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The activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. PD1 drives T cells to an unresponsive state called exhaustion, characterized by a markedly decreased capacity to exert effector functions upon binding the ligands PDL1 and PDL2. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling pathway is activated upon the ligands' binding remains an open question. In this work, we used molecular dynamics simulations to assess the differences of the PD1 motion in the free state and in complex with the ligands. We found that, in both human and murine systems, the binding of PDL1 and PDL2 stabilizes the conformation of the FG loop similarly. This result, combined with the conservation of the FG loop residues across species, suggests that the conformation of the FG loop is somehow related to the signaling process. We also found a high similarity between the PD1-PDL1 structures with the variable region of an antibody structure, where the FG loop occupies a similar position to the CDR3 light chain.

Radiation therapy is a complex process involving multiple professionals and steps from simulation to treatment planning to delivery, and these procedures are prone to error. Additionally, the imaging and treatment delivery equipment in radiotherapy is highly complex and interconnected and represents another risk point in the quality of care. Numerous quality assurance tasks are carried out to ensure quality and to detect and prevent potential errors in the process of care. Recent developments in artificial intelligence provide potential tools to the radiation oncology community to improve the efficiency and performance of quality assurance efforts. Targets for artificial intelligence enhancement include the quality assurance of treatment plans, target and tissue structure delineation used in the plans, delivery of the plans and the radiotherapy delivery equipment itself. Here we review recent developments of artificial intelligence applications that aim to improve quality assurance processes in radiation therapy and discuss some of the challenges and limitations that require further development work to realise the potential of artificial intelligence for quality assurance.

To validate an approach to measuring professional identity formation (PIF), we explore if the Professional Identity Essay (PIE), a stage score measure of medical professional identity (PI), predicts clinical communication skills.Students completed the PIE during medical school orientation and a 3-case Objective Structured Clinical Exam (OSCE) where standardized patients reliably assessed communication skills in 5 domains. Using mediation analyses, relationships between PIE stage scores and communication skills were explored.For the 351 (89%) consenting students, controlling for individual characteristics, there were increases in patient counseling (6.5%, p0.01), information gathering (4.3%, p = 0.01), organization and management (4.1%, p = 0.02), patient assessment (3.6%, p = 0.04), and relationship development (3.5%, p = 0.03) skills for every half stage increase in PIE score. The communication skills of lower socio-economic status (SES) students are indirectly impacted by their slightly higher PIE stage scores.Higher PIE stage scores are associated with higher communication skills and lower SES.PIE predicts critical clinical skills and identifies how SES and other characteristics indirectly impact future clinical performance, providing validity evidence for using PIE as a tool in longitudinal formative academic coaching, program and curriculum evaluation, and research.

To evaluate the impact of a digital whiteboard system integrated with data from the oncology information system (OIS) on the urgency of physics quality assurance (QA) tasks in the radiation oncology department.Quality check list (QCL) items in the Mosaiq OIS corresponding to eight discrete, sequential steps in the treatment planning process were created. A whiteboard to graphically display active QCLs automatically and in real time was implemented in March 2020 using R shiny. QCL data with completion status were collected in two 12-month time periods before and after whiteboard implementation: January 2019-December 2019 and July 2020-June 2021. For all plans requiring patient-specific QA, we recorded when each plan was available for physics QA and which treatments started the following day. We further classified those plans into four categories (urgency levels 1-4 with 4 being the most urgent) depending on how much time was available to perform QA. We compared the proportion of these next-day QAs in each category between time periods accounting for plan type, day of the week, and time of year.Overall QA numbers were similar between time periods with 797 and 765 QAs total. The total proportion of next-day QA decreased by 27% and the proportions of urgency levels 1 and 4 both showed significant decreases after whiteboard implementation of 29.2% and 54.9%, respectively (The integrated whiteboard system significantly reduced the proportion of last-minute physics work, increasing patient safety. Advantages of the integrated whiteboard were low cost, low overhead with automatic interface to the OIS, and concurrent user support.

Introduction A novel approach of in-advance preparatory respiratory training and practice for deep inspiration breath holding (DIBH) has been shown to further reduce cardiac dose in breast cancer radiotherapy patients, enabled by deeper (extended) DIBH. Here we investigated the consistency and stability of such training-induced extended DIBH after training completion and throughout the daily radiotherapy course. Methods Daily chestwall motion from real-time surface tracking transponder data was analysed in 67 left breast radiotherapy patients treated in DIBH. Twenty-seven received preparatory DIBH training/practice (prep Trn) 1-2 weeks prior to CT simulation, resulting in an extended DIBH (ext DIBH) and reduced cardiac dose at simulation. Forty had only conventional immediate pre-procedure DIBH instruction without prep Trn and without extended DIBH (non-Trn group). Day-to-day variability in chestwall excursion pattern during radiotherapy was compared among the groups. Results The average of daily maximum chestwall excursions was overall similar, 2.5 ± 0.6 mm for prep Trn/ext DIBH vs. 2.9 ± 0.8 mm for non-Trn patients (P = 0.24). Chestwall excursions beyond the 3-mm tolerance threshold were less common in the prep Trn/ext DIBH group (18.8% vs. 37.5% of all fractions within the respective groups, P = 0.038). Among patients with cardiopulmonary disease those with prep Trn/ext DIBH had fewer chestwall excursions beyond 3 mm (9.4% vs. 46.7%, P = 0.023) and smaller average maximum excursions than non-Trn patients (2.4 ± 0.3 vs. 3.0 ± 0.6 mm, P = 0.047, respectively). Conclusion Similar stability of daily DIBH among patients with and without preparatory training/practice suggests that the training-induced extended DIBH and cardiac dose reductions were effectively sustained throughout the radiotherapy course. Training further reduced beyond-tolerance chestwall excursions, particularly in patients with cardiopulmonary disease.

Interleukin (IL) 2 and IL15 are two members of the common gamma chain cytokine family, involved in the regulation of the T cell differentiation process. Both molecules use a specific alpha subunit, IL2Rα and IL15Rα, and share the same beta and gamma chains signaling receptors. The presence of the specific alpha subunit modulates the T cell ability to compete for both soluble cytokines while the beta and gamma subunits are responsible for the signal transduction. Recent experimental results point out that the specific alpha subunits modulate the capacity of IL2 and IL15 to induce the differentiation of stimulated T cells. In other membrane receptors, the outcome of the signal transduction has been associated with the strength of the interaction of the signaling subunits. Here, we investigate how IL2Rα and IL15Rα modulate the stability of their signaling complexes by combining molecular dynamics simulations and free energy calculations. Our simulations predict that IL2Rα binding destabilizes the β-γc interaction mediated by IL2, while IL15Rα has the opposite effect. These results explain the ability of IL2Rα and IL15Rα to modulate the signaling outcome and suggest new strategies for the development of better CD8+ T cell differentiation protocols for adoptive cell transfer (ACT).

The cell culture is the central piece of a biotechnological industrial process. It includes upstream (e.g. media preparation, fixed costs, etc.) and downstream steps (e.g. product purification, waste disposal, etc.). In the continuous mode of cell culture, a constant flow of fresh media replaces culture fluid until the system reaches a steady state. This steady state is the standard operation mode which, under very general conditions, is a function of the ratio between the cell density and the dilution rate and depends on the media supplied to the culture. To optimize the production process it is widely accepted that the concentration of the metabolites in this media should be carefully tuned. A poor media may not provide enough nutrients to the culture, while a media too rich in nutrients may be a waste of resources because, either the cells do not use all of the available nutrients, or worse, they over-consume them producing toxic byproducts. In this work, we show how an in-silico study of a genome scale metabolic network coupled to the dynamics of a chemostat could guide the strategy to optimize the media to be used in a continuous process. Given a known media we model the concentrations of the cells in a chemostat as a function of the dilution rate. Then, we cast the problem of optimizing the production process within a linear programming framework in which the goal is to minimize the cost of the media keeping fixed the cell concentration for a given dilution rate in the chemostat. We evaluate our results in two metabolic models: first a simplified model of mammalian cell metabolism, and then in a realistic genome-scale metabolic network of mammalian cells, the Chinese Hamster Ovary (CHO) cell line. We explore the latter in more detail given specific meaning to the predictions of the concentrations of several metabolites. This article is protected by copyright. All rights reserved.

In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality., Lay abstract In COVID-19 patients, inflammation is associated with the progression of the disease. This inflammation comes from immune system activation in response to SARS-COV-2. Itolizumab is an antibody that recognizes a protein expressed in immune cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of inflammation and immune system activation. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access clinical protocol. Itolizumab was able to reduce inflammation in all patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.

The COVID-19 pandemic continues to limit medical students' full reintegration into clinical learning environments, thus exacerbating an ongoing challenge in identifying a robust number of clinical educational activities at excellent clinical sites for all students. Because medical students across the United States were removed from direct patient care activities in mid-March 2020 due to COVID-19, medical centers have prioritized and implemented changes to the process of patient care. As some barriers are being lifted in the face of a highly contagious and deadly infection, the use of telehealth (delivery of health services remotely via telephone, video, and secure messaging), although not new, is rapidly expanding into all aspects of patient care. Health care providers have been encouraged to conduct many interactions at a physical distance. Telehealth largely replaced face-to-face visits for nonemergency care in an attempt to slow viral transmission while enabling physicians to continue to deliver patient education, manage acute and chronic illness, and nurture caring doctor-patient relationships. Health care providers, many of whom were initially reluctant to embrace telehealth technology and logistics, are becoming nimbler and more aware of the many positive aspects of telehealth. The authors suggest that integrating medical students into telehealth activities would help maintain and improve patients' health, extend the capabilities of health care teams and systems during and after the pandemic, and increase medical students' opportunities for experiential learning and professional identity formation. The authors expand on these 3 goals, suggest several concrete student telehealth activities, propose a curricular strategy, and outline opportunities to overcome key barriers to full alignment of telehealth and undergraduate medical education.

Background: Research is needed to improve understanding of work-life integration issues in academic medicine and to guide the implementation of the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists (FRCS), a national initiative offering financial support to physician-scientists facing caregiving challenges. Materials and Methods: In 2018, as part of a prospective program evaluation, the authors conducted a qualitative study to examine FRCS program participants' initial impressions, solicit descriptions of their career and caregiving experiences, and inquire how such factors might influence their professional advancement. The authors invited all 33 awardees who had been granted FRCS funding in the first year of the program to participate in the study, of whom 28 agreed to complete an interview. Analysts evaluated de-identified transcripts and explicated the data using a thematic analysis approach. Results: While participants described aspects of a culture that harbor stigma against caregivers and impede satisfactory work-life integration, they also perceived an optimistic cultural shift taking place as a result of programs like the FRCS. Their comments indicated that the FRCS has the potential to influence culture if institutional leadership simultaneously fosters a community that validates individuals both as caregivers and as scientists. Conclusions: Insights garnered from this qualitative study suggest that there is a pressing need for institutional leaders to implement programs that can foster awareness and normalization of caregiving challenges. In addition to providing funding and other tangible resources, interventions should strive to reinforce a broader culture that affirms the presence of work-life integration challenges and openly embraces solutions.

As the nation seeks to recruit and retain physician-scientists, gaps remain in understanding and addressing mitigatable challenges to the success of faculty from underrepresented minority (URM) backgrounds. The Doris Duke Charitable Foundation Fund to Retain Clinical Scientists program, implemented in 2015 at 10 academic medical centers in the United States, seeks to retain physician-scientists at risk of leaving science because of periods of extraordinary family caregiving needs, hardships that URM faculty-especially those who identify as female-are more likely to experience. At the annual Fund to Retain Clinical Scientists program directors conference in 2018, program directors-21% of whom identify as URM individuals and 13% as male-addressed issues that affect URM physician-scientists in particular. Key issues that threaten the retention of URM physician-scientists were identified through focused literature reviews; institutional environmental scans; and structured small- and large-group discussions with program directors, staff, and participants. These issues include bias and discrimination, personal wealth differential, the minority tax (i.e., service burdens placed on URM faculty who represent URM perspectives on committees and at conferences), lack of mentorship training, intersectionality and isolation, concerns about confirming stereotypes, and institutional-level factors. The authors present recommendations for how to create an environment in which URM physician-scientists can expect equitable opportunities to thrive, as institutions demonstrate proactive allyship and remove structural barriers to success. Recommendations include providing universal training to reduce interpersonal bias and discrimination, addressing the consequences of the personal wealth gap through financial counseling and benefits, measuring the service faculty members provide to the institution as advocates for URM faculty issues and compensating them appropriately, supporting URM faculty who wish to engage in national leadership programs, and sustaining institutional policies that address structural and interpersonal barriers to inclusive excellence.