PRISM protocol: A randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established

Your professionalism is not my professionalism:congruence and variance in the views of medical students and faculty about professionalism

Abstract Background Medical professionalism is an essential aspect of medical education and practice worldwide and it must be adopted according to different social and cultural contexts. We examined the current congruence and variance in the perception of professionalism in undergraduate medical students and faculty members in one medical school in Saudi Arabia. Methods The target population was first year to final year medical students of College of Medicine, King Saud University. Out of a total of 1431 students at College of Medicine 750 students (52 %) participated in the study. Fifty faculty members from clinical and non-clinical departments of the College of Medicine were randomly selected for this study and all participated in the study. The respondents recorded their responses through the Bristol online survey system, using a bilingual (English and Arabic) version of the Dundee Polyprofessionalism Inventory I: Academic integrity, which has 34 items. Results There are 17 lapses (50 % of the total) in professional behaviour where none of the faculty recommend the ignore sanction while students recommended a variable ignore sanction in a range of 6–29 % for different behaviours. Students and faculty recommended similar sanctions for 5 lapses (14.7 % of the total) in professional behaviours. Furthermore, there is statistically significant two level difference between the sanctions approved by faculty and students in the recommended sanctions for 12 lapses (35 % of the total (p < 0.050). Conclusions These results raised concerns in relation to the students’ understanding of professionalism. It is therefore, important to enhance their learning around the attributes of medical professionalism

Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE

\ua9 2022 by American Society of Clinical Oncology. PURPOSE CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial. METHODS Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm. RESULTS The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology. CONCLUSION The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations

Benefits for Dominant Red Deer Hinds under a Competitive Feeding System: Food Access Behavior, Diet and Nutrient Selection

Social dominance is widely known to facilitate access to food resources in many animal species such as deer. However, research has paid little attention to dominance in ad libitum access to food because it was thought not to result in any benefit for dominant individuals. In this study we assessed if, even under ad libitum conditions, social rank may allow dominant hinds to consume the preferred components of food. Forty-four red deer hinds (Cervus elaphus) were allowed to consume ad libitum meal consisting of pellets of sunflower, lucerne and orange, and seeds of cereals, corn, cotton, and carob tree. The meal was placed only in one feeder, which reduced accessibility to a few individuals simultaneously. During seven days, feeding behavior (order of access, time to first feeding bout, total time spent feeding, and time per feeding bout) were assessed during the first hour. The relative abundance of each meal component was assessed at times 0, 1 and 5 h, as well as its nutritional composition. Social rank was positively related to the amount of time spent feeding during the 1st h (P = 0.048). Selection indices were positively correlated with energy (P = 0.018 during the 1st h and P = 0.047 from 1st to 5th) and fat (only during the 1st h; P = 0.036), but also negatively with certain minerals. Thus, dominant hinds could select high energy meal components for longer time under an ad libitum but restricted food access setting. Selection indices showed a higher selectivity when food availability was higher (1st hour respect to 1st to 5th). Finally, high and low ranking hinds had longer time per feeding bout than mid ones (P = 0.011), suggesting complex behavioral feeding tactics of low ranking social ungulates

Do guidelines influence breathlessness management in advanced lung diseases? A multinational survey of respiratory medicine and palliative care physicians

Background Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung disease (fILD) and lung cancer (LC), and the influence of practice guidelines was explored via an online survey. Methods A voluntary, online survey was distributed to RM and PC physicians via society newsletter mailing lists. Results 450 evaluable questionnaires (348 (77%) RM and 102 (23%) PC) were analysed. Significantly more PC physicians indicated routine use (often/always) of opioids across conditions (COPD: 92% vs. 39%, fILD: 83% vs. 36%, LC: 95% vs. 76%; all p < 0.001) and significantly more PC physicians indicated routine use of benzodiazepines for COPD (33% vs. 10%) and fILD (25% vs. 12%) (both p < 0.001). Significantly more RM physicians reported routine use of a breathlessness score (62% vs. 13%, p < 0.001) and prioritised exercise training/rehabilitation for COPD (49% vs. 7%) and fILD (30% vs. 18%) (both p < 0.001). Overall, 40% of all respondents reported reading non-cancer palliative care guidelines (either carefully or looked at them briefly). Respondents who reported reading these guidelines were more likely to: routinely use a breathlessness score (χ2 = 13.8; p < 0.001), use opioids (χ2 = 12.58, p < 0.001) and refer to pulmonary rehabilitation (χ2 = 6.41, p = 0.011) in COPD; use antidepressants (χ2 = 6.25; p = 0.044) and refer to PC (χ2 = 5.83; p = 0.016) in fILD; and use a handheld fan in COPD (χ2 = 8.75, p = 0.003), fILD (χ2 = 4.85, p = 0.028) and LC (χ2 = 5.63; p = 0.018). Conclusions These findings suggest a need for improved dissemination and uptake of jointly developed breathlessness management guidelines in order to encourage appropriate use of existing, evidence-based therapies. The lack of opioid use by RM, and continued benzodiazepine use in PC, suggest that a wider range of acceptable therapies need to be developed and trialled

University admission based on tests and interviews : Implementation and assessment

Admission to higher education has far-reaching implications and an impact not only on individuals, but also on society. In most developed countries, admission to university studies remains a key issue in higher education: the admissions system determines who will have access to higher education and raises the issue of equal opportunity, in terms of e.g. age, gender, and social class. Traditionally, admission to university studies in Sweden has been centralised, but in recent decades, universities have been permitted to reserve a specified number of undergraduate places for individual admission of selected students. Such a system was introduced to the dental course at the Dental School, Karolinska Institutet, in 1993. The main objective is to seek out, from a pool of applicants with good academic standards, highly motivated students with the potential to become good dentists. The overall aim of the thesis was to assess the relationship between individual student selection adopted at the Dental School and subsequent student achievement, including professional competence. It also presents an overall impression of the selection procedures, as perceived by successful applicants and by members of the selection committee. The specific aims of the thesis were to assess the outcome of an individualised admissions system for dental undergraduates in terms of. student drop-out rates, academic performance during the preclinical years and professional competence of dental students in their final undergraduate year. Students admitted through traditional modes served as a control group. The results are based on data from the first three rounds of admission using the system. During the first years of the undergraduate course, the results of three major integrated examinations, designed to disclose both comprehension and academic ability were analysed to give an early indication of students' potential to become 'good dentists'. The individually selected students achieved better results than those accepted through traditional modes. After three intakes, there have been few or no dropouts among the individually selected students. With respect to professional competence, faculty members who were clinical supervisors in the comprehensive care clinic and knew the students well assessed all the final-year students from the same three rounds of admission. The assessors were uninformed of the means by which the students had originally been admitted to the undergraduate course. Assessment by means of a specially designed protocol comprised seven different criteria and one overall - global - rating. Students originally admitted by individual selection seem to be more professionally competent than students admitted by traditional means. With respect to the relationship between student selection procedures and academic achievement, both interviewed students and the admissions committee are of the same opinion: that the individualised admissions procedure has a positive influence on students' academic achievement and professional competence. The students feel specially selected for their potential to become good dentists and the committee members agree that this awareness lead the students to aspire to higher achievements. It is concluded that motivation and commitment are important determinants of student achievement and that these criteria are more readily disclosed through tests and interview than through traditional modes such as matriculation grades and aptitude tests