothérapie
A better understanding of physiopathological mechanisms and better-targeted treatments, according to the characteristics of the patient and his/her tumor, are the focus of intensive research, within the framework of precision and personalized cancer medicine. Precision medicine is now beginning to integrate molecular circadian clocks, which generate periodic oscillations of around 24 h in metabolism, cell proliferation and death, as well as responses to toxic or therapeutic drugs. Several experimental, clinical and epidemiological studies have demonstrated the important role of the circadian timing system in all stages of carcinogenesis, from initiation and promotion to progression and metastatic dissemination. The circadian timing system also influences tolerance and efficacy of anti-cancer treatments, both in experimental models and in patients. After my initial observation of an apparent great homogeneity in the temporal responses to cancer immunotherapy in my clinical practice, I have been investigating the role of dosing time and circadian rhythms in the efficacy of immune checkpoint inhibitors. Indeed, immunotherapy has emerged as a standard anticancer treatment for several cancer types in the last decade. However, not all patients benefit from it, and only a small number are cured. My current thesis project results first highlighted the role of the time of administration of immune checkpoint inhibitors on their efficacy and tolerability in patients with non-small cell lung cancer, with a four-fold increase in survival of patients treated in the morning compared with the afternoon or evening. I then showed, in a first meta-analysis and then in a review, that morning administration of immunotherapy doubled on average the survival and progression-free survival of patients with eight different types of cancer. I then propose the main circadian mechanisms that can influence the efficacy of immunotherapy over the course of 24 hours. Finally, my work shows that morning administration of an immune checkpoint inhibitor also doubles its efficacy compared with afternoon administration, despite its combination with immunosuppressive chemotherapy. Moreover, the administration times of the first four immunochemotherapy cycles recapitulate the chrono-immunotherapeutic effect of the treatment over its full duration the vast entire. In conclusion, the discovery of a major impact of the time of administration of cancer immunotherapy on its efficacy is in favor of between-patient synchronization of the circadian mechanisms of its pharmacodynamics vis-à-vis immune system cells. The characterization of between-patient differences in circadian synchronization could further enable personalized optimization of cancer chronoimmunotherapy

This thesis reports a phenomenological study of the lived experiences of six female beginning directors of Queensland child care centres. The perspectives of the participants were shared with the researcher over a five-month period through interviews, synergetic focus groups and drawings. Their stories revealed leaders inprocess who, being faced with new contexts, were forced to reconsider values and beliefs about themselves and the meaning of leadership. They described themselves as jugglers of multiple roles and relationships which often seemed overwhelming, particularly within time constraints. Their stories, however, reveal resilient women who variously struggled, coped, coped competently and were transformed through their experiences. Self-awareness is, of essence, an individual self-directed journey. The study presents strategies to provide safe and secure situations for shared and individual exploration of self. This thesis argues that we need to reconceptualise leadership in terms of time and in dispelling delusions of goodness in leaders and followers. It argues that, for beginning directors to 'find themselves', as one participant described the process, they need safe and secure situations that support the self-awareness journey necessary to navigate their new contexts as leaders. This, in turn, stands to support higher levels of authenticity, self-esteem, motivation, and resilience for the individual, as well as increased trust within the organisation. The study presents a model for supporting beginning leaders toward resilience and authenticity. It is based on the essentialness of self-awareness to becoming a leader. Moreover, the study has implications for the public good as it informs policy and legislation governing early childhood centres in Queensland and early childhood training courses. Implications for the private good involve supporting beginning directors toward a greater understanding of their multiple roles, and, themselves within those roles.

The courts and professional organizations recognize access to clinically appropriate and timely treatment with psychotropic medication as an essential element of an adequate correctional mental health system. While receiving treatment, incarcerated patients must be monitored and supervised clinically so that optimal patient outcomes are achieved. For many mentally ill inmates incarceration is an opportunity to receive treatment that was not accessible in the community; in one study only one third of those diagnosed with schizophrenia or bipolar disorder were receiving medication at the time of arrest compared to two thirds during incarceration. There are many steps, people, and processes involved in getting medication to the patient within a correctional facility. The major components of pharmacy services are prescribing, dispensing, distribution and continuity. The structural aspects of medication administration can also be altered to improve adherence. These include simplifying the medication regime by reducing the number of doses each day, changing to a long acting preparation, and administering medication at times and in ways that are safer and more convenient for the patient and yet clinically acceptable. Reducing reasons for medication discontinuity due to transfers and schedule conflicts also reduces the incidence of adverse events and optimizes treatment efficacy. Almost universally, all medication administration to psychiatric patients in jails and prisons is through directly observed therapy. This allows for opportunities and challenges for correctional patient care in medication lines and on cell blocks or dormitories. This chapter reviews the structural, procedural, and clinical concerns of medication administration and management in jails and prisons.

The courts and professional organizations recognize access to clinically appropriate and timely treatment with psychotropic medication as an essential element of an adequate correctional mental health system. While receiving treatment, incarcerated patients must be monitored and supervised clinically so that optimal patient outcomes are achieved. For many mentally ill inmates incarceration is an opportunity to receive treatment that was not accessible in the community; in one study only one third of those diagnosed with schizophrenia or bipolar disorder were receiving medication at the time of arrest compared to two thirds during incarceration. There are many steps, people, and processes involved in getting medication to the patient within a correctional facility. The major components of pharmacy services are prescribing, dispensing, distribution and continuity. The structural aspects of medication administration can also be altered to improve adherence. These include simplifying the medication regime by reducing the number of doses each day, changing to a long acting preparation, and administering medication at times and in ways that are safer and more convenient for the patient and yet clinically acceptable. Reducing reasons for medication discontinuity due to transfers and schedule conflicts also reduces the incidence of adverse events and optimizes treatment efficacy. Almost universally, all medication administration to psychiatric patients in jails and prisons is through directly observed therapy. This allows for opportunities and challenges for correctional patient care in medication lines and on cell blocks or dormitories. This chapter reviews the structural, procedural, and clinical concerns of medication administration and management in jails and prisons.

Since the communautarisation of the Schengen acquis, the EU is meant to build a system of ‘integrated border management’ (IBM) to help ensuring the administration of migratory flows ‘at all their stages’. The idea is that effective entry control cannot be based solely on checks at the external borders of the Member States but ‘must cover every step taken by a third country national from the time he begins his journey to the time he reaches his destination’. EU entry/pre-entry controls thus comprise a series of extraterritorial measures carried out abroad. This chapter describes this evolution in detail. It traces the origins and development of IBM, covering institutional, constitutional, as well as legal and political changes to the present day. The recognition that the ‘strengthening of European border controls should not prevent access to protection systems by those people entitled to benefit under them’ is introduced also at this stage, providing the starting point to the entire research.

Covering material from the time of Julius Caesar to the sack of Rome, this topically arranged reference set provides substantive entries on people, cities, government, institutions, military developments, material culture, and other topics related to the Roman Empire. The Roman Empire was one of the greatest and most influential forces of the ancient world, and many of its achievements endure in one form or another to this day. Because of its geographic breadth, cultural diversity, and overall complexity, it is also one of the most difficult organizations to understand. This book focuses on the Roman Empire from the time of Julius Caesar to the sack of Rome. While most references on the Roman world provide a series of alphabetically arranged entries, this work is organized in broad topical chapters on government and politics, administration, individuals, groups and organizations, places, events, military developments, and objects and artifacts. Each section provides 20 to 30 substantive entries along with an overview essay. The work also provides a selection of primary source documents and closes with a bibliography of important print and electronic resources.

Covering material from the time of Julius Caesar to the sack of Rome, this topically arranged reference set provides substantive entries on people, cities, government, institutions, military developments, material culture, and other topics related to the Roman Empire. The Roman Empire was one of the greatest and most influential forces of the ancient world, and many of its achievements endure in one form or another to this day. Because of its geographic breadth, cultural diversity, and overall complexity, it is also one of the most difficult organizations to understand. This book focuses on the Roman Empire from the time of Julius Caesar to the sack of Rome. While most references on the Roman world provide a series of alphabetically arranged entries, this work is organized in broad topical chapters on government and politics, administration, individuals, groups and organizations, places, events, military developments, and objects and artifacts. Each section provides 20 to 30 substantive entries along with an overview essay. The work also provides a selection of primary source documents and closes with a bibliography of important print and electronic resources.

BURUNDI: THE STATE AND SOCIETY (FROM THE COLONIAL PERIOD UNTIL THE PRESENT DAY) Burundi, a small country located in east-central Africa, is one of the most unstable countries on the continent. Similarly to the neighbouring Rwanda, over the last 50 years, the country has suffered tragic consequences of a civil war resulting from the conflict between politicians from the Tutsi and Hutu ethnic groups. The presented monograph covers a period of 130 years in a chronological manner, starting from the establishment of the foundations of the European colonial administration in the 1890s; however, the main emphasis is placed on the problems connected with the development of an independent country and strengthening (or even establishing) the national identity of its citizens. Burundi gained independence in 1962; the existing time gap allows for drawing certain conclusions and conducting an evaluation of the first 50 years of the independent existence of the country, which has little prospect of really changing the unfavorable development trends of, at least, the last three decades. At the moment, there are still no positive indications of a possible stable development of the country in the future, and the relatively stable years of the first half of the 20th century have been overshadowed by the subsequent decades of coups, genocides, and the governments’ lack of will to effectively establish peace and the rule of law.

Oxygen administration is the most commonly used therapy in emergency medicine. It is given to 18,000 patients in the United Kingdom every day, and 14% of patients in hospital receive it at some time during their stay. Whilst some of this activity is helpful, or indeed lifesaving, in some patients, oxygen can lead to harm, or even death. The domiciliary use of oxygen is also an area in which there is the potential for both waste and harm. When appropriately used, it prolongs life and provides valuable symptom relief; yet, in up to 43% of the cases, such therapy was either not used by patients as directed or provided no clinical benefit. At an annual cost in excess of £110 million, this is a lot of waste. This chapter examines the use of oxygen in both the acute setting and the assessment for home oxygen, with a focus on the pathophysiology behind oxygen therapy and the potential dangers.

It's time to revisit Watergate. In this compelling reexamination, Liebovich draws extensively from newly available sources, including recently released Nixon Oval Office tapes, FBI reports, and personal reminiscences of cover-up leader John Dean. Liebovich sheds new light on the Nixon administration's extensive foul play, zeal to battle and manipulate the press, scandalous miring, and eventual political disgrace. After detailing the nation's news media coverage of the Watergate debacle and the ensuing breakup of American politics, Liebovich recounts the scandal's long-lasting, corrosive effect on presidential and popular politics. Scholars and students of the media and latter-20th-century American political malaise will be provoked and persuaded by Liebovich's argument that much of the public's cynicism toward the press, the president, and politics stems from the bitter battles-fought in the White House, on the front pages, and on television screens-between the press and Nixon's administration. The book focuses on the fight against a press perceived as hostile to the President and charts how the nation's major newspapers and magazines covered the unfolding scandal. Newly released sources show how Nixon and his advisors immersed themselves so deeply in a maze of deception and mistrust that none involved could extricate themselves, creating a political tragedy that haunts us to this day.

Nationalism: Past as Prologue began as a single volume being compiled by Ad Akande, a scholar from South Africa, who proposed it to me as co-author about two years ago. The original idea was to examine how the damaging roots of nationalism have been corroding political systems around the world, and creating dangerous obstacles for necessary international cooperation. Since I (Bruce E. Johansen) has written profusely about climate change (global warming, a.k.a. infrared forcing), I suggested a concerted effort in that direction. This is a worldwide existential threat that affects every living thing on Earth. It often compounds upon itself, so delays in reducing emissions of fossil fuels are shortening the amount of time remaining to eliminate the use of fossil fuels to preserve a livable planet. Nationalism often impedes solutions to this problem (among many others), as nations place their singular needs above the common good. Our initial proposal got around, and abstracts on many subjects arrived. Within a few weeks, we had enough good material for a 100,000-word book. The book then fattened to two moderate volumes and then to four two very hefty tomes. We tried several different titles as good submissions swelled. We also discovered that our best contributors were experts in their fields, which ranged the world. We settled on three stand-alone books:” 1/ nationalism and racial justice. Our first volume grew as the growth of Black Lives Matter following the brutal killing of George Floyd ignited protests over police brutality and other issues during 2020, following the police assassination of Floyd in Minneapolis. It is estimated that more people took part in protests of police brutality during the summer of 2020 than any other series of marches in United States history. This includes upheavals during the 1960s over racial issues and against the war in Southeast Asia (notably Vietnam). We choose a volume on racism because it is one of nationalism’s main motive forces. This volume provides a worldwide array of work on nationalism’s growth in various countries, usually by authors residing in them, or in the United States with ethnic ties to the nation being examined, often recent immigrants to the United States from them. Our roster of contributors comprises a small United Nations of insightful, well-written research and commentary from Indonesia, New Zealand, Australia, China, India, South Africa, France, Portugal, Estonia, Hungary, Russia, Poland, Kazakhstan, Georgia, and the United States. Volume 2 (this one) describes and analyzes nationalism, by country, around the world, except for the United States; and 3/material directly related to President Donald Trump, and the United States. The first volume is under consideration at the Texas A & M University Press. The other two are under contract to Nova Science Publishers (which includes social sciences). These three volumes may be used individually or as a set. Environmental material is taken up in appropriate places in each of the three books. * * * * * What became the United States of America has been strongly nationalist since the English of present-day Massachusetts and Jamestown first hit North America’s eastern shores. The country propelled itself across North America with the self-serving ideology of “manifest destiny” for four centuries before Donald Trump came along. Anyone who believes that a Trumpian affection for deportation of “illegals” is a new thing ought to take a look at immigration and deportation statistics in Adam Goodman’s The Deportation Machine: America’s Long History of Deporting Immigrants (Princeton University Press, 2020). Between 1920 and 2018, the United States deported 56.3 million people, compared with 51.7 million who were granted legal immigration status during the same dates. Nearly nine of ten deportees were Mexican (Nolan, 2020, 83). This kind of nationalism, has become an assassin of democracy as well as an impediment to solving global problems. Paul Krugman wrote in the New York Times (2019:A-25): that “In their 2018 book, How Democracies Die, the political scientists Steven Levitsky and Daniel Ziblatt documented how this process has played out in many countries, from Vladimir Putin’s Russia, to Recep Erdogan’s Turkey, to Viktor Orban’s Hungary. Add to these India’s Narendra Modi, China’s Xi Jinping, and the United States’ Donald Trump, among others. Bit by bit, the guardrails of democracy have been torn down, as institutions meant to serve the public became tools of ruling parties and self-serving ideologies, weaponized to punish and intimidate opposition parties’ opponents. On paper, these countries are still democracies; in practice, they have become one-party regimes….And it’s happening here [the United States] as we speak. If you are not worried about the future of American democracy, you aren’t paying attention” (Krugmam, 2019, A-25). We are reminded continuously that the late Carl Sagan, one of our most insightful scientific public intellectuals, had an interesting theory about highly developed civilizations. Given the number of stars and planets that must exist in the vast reaches of the universe, he said, there must be other highly developed and organized forms of life. Distance may keep us from making physical contact, but Sagan said that another reason we may never be on speaking terms with another intelligent race is (judging from our own example) could be their penchant for destroying themselves in relatively short order after reaching technological complexity. This book’s chapters, introduction, and conclusion examine the worldwide rise of partisan nationalism and the damage it has wrought on the worldwide pursuit of solutions for issues requiring worldwide scope, such scientific co-operation public health and others, mixing analysis of both. We use both historical description and analysis. This analysis concludes with a description of why we must avoid the isolating nature of nationalism that isolates people and encourages separation if we are to deal with issues of world-wide concern, and to maintain a sustainable, survivable Earth, placing the dominant political movement of our time against the Earth’s existential crises. Our contributors, all experts in their fields, each have assumed responsibility for a country, or two if they are related. This work entwines themes of worldwide concern with the political growth of nationalism because leaders with such a worldview are disinclined to co-operate internationally at a time when nations must find ways to solve common problems, such as the climate crisis. Inability to cooperate at this stage may doom everyone, eventually, to an overheated, stormy future plagued by droughts and deluges portending shortages of food and other essential commodities, meanwhile destroying large coastal urban areas because of rising sea levels. Future historians may look back at our time and wonder why as well as how our world succumbed to isolating nationalism at a time when time was so short for cooperative intervention which is crucial for survival of a sustainable earth. Pride in language and culture is salubrious to individuals’ sense of history and identity. Excess nationalism that prevents international co-operation on harmful worldwide maladies is quite another. As Pope Francis has pointed out: For all of our connectivity due to expansion of social media, ability to communicate can breed contempt as well as mutual trust. “For all our hyper-connectivity,” said Francis, “We witnessed a fragmentation that made it more difficult to resolve problems that affect us all” (Horowitz, 2020, A-12). The pope’s encyclical, titled “Brothers All,” also said: “The forces of myopic, extremist, resentful, and aggressive nationalism are on the rise.” The pope’s document also advocates support for migrants, as well as resistance to nationalist and tribal populism. Francis broadened his critique to the role of market capitalism, as well as nationalism has failed the peoples of the world when they need co-operation and solidarity in the face of the world-wide corona virus pandemic. Humankind needs to unite into “a new sense of the human family [Fratelli Tutti, “Brothers All”], that rejects war at all costs” (Pope, 2020, 6-A). Our journey takes us first to Russia, with the able eye and honed expertise of Richard D. Anderson, Jr. who teaches as UCLA and publishes on the subject of his chapter: “Putin, Russian identity, and Russia’s conduct at home and abroad.” Readers should find Dr. Anderson’s analysis fascinating because Vladimir Putin, the singular leader of Russian foreign and domestic policy these days (and perhaps for the rest of his life, given how malleable Russia’s Constitution has become) may be a short man physically, but has high ambitions. One of these involves restoring the old Russian (and Soviet) empire, which would involve re-subjugating a number of nations that broke off as the old order dissolved about 30 years ago. President (shall we say czar?) Putin also has international ambitions, notably by destabilizing the United States, where election meddling has become a specialty. The sight of Putin and U.S. president Donald Trump, two very rich men (Putin $70-$200 billion; Trump $2.5 billion), nuzzling in friendship would probably set Thomas Jefferson and Vladimir Lenin spinning in their graves. The road of history can take some unanticipated twists and turns. Consider Poland, from which we have an expert native analysis in chapter 2, Bartosz Hlebowicz, who is a Polish anthropologist and journalist. His piece is titled “Lawless and Unjust: How to Quickly Make Your Own Country a Puppet State Run by a Group of Hoodlums – the Hopeless Case of Poland (2015–2020).” When I visited Poland to teach and lecture twice between 2006 and 2008, most people seemed to be walking on air induced by freedom to conduct their own affairs to an unusual degree for a state usually squeezed between nationalists in Germany and Russia. What did the Poles then do in a couple of decades? Read Hlebowicz’ chapter and decide. It certainly isn’t soft-bellied liberalism. In Chapter 3, with Bruce E. Johansen, we visit China’s western provinces, the lands of Tibet as well as the Uighurs and other Muslims in the Xinjiang region, who would most assuredly resent being characterized as being possessed by the Chinese of the Han to the east. As a student of Native American history, I had never before thought of the Tibetans and Uighurs as Native peoples struggling against the Independence-minded peoples of a land that is called an adjunct of China on most of our maps. The random act of sitting next to a young woman on an Air India flight out of Hyderabad, bound for New Delhi taught me that the Tibetans had something to share with the Lakota, the Iroquois, and hundreds of other Native American states and nations in North America. Active resistance to Chinese rule lasted into the mid-nineteenth century, and continues today in a subversive manner, even in song, as I learned in 2018 when I acted as a foreign adjudicator on a Ph.D. dissertation by a Tibetan student at the University of Madras (in what is now in a city called Chennai), in southwestern India on resistance in song during Tibet’s recent history. Tibet is one of very few places on Earth where a young dissident can get shot to death for singing a song that troubles China’s Quest for Lebensraum. The situation in Xinjiang region, where close to a million Muslims have been interned in “reeducation” camps surrounded with brick walls and barbed wire. They sing, too. Come with us and hear the music. Back to Europe now, in Chapter 4, to Portugal and Spain, we find a break in the general pattern of nationalism. Portugal has been more progressive governmentally than most. Spain varies from a liberal majority to military coups, a pattern which has been exported to Latin America. A situation such as this can make use of the term “populism” problematic, because general usage in our time usually ties the word into a right-wing connotative straightjacket. “Populism” can be used to describe progressive (left-wing) insurgencies as well. José Pinto, who is native to Portugal and also researches and writes in Spanish as well as English, in “Populism in Portugal and Spain: a Real Neighbourhood?” provides insight into these historical paradoxes. Hungary shares some historical inclinations with Poland (above). Both emerged from Soviet dominance in an air of developing freedom and multicultural diversity after the Berlin Wall fell and the Soviet Union collapsed. Then, gradually at first, right wing-forces began to tighten up, stripping structures supporting popular freedom, from the courts, mass media, and other institutions. In Chapter 5, Bernard Tamas, in “From Youth Movement to Right-Liberal Wing Authoritarianism: The Rise of Fidesz and the Decline of Hungarian Democracy” puts the renewed growth of political and social repression into a context of worldwide nationalism. Tamas, an associate professor of political science at Valdosta State University, has been a postdoctoral fellow at Harvard University and a Fulbright scholar at the Central European University in Budapest, Hungary. His books include From Dissident to Party Politics: The Struggle for Democracy in Post-Communist Hungary (2007). Bear in mind that not everyone shares Orbán’s vision of what will make this nation great, again. On graffiti-covered walls in Budapest, Runes (traditional Hungarian script) has been found that read “Orbán is a motherfucker” (Mikanowski, 2019, 58). Also in Europe, in Chapter 6, Professor Ronan Le Coadic, of the University of Rennes, Rennes, France, in “Is There a Revival of French Nationalism?” Stating this title in the form of a question is quite appropriate because France’s nationalistic shift has built and ebbed several times during the last few decades. For a time after 2000, it came close to assuming the role of a substantial minority, only to ebb after that. In 2017, the candidate of the National Front reached the second round of the French presidential election. This was the second time this nationalist party reached the second round of the presidential election in the history of the Fifth Republic. In 2002, however, Jean-Marie Le Pen had only obtained 17.79% of the votes, while fifteen years later his daughter, Marine Le Pen, almost doubled her father's record, reaching 33.90% of the votes cast. Moreover, in the 2019 European elections, re-named Rassemblement National obtained the largest number of votes of all French political formations and can therefore boast of being "the leading party in France.” The brutality of oppressive nationalism may be expressed in personal relationships, such as child abuse. While Indonesia and Aotearoa [the Maoris’ name for New Zealand] hold very different ranks in the United Nations Human Development Programme assessments, where Indonesia is classified as a medium development country and Aotearoa New Zealand as a very high development country. In Chapter 7, “Domestic Violence Against Women in Indonesia and Aotearoa New Zealand: Making Sense of Differences and Similarities” co-authors, in Chapter 8, Mandy Morgan and Dr. Elli N. Hayati, from New Zealand and Indonesia respectively, found that despite their socio-economic differences, one in three women in each country experience physical or sexual intimate partner violence over their lifetime. In this chapter ther authors aim to deepen understandings of domestic violence through discussion of the socio-economic and demographic characteristics of theit countries to address domestic violence alongside studies of women’s attitudes to gender norms and experiences of intimate partner violence. One of the most surprising and upsetting scholarly journeys that a North American student may take involves Adolf Hitler’s comments on oppression of American Indians and Blacks as he imagined the construction of the Nazi state, a genesis of nationalism that is all but unknown in the United States of America, traced in this volume (Chapter 8) by co-editor Johansen. Beginning in Mein Kampf, during the 1920s, Hitler explicitly used the westward expansion of the United States across North America as a model and justification for Nazi conquest and anticipated colonization by Germans of what the Nazis called the “wild East” – the Slavic nations of Poland, the Baltic states, Ukraine, and Russia, most of which were under control of the Soviet Union. The Volga River (in Russia) was styled by Hitler as the Germans’ Mississippi, and covered wagons were readied for the German “manifest destiny” of imprisoning, eradicating, and replacing peoples the Nazis deemed inferior, all with direct references to events in North America during the previous century. At the same time, with no sense of contradiction, the Nazis partook of a long-standing German romanticism of Native Americans. One of Goebbels’ less propitious schemes was to confer honorary Aryan status on Native American tribes, in the hope that they would rise up against their oppressors. U.S. racial attitudes were “evidence [to the Nazis] that America was evolving in the right direction, despite its specious rhetoric about equality.” Ming Xie, originally from Beijing, in the People’s Republic of China, in Chapter 9, “News Coverage and Public Perceptions of the Social Credit System in China,” writes that The State Council of China in 2014 announced “that a nationwide social credit system would be established” in China. “Under this system, individuals, private companies, social organizations, and governmental agencies are assigned a score which will be calculated based on their trustworthiness and daily actions such as transaction history, professional conduct, obedience to law, corruption, tax evasion, and academic plagiarism.” The “nationalism” in this case is that of the state over the individual. China has 1.4 billion people; this system takes their measure for the purpose of state control. Once fully operational, control will be more subtle. People who are subject to it, through modern technology (most often smart phones) will prompt many people to self-censor. Orwell, modernized, might write: “Your smart phone is watching you.” Ming Xie holds two Ph.Ds, one in Public Administration from University of Nebraska at Omaha and another in Cultural Anthropology from the Chinese Academy of Social Sciences, Beijing, where she also worked for more than 10 years at a national think tank in the same institution. While there she summarized news from non-Chinese sources for senior members of the Chinese Communist Party. Ming is presently an assistant professor at the Department of Political Science and Criminal Justice, West Texas A&M University. In Chapter 10, analyzing native peoples and nationhood, Barbara Alice Mann, Professor of Honours at the University of Toledo, in “Divide, et Impera: The Self-Genocide Game” details ways in which European-American invaders deprive the conquered of their sense of nationhood as part of a subjugation system that amounts to genocide, rubbing out their languages and cultures -- and ultimately forcing the native peoples to assimilate on their own, for survival in a culture that is foreign to them. Mann is one of Native American Studies’ most acute critics of conquests’ contradictions, and an author who retrieves Native history with a powerful sense of voice and purpose, having authored roughly a dozen books and numerous book chapters, among many other works, who has traveled around the world lecturing and publishing on many subjects. Nalanda Roy and S. Mae Pedron in Chapter 11, “Understanding the Face of Humanity: The Rohingya Genocide.” describe one of the largest forced migrations in the history of the human race, the removal of 700,000 to 800,000 Muslims from Buddhist Myanmar to Bangladesh, which itself is already one of the most crowded and impoverished nations on Earth. With about 150 million people packed into an area the size of Nebraska and Iowa (population less than a tenth that of Bangladesh, a country that is losing land steadily to rising sea levels and erosion of the Ganges river delta. The Rohingyas’ refugee camp has been squeezed onto a gigantic, eroding, muddy slope that contains nearly no vegetation. However, Bangladesh is majority Muslim, so while the Rohingya may starve, they won’t be shot to death by marauding armies. Both authors of this exquisite (and excruciating) account teach at Georgia Southern University in Savannah, Georgia, Roy as an associate professor of International Studies and Asian politics, and Pedron as a graduate student; Roy originally hails from very eastern India, close to both Myanmar and Bangladesh, so he has special insight into the context of one of the most brutal genocides of our time, or any other. This is our case describing the problems that nationalism has and will pose for the sustainability of the Earth as our little blue-and-green orb becomes more crowded over time. The old ways, in which national arguments often end in devastating wars, are obsolete, given that the Earth and all the people, plants, and other animals that it sustains are faced with the existential threat of a climate crisis that within two centuries, more or less, will flood large parts of coastal cities, and endanger many species of plants and animals. To survive, we must listen to the Earth, and observe her travails, because they are increasingly our own.

AbstractIn the development of smart cities, there is a great emphasis on setting up so-called Smart City Control Rooms, SCCR. This paper presents Snap4City as a big data smart city platform to support the city decision makers by means of SCCR dashboards and tools reporting in real time the status of several of a city’s aspects. The solution has been adopted in European cities such as Antwerp, Florence, Lonato del Garda, Pisa, Santiago, etc., and it is capable of covering extended geographical areas around the cities themselves: Belgium, Finland, Tuscany, Sardinia, etc. In this paper, a major use case is analyzed describing the workflow followed, the methodologies adopted and the SCCR as the starting point to reproduce the same results in other smart cities, industries, research centers, etc. A Living Lab working modality is promoted and organized to enhance the collaboration among municipalities and public administration, stakeholders, research centers and the citizens themselves. The Snap4City platform has been realized respecting the European Data Protection Regulation (GDPR), and it is capable of processing every day a multitude of periodic and real-time data coming from different providers and data sources. It is therefore able to semantically aggregate the data, in compliance with the Km4City multi-ontology and manage data: (i) having different access policies; and (ii) coming from traditional sources such as Open Data Portals, Web services, APIs and IoT/IoE networks. The aggregated data are the starting point for the services offered not only to the citizens but also to the public administrations and public-security service managers, enabling them to view a set of city dashboards ad hoc composed on their needs, for example, enabling them to modify and monitor public transportation strategies, offering the public services actually needed by citizens and tourists, monitor the air quality and traffic status to establish, if impose or not, traffic restrictions, etc. All the data and the new knowledge produced by the data analytics of the Snap4City platform can also be accessed, observing the permissions on each kind of data, thanks to the presence of an APIs complex system.

Numerous studies have shown that a broad range of activities—both physical and cognitive—vary across the 24-hour day. The blood pressure and heart rate of a human shows striking day–night variations. Simply, an organism is set up to function differently at different times of the day. ‘Time of day matters’ outlines the different human chronotypes—the different preferred waking and sleeping times of humans—and explains concepts such as ‘social jet lag’. There are optimal times of day for physical and cognitive activities, and chronotherapy has also shown that the administration of medication at different times of day can have an important impact on efficacy.

Volatile substances are chemicals such as inhalants, glues, and solvents which are misused by people. In this work, the time of use of volatile substances is determined using seven personality features and five demographic information. 1D CNN is used for classification whether the user has consumed the volatile substances on last day, last week, last month, last year, or has never consumed. The accuracy obtained is 93.76% which is much higher than all previous studies on volatile substance abuse (VSA).

This chapter talks about Ezra Taft Benson who commenced work as secretary of agriculture in the Dwight D. Eisenhower administration in 1953, while serving as one of the twelve apostles of the Church of Jesus Christ of Latter-day Saints. It describes Benson as a central figure in postwar American politics who represented the confluence and conflict between the various stripes of Mormon and American conservatism. It also discusses how Benson was the subject of national media interest and scrutiny in the 1950s and 1960. The chapter points out how Benson often took clear and controversially conservative positions on many of the historic conflicts of the twentieth century, such as anticommunism, the women's movement, international and domestic conflicts, and the culture wars. It traces American public representations of Mormonism by looking at Benson as a media filter.

Abstract ‘I have no time!’, ‘There isn’t enough time in a day!’, are some of the most common expressions used in the academic world these days. Fast-growing numbers of hours that academics are required to devote to administration, teaching, and grant applications make more and more people resort to com- plaints about time. Perhaps it is worth asking oneself, what exactly do such expressions mean? If I don’t have time, what is it exactly that I don’t have? Let us imagine the following scenario. There is a ski lift going up a snowy mountain and a line of skiers waiting to catch it to be lifted up on their skis. The lift is moving at a certain steady speed and most of the skiers manage to latch on and go up, but some less experienced ones miss their slot or fall off the lift before they get to the top.

This chapter is focused on the relationship between ancient narratives “music” and “mythology.” Technological developments and changes in social structure caused the occurrence of different music genres over time. “Metal music” is one of these genres. In the present day, it is possible to observe that there is a tendency to mythology in sub-genres of metal music. This tendency is observed in lyrics, album artworks, videos, and gig performances of some bands. In this chapter, metal music is examined based on its root, content, and technical features, primarily. Afterwards, mythology, content of mythology, and cultural and social functions of mythology are discussed. In the praxis of this study, the cover of the album Twilight of the Thunder God (2008) of the Swedish metal band Amon Amarth is analyzed by semiological analysis.

Abstract Churchill enormously enjoyed his time at the Admiralty. (How much Clementine enjoyed it is another matter.) His pages about it in The World Crisis fizz with hyperactivity vividly recalled, giving the impression while you read them that he can have had no time for anything else—and also giving the impression that the senior admirals liked him more than most of them actually did. In fact the Royal Navy was by no means the only political problem he had to cope with at that time, and his work at the Admiralty was not as widely appreciated at the time as he thought it ought to be. These were great days. From dawn to midnight, day after day, one’s whole mind was absorbed by the fascination and novelty of the problems which came crowding forward. And all the time there was a sense of power to act, to form, to organize: all the ablest officers in the Navy standing ready, loyal and eager, with argument, guidance, information ... Saturdays, Sundays and any other spare day I spent always with the Fleets [of battleships] at Portsmouth or at Portland or Devonport, or with the Flotillas [ of destroyers and such] at Harwich. Officers of every rank came on board to lunch or dine and discussion proceeded without ceasing on every aspect of naval war and administration.

Emergency medicine is a rapidly developing medical specialty which focuses on the diagnostic process, initial stabilization, and the treatment of patients suffering from acute illnesses or injuries. Emergency care can be provided in prehospital settings by emergency medical services, as well as in emergency departments. The primary providers of emergency care are: emergency medicine physicians, emergency nurses, and paramedics. Emergency medical personnel are required to be prepared to take decisive action at any time of day or night. It is essential for them to possess basic knowledge relating to psychology and an ability to utilize interpersonal communication skills. A critical role of medical workers in emergency settings is to provide a patient with emotional support coupled with medical assistance. Interpersonal communication skills depend on the personal abilities of an individual, however, these skills can be also enhanced through training and work experience.

This chapter discusses the items of private international law of foreign judgments covered in part by a number of European regulations and other instruments prior to Exit Day. These are the Brussels I Regulation 44/2001 and the recast Brussels I Regulation 1215/2012; the 1988 Lugano Convention and the 2007 Lugano II Convention; the 1968 Brussels Convention as amended from time to time; and a number of minor Regulations such as the European Enforcement Order Regulation 805/2004. According to the Civil Jurisdiction and Judgments (Amendment) (EU Exit) Regulations 2019, SI 2019 No 479, on Exit Day these instruments are revoked or, in the case of the Conventions given effect by the Civil Jurisdiction and Judgments Act 1982, as amended, repealed. The gap will be filled by the rules of the common law, or by the provisions of a bilateral Convention made under the Foreign Judgements (Reciprocal Enforcement) Act 1933 (or in the case of Cyprus and Malta, presumably by registration under the Administration of Justice Act 1920).

The case presents an analysis of the postings of a group of online teachers from a Mexican public university as they confront the challenges and rewards of their day-to-day teaching activities. They commented on their problems and accomplishments in a discussion forum during one semester. The problems included academic-administrative issues, difficulties of students in the appropriation of the platforms and the self-regulation of their learning, time management, negotiation and penalization of tasks delayed, and other pedagogical concerns to the lack of institutional support. The findings suggest that the problems that online teachers face share specific characteristics and, according to the teachers, are mostly due to the pedagogical relationship being technologically mediated. Through the analysis, the author hopes to illustrate the complex technological, organizational, and cultural issues that accompany online teaching and learning, and how the institution and the individual teachers dealt with them.

It is known that mM concentrations of vitamin B6 inhibit human platelet aggregation and fibrin formation in vitro. There are very few and controversial data on the ex vivo effects of vitamin B6 on hemostatic parameters. We evaluated the effects of oral administration of vitamin B6 on bleeding time (BT), fibrin formation, platelet aggregation (PA) and the release reaction (RR). Vitamin B6 300 mg/day p.o., was given to 18 healthy volunteers (8 M, 10 F, aged 23-35) for 8 days. BT was measured before the first dose (Baseline), 2 hr after the first (Day 1) and the last dose (Day 8). In 7 subjects BT was measured also 7 days after the suspension of the drug (Day 15). Before and 2 hr after the first dose, prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), PA and the RR induced by different concentrations of ADP, PAF-acether, collagen (coll), epinephrine (epi), arachidonate (AA) were studied. BT was significantly prolonged after vitamin B6 administration, and returned to baseline values 7 days after suspension of the drug. PA and the RR induced by 1 uM ADP, 1 ug/ml coll or 5 uM epi were significantly inhibited 2 hours after vitamin B6 administration. Vitamin B6, however, did not affect PA or the RR induced by 0.2-2 uM PAF-acether, 2 uM ADP, 1 mM AA, 2 ug/ml coll, nor did it affect PT, PTT or TT. These data show that orally administered vitamin B impairs primary hemostasis, but does not affect fibrin 6 formation, as measured with standard coagulation tests.

68 patients (pts) with acute deep vein thrombosis (DVT) were randomized to either CY 222 (Choay Institut, Cl, France) (n=33) in a dose of 750 u anti-Xa Cl/kg/day or standard heparin (SH) (n=35), 500 ui/kg/day, both given by 2 daily subcutaneous (sc) injections for 10 days. In SH group, dose was monitored by daily activated partial thromboplastin time to maintain a prolongation between 2 to 3 times the control value ; in CY 222 group dose remained unchanged during the 10-day treatment. Venography was repeated at day 10. Initial DVT localization and derived Marder’s score was similar in both groups (14.1 ± 11.7 in CY 222 group and 14.3 ± 10.6 in SH group, p = NS).The results show that : 1/ no bleeding complication was observed in CY 222 pts, but large hematoma occured in 3 SH pts, 1 patient in each group developed a recurrent pulmonary embolism and 2 others pts (1 in each group) did not undergo control phlebography ; 2/ in CY 222 group, 8 pts obtained complete lysis (CL, thrombolysis more than 90%), 11 partial lysis (PL, thrombolysis between 30% and 90%), and 11 no change (NC, less than 30%) ; 3/ in SH group, 4 pts obtained CL, 15 PL, 8 NC and extension was seen in 2 pts. Thus, phlebographic improvement (thrombolysis more than 30%) was observed in 65% in both groups.In conclusion, these preliminary results suggested that sc administration of CY 222 and SH, both given by 2 daily injections, was equally effective in pts with acute DVT, and CY 222 seemed to be safer than SH.

Road accidents are a major world economic and social problem, as shown by the report of loss of lives and properties in many countries worldwide. Reporting indicated the number of fatalities from road accidents per year of about 1.35 million and 50 million injuries was recorded or an average of 3000 deaths/day and 30,000 injuries/ day. Furthermore, its consequences have an impact on economic and social conditions in terms of health care costs of injuries and disabilities. The objectives of this paper are to implement four modeling techniques, Logistic Regression, Naïve Bayes, Support Vector Machine (SVM), and Artificial Neural Networks (ANN), to predict accident severity and compare the performance of these models in terms of their prediction accuracy. More than 117,000 accident records with over 32 variables were retrieved from London. The results showed that the nonlinear SVM model outperformed other techniques in terms of performance with an accuracy of 78.32%. On the other hand, the linear SVM was the worst overall model with an accuracy of 69.27%. In terms of training time, a considerable difference was found between two groups of models: Logistic Regression, Naïve Bayes on one hand, and SVM and ANN on the other group. The former required a shorter training time (less than 10 min for each model), while the latter had training times between 20 to 70 min per model. Overall, the nonlinear SVM seems to perform the best in terms of accuracy, while Naïve Bayes is the best for fast prediction. This result can be beneficial for researchers and practitioners to predict accident severity levels and suggest improvements to traffic safety.

The presence of road traffic accidents is subjected to various contributing factors including drowsy driving. The occurrence of drowsy driving has been a major cause of road accidents globally. Therefore, this study aims to analyze demographic, socio-economic, daily habits and drowsy-related characteristics associated with fatigued or drowsy driving in the United Arab Emirates (UAE). The data were gathered upon a questionnaire-based survey among a sample size of 525 drivers in the UAE. Inputs were given weights upon consulting experts in the field of transportation. Data were analyzed using artificial neural networks (ANN). Daily habits significantly affect the driver’s risk to experience fatigued driving. Socio-economic, drowsy-related, and demographic characteristics followed sequentially. Time of day to experience drowsy driving has the largest importance. Moreover, daily habits such as driving durations, distance driven, and sleeping hours demanded the importance of drowsy driving risk next. Socio-economic characteristic such as the average monthly income was the least significant. Prevalence of sleep-related accidents in the UAE is a fact, where drivers are less concerned about fatigue driving than other traffic safety issues. Raising awareness of drowsy driving among society is a need since people tend to see other factors to be riskier than drowsy driving. The results highlight the need to counteract drowsy driving with treatments on-road and more education to the public.

Abstract Introduction Acute adverse drug reactions (ADRs) in day care chemotherapy are not uncommon and easily manageable many a time. However, sometimes they may lead to untoward events. It is of paramount importance to document and analyze such events in contemporary medical oncology practice for the best utilization and planning of available personnel and resources. Objectives This study was aimed to analyze the acute ADRs occurring in day care cancer chemotherapy setting. Materials and Methods All acute ADRs reported in day care cancer chemotherapy setting, during the administration of chemotherapy, at Basavatarakam Indo American Cancer Hospital, Hyderabad, Telangana, India, were included in the study from June 15, 2020 to September 30, 2020. The ADRs were classified in to anaphylactic, allergic, and gastrointestinal (nausea/vomiting/heart burns/chest tightness). All ADRs were graded according to CTCAE version 5.0. Suspected drugs, time to reaction, and corrective measures were analyzed. Results During the study period, a total of 8,600 sessions of day care chemotherapy were administered. ADRs were noticed in 83 cases (~1%). Among the reported ADRs, anaphylactic reactions were noted in 20 patients (24%); allergic reactions of grades 1 and 2 were noted in 41 patients (49%). Gastrointestinal ADRs were noted in 30 patients (36%). Adverse reactions are mostly seen in oxaliplatin (22.8%), rituximab (14.4%), paclitaxel (15.6%), carboplatin (13.2%), and docetaxel (7.2%). In grade-I (10%) and grade-II (63%) resections, supportive treatment was provided and chemotherapy was continued. Grade-III ADRs were noted in 21 patients (25%) out of whom, 3 patients required short-term intensive care, chemotherapy was withheld until the next cycle in one patient, and chemotherapy regimen was changed in 3 patients. No patient died of ADR. Conclusion Serious ADRs are rare in contemporary medical oncology practice during day care chemotherapy administration. Most acute ADRs were easily managed.

Negative consequences associated with excessive use of cannabis are well documented. Previous findings indicate timing of use is an important factor when assessing severity of dependence for use of substances including alcohol and cigarettes. However, little attention in the academic literature has been paid to timing of cannabis use and its associations with negative consequences. The present study employed a latent class analysis on data collected from college students who use cannabis, located across four U.S. universities in four different states (N = 1,122). The goal was to examine whether distinct classifications of cannabis use exist based on timing (i.e., hour of day and day of week), and whether these classifications differ on cannabis use indicators (Marijuana Use Grid; MUG), cannabis-related negative consequences (Marijuana Consequences Questionnaire; MACQ), and cannabis use disorder symptoms (Cannabis Use Disorder Identification Test-Revised; CUDIT-R). The MUG assesses the amount (in grams) of cannabis used during a week of typical marijuana use in the past 30 days on each of the seven days per week (Monday-Sunday) during each of six 4-hour time periods (12a-4a, 4a-8a, 8a-12p, 12p-4p, 4p-8p, 8p-12p). By summing across time periods for each day, we binarized the presence of cannabis use (0 = no use, 1 = use) for each day of the week. By summing across days for each time period, we binarized the presence of cannabis use for each time period. Based on the Lo-Mendell-Rubin Likelihood Ratio Test (LRT) and other fit indices, we found support for a 4-class solution with high classification precision (relative entropy = .905). The four classes were characterized as follows: (1) daily (greater than 98% of the class endorsed use on each day of the week), common morning use (N = 140.17, 12.5%), (2) daily (greater than 88% of the class endorsed use each day of the week), uncommon morning use (N = 241.02, 21.5%), (3) weekend, common morning use (N = 72.22, 6.4%), and (4) weekend, uncommon morning use (N = 668.59, 59.6%). Individuals reporting daily, common morning use experienced the highest cannabis-related negative consequences (MACQ M = 7.53) and reported the highest levels of cannabis use disorder symptoms (CUDIT-R M = 15.74), whereas individuals reporting weekend, uncommon morning use experienced few cannabis-related negative consequences (MACQ M = 2.24)) and reported low cannabis use disorder symptoms (CUDIT-R M = 5.45). Taken together, our classes were defined by crossing the presence/absence of morning cannabis use by the presence/absence of weekday cannabis use, and we found evidence that both the timing of week and timing of day contribute to the level of cannabis-related harms that individuals experience. Additional research is needed to explore the unique contributions of time of week and time of day while controlling for other characteristics of one’s cannabis use (i.e., frequency, quantity, product type, route of administration, etc.).

The thienopyridine, PCR 4099, is a synthetic structural analog of ticlopidine. After oral administration in man, it prolongs the bleeding time (BT) and inhibits ADP-induced aggregation. The aim of the study was to evaluate the effects of oral administration of 200 mg per day PCR 4099 to 10 human volunteers for 7 days on primary hemostasis and to study the mechanism of inhibition of the drug on the ADP-fibrinogen-GPIIb-IIIa pathway of aggregation. BT (measured by a Simplate device) was 4-8 min before treatment and 30 min after 7 days of treatment. Platelets were washed and resuspended in Tyrode’s buffer containing apyrase and 0.35 % human albumin. Washed platelet suspensions were used at 37°C for aggregation and fibrinogen binding studies. Human fibrinogen was purified by successive ether precipitation and gelatin affinity chromatography to remove fibronectin. Fibrinogen was pure bv SDS-PAGE and > 95 % clottable by thrombin. It was labeled with 125I by the Iodogen method. The binding of 125I-fibrinogen to intact washed platelets exposed to ADP or thrombin was measured after centrifugation at 11 ,000 g for 1 min in the presence of 131I-human albumin as a space marker. The membrane GPIIb-IIIa complex was examined by crossed immunoelectrophoresis (CIE) in the presence of rabbit anti-human platelet antiserum. The prolonged administration of PCR 4099 inhibited almost completely platelet aggregation induced by 0.5 to 10 μM ADP. Although the effect of ADP on aggregation was blocked at high concentrations, PCR 4099 did not modify ADP-induced shape change. Only the effects of low concentrations of thrombin (< 0.05 U/ml) were inhibited by PCR 4099 administration. The binding of 125I-fibrin0gen was reduced by 50 to 90 % when platelets were stimulated by 5 μM ADP or by 0.05 U/ml thrombin. PCR 4099 did not modify the pattern of immunoprecipitates as revealed by CIE. In particular the GPIIb-IIIa complex was not dissociated and its electrophoretic mobility was not changed. In conclusion, PCR 4099, which is more potent than ticlopidine in man, inhibits specifically the ADP aggregation pathway by interfering with the binding of fibrinogen to the GPIIb-IIIa complex in platelets having undergone shape change.

In order to protect thrombus formation, administration of low dose aspirin has become common. However, its significance for this purpose is still not clear. Effect of small dose of aspirin (ASA) onplatelet aggregation and ability of malondialdehyde(MDA) formation in platelet by the addition of arachidonic acid in vitro were investigated. In clinical study, platelet aggregation, MDA formation of platelet, serum P-thromboglobulin(p-TG), platelet factor 4(PF4) and thromboxane B2(TX-B2) levelswere measured before and after low doseaspirin therapy.Platelet aggregations by ADP, collagen, epinephrin and arachidonate as inducers were significantly suppressed under 12.5 ug/ml ASA in the medium. MDA formation of platelet was remarkably inhibited under 1.6 ug/ml of ASA in the medium in vitro.In patients, single oral dose of 50 mg ASA showed no change on platelet aggregation while the ability of MDA formation decreased 50# of the before. Serum concentration of ASA after oral dose of 50 mg ASA only showed 1.5 to 6.0 ug/ml at maximum.Daily dose of 50 mg ASA was continued during 10 days. Changes of various factors due to the time course were observed. Inhibitions of platelet aggregation were seen from 5th day on ADP and collagenand from 2nd day on epinephrin and arachidonate as inducers during the therapy. MDA formations of platelet were decreased quickly and it became almost zero at 5th day. ASA levels in the patient serum reached plateau as 8 or 9 ug/ml from 3rdday.Various patients with a possibility of thrombus formation were administered daily 50 mg ASA during 10 days. Platelet aggregations and MDA production, serum β-TG, PF4 and TXB2 levels were measured before and after the therapy. Platelet aggregations by ADP, collagen and epinephrin as inducers were significantly suppressed after the therapyand MDA production of platelet was also markedly decreased after the therapy. There were no significant changes in serumβ-TG and PF4 levels while TXB2 level tended to decrease after the therapy.From these results, it was concluded that daily 50 mg ASA oral dose was certainly effective for protection of thrombus formation.

In the rat, intravenous injection of large doses (30 mg/Kg) of ellagic acid (EA) induced a decrease in the plasma level of fibrinogen and in the blood platelet content and an increase of the activated partial thromboplastin time. EA induced the accumulation of Crs1-labelled platelets into the lung and the liver accompanied by a 64% fall in Cr51 blood radioactivity.The long-lasting thrombocytopenia induced by EA was inhibited by heparin (4 mg/Kg), defibrase (20 U/Kg), and clocoumarol (4 mg/Kg). It was not inhibited by aspirin (90 mg/Kg), indomethacin (8 mg/Kg) and ketoprofen (4-10 mg/Kg). The thrombocytopenia would depend on an intravascular coagulation.Using this model of platelet stimulation, we studied the protective effect of PCR 4099. This drug was first given as a single dose, orally four hours before the injection of EA. It reduced the thrombocytopenia for 10 mg/Kg and suppressed it for 40 mg/Kg. The thrombocytopenia was also inhibited by 3 day oral administration of PCR 4099 4 mg/Kg. PCR 4099 is thus a potent inhibitor of this kind of platelet stimulation.

In this research work, we develop a drowsy driver detection system through the application of visual and radar sensors combined with machine learning. The system concept was derived from the desire to achieve a high level of driver safety through the prevention of potentially fatal accidents involving drowsy drivers. According to the National Highway Traffic Safety Administration, drowsy driving resulted in 50,000 injuries across 91,000 police-reported accidents, and a death toll of nearly 800 in 2017. The objective of this research work is to provide a working prototype of Advanced Driver Assistance Systems that can be installed in present-day vehicles. By integrating two modes of visual surveillance to examine a biometric expression of drowsiness, a camera and a micro-Doppler radar sensor, our system offers high reliability over 95% in the accuracy of its drowsy driver detection capabilities. The camera is used to monitor the driver’s eyes, mouth and head movement and recognize when a discrepancy occurs in the driver's blinking pattern, yawning incidence, and/or head drop, thereby signaling that the driver may be experiencing fatigue or drowsiness. The micro-Doppler sensor allows the driver's head movement to be captured both during the day and at night. Through data fusion and deep learning, the ability to quickly analyze and classify a driver's behavior under various conditions such as lighting, pose-variation, and facial expression in a real-time monitoring system is achieved.

Objectives The original project had 2 major objectives: (1) To determine the effects of centrally administered leptin antagonist on appetite and adaptive metabolism in the sheep; (2) To develop and prepare second-generation leptin antagonists combining high binding affinity and prolonged in vivo half-life. Background Periods of suboptimal nutrition or exaggerated metabolic activity demands lead to a state of chronic energy insufficiency. Ruminants remain productive for a surprisingly long period of time under these circumstances by evoking adaptations sparing available energy and nutrients. The mechanism driving these adaptations in ruminant remains unknown, but could involve a reduction in plasma leptin, a hormone acting predominantly in the brain. In laboratory animals, reduced leptin signaling promotes survival during nutritional insufficiency by triggering energy sparing adaptations such as reduced thyroid hormone production and insulin resistance. Our overall hypothesis is that similar adaptations are triggered by reduced leptin signaling in the brain of ruminants. Testing of this hypothesis in ruminants has not been possible due to inability to block the actions of endogenous leptin and access to ruminant models where leptin antagonistic therapy is feasible and effective. Major achievements and conclusions The Israeli team had previously mutated 3 residues in ovine leptin, with no effect on receptor binding. This mutant was renamed ovine leptin antagonist (OLA) because it cannot activate signaling and therefore antagonizes the ability of wild type leptin to activate its receptor. To transform OLA into an effective in vivo antagonist, the Israeli made 2 important technical advances. First, it incorporated an additional mutation into OLA, increasing its binding affinity and thus transforming it into a super ovine leptin antagonist (SOLA). Second, the Israeli team developed a method whereby polyethylene glycol is covalently attached to SOLA (PEG-SOLA) with the goal of extending its half-life in vivo. The US team used OLA and PEG-SOLA in 2 separate animal models. First, OLA was chronically administered directly into the brain of mature sheep via a cannula implanted into the 3rdcerebroventricule. Unexpectedly, OLA had no effect of voluntary feed intake or various indicators of peripheral insulin action but reduced the plasma concentration of thyroid hormones. Second, the US team tested the effect of peripheral PEG-SOLA administration in an energy sensitive, rapidly growing lamb model. PEG-SOLA was administered for 14 consecutive days after birth or for 5 consecutive days before sacrifice on day 40 of life. Plasma PEG-SOLA had a half-life of over 16 h and circulated in 225- to 288-fold excess over endogenous leptin. PEG-SOLA administration reduced plasma thyroid hormones and resulted in a higher fat content in the carcass at slaughter, but had no effects on feed intake, body weight, plasma glucose or insulin. These results show that the team succeeded in developing a leptin antagonist with a long in vivo half-life. Moreover, in vivo results show that reduced leptin signaling promotes energy sparing in ruminants by repressing thyroid hormone production. Scientific and agricultural implications The physiological role of leptin in ruminants has been difficult to resolve because peripheral administration of wild type leptin causes little effects. Our work with leptin antagonists show for the first time in ruminants that reduced leptin signaling induces energy sparing mechanisms involving thyroid hormone production with little effect on peripheral insulin action. Additional work is needed to develop even more potent leptin antagonists, to establish optimal administration protocols and to narrow down phases of the ruminant life cycle when their use will improve productivity.

The corpus luteum (CL) is a transient endocrine gland that has a vital role in the regulation of the estrous cycle, fertility and the maintenance of pregnancy. In the absence of appropriate support, such as occurs during maternal recognition of pregnancy, the CL will regress. Prostaglandin F2a (PGF) was first suggested as the physiological luteolysin in ruminants several decades ago. Yet, the cellular mechanisms by which PGF causes luteal regression remain poorly defined. In recent years it became evident that the process of luteal regression requires a close cooperation between steroidogenic, endothelial and immune cells, all resident cells of this gland. Changes in the population of these cells within the CL closely consort with the functional changes occurring during various stages of CL life span. The proposal aimed to gain a better understanding of the intra-ovarian regulation of luteolysis and focuses especially on the possible reasons causing the early CL (before day 5) to be refractory to the luteolytic actions of PGF. The specific aims of this proposal were to: determine if the refractoriness of the early CL to PGF is due to its inability to synthesize or respond to endothelin–1 (ET-1), determine the cellular localization of ET, PGF and tumor necrosis factor a (TNF a) receptors in early and mid luteal phases, determine the functional relationships among ET-1 and cytokines, and characterize the effects of PGF and ET-1 on prostaglandin production by luteal cell types. We found that in contrast to the mature CL, administration of PGF2a before day 5 of the bovine cycle failed to elevate ET-1, ETA receptors or to induce luteolysis. In fact, PGF₂ₐ prevented the upregulation of the ET-1 gene by ET-1 or TNFa in cultured luteal cells from day 4 CL. In addition, we reported that ECE-1 expression was elevated during the transitionof the CL from early to mid luteal phase and was accompanied by a significant rise in ET-1 peptide. This coincides with the time point at which the CL gains its responsiveness to PGF2a, suggesting that ability to synthesize ET-1 may be a prerequisite for luteolysis. We have shown that while ET-1 mRNA was exclusively localized to endothelial cells both in young and mature CL, ECE-1 was present in the endothelial cells and steroidogenic cells alike. We also found that the gene for TNF receptor I is only moderately affected by the cytokines tested, but that the gene for TNF receptor II is upregulated by ET-1 and PGF₂ₐ. However, these cytokines both increase expression of MCP-1, although TNFa is even more effective in this regard. In addition, we found that proteins involved in the transport and metabolism of PGF (PGT, PGDH, COX-2) change as the estrous cycle progresses, and could contribute to the refractoriness of young CL. The data obtained in this work illustrate ET-1 synthesis throughout the bovine cycle and provide a better understanding of the mechanisms regulating luteal regression and unravel reasons causing the CL to be refractory to PGF2a.