CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses

Learning from the implementation of clinical empathy training: an explorative qualitative study in search of the barriers and facilitators

Background: Amid concerns about the decline of empathy during the clinical training of medical clerks, evidence that empathy improves patient outcomes suggests some potential for teaching empathy in ways that will affect the knowledge, attitude and behaviour of medical clerks. This potential alone cannot, however, guarantee the success of educational innovations to introduce empathy to the medical curriculum. This research aims to identify the barriers and facilitators of the implementation of a specific clinical initiative to enhance the empathy skills of clerks, namely the training of clerks to act as a ‘MedGezel’ or ‘medical coach’. Method: We conducted an explorative qualitative study based on interview data collected and analyzed using reflexive thematic analysis and the readiness for change theory. We conducted semi-structured interviews with relevant stakeholders in this particular qualitative study. Thematic analysis was based on open and axial coding using ATLAS.ti 9, which facilitated the emergence of common themes of interest and meaning for the study. Results: A total of 13 relevant stakeholders participated as interviewees in our study. The data was collected from April to June 2021. Our analysis generated 6 main themes which can provide insights into why the implementation of the MedGezel educational innovation failed so far. The following themes emerged: the case for change: why change?; practical necessity; leadership; management and resources; staff culture; and alignment with the corporate strategy. Discussion: The implementation failure can be partially explained as resulting from the personal attitudes and choices of participants, who struggled to reconcile a vision that they liked with side effects that they feared. While participants repeatedly mentioned management and leadership issues, these organizational issues seemed less important as they could be easily resolved in practice. What was more important and fatal for the initiative was its lack of alignment with staff culture, despite its alignment with corporate strategy. Conclusion: This investigation into the barriers and facilitators influencing the implementation of the MedGezel program identified 6 explanatory themes, the most impactful one being staff culture

ESPON ACTAREA: Thinking and planning in areas of territorial cooperation European Atlas of Soft Territorial Cooperation

This Atlas contains detailed descriptions of 13 European examples of soft territorial cooperation areas. The selection of cases presented makes no claim to comprehensiveness nor (statistical) representativeness. Cases were selected out of a multitude of identified examples with a view on fitting the project's definition of soft territorial cooperation. Soft territorial cooperation areas were defined as initiatives that define the sectoral scope and geographical boundaries in an ‘open' or ‘fuzzy' way, based on a notion of ‘community of intent' as a voluntary collaboration open to public and private actors who decide to jointly address territory-specific opportunities and challenges. Their other main characteristics are: • a medium to long term integrative perspective (i.e. not limited to the implementation of a single project); • seeking to enhance the capacities of involved players, making them actors of their own development; • renewing relations between institutional levels, sectors of activity and types of actors (e.g. NGOs, private companies, local and regional authorities, agencies…). The soft territorial cooperation areas presented in this Atlas show variations of these characteristics and “openness” in how they define their cooperation area, partnership, thematic scope, type of interventions and governance structure. The way in which case study descriptions are structured shall allow the reader to quickly capture case study characteristics, make cross-connections between the different cases and draw his/ her own conclusions from the presented material. The project team's findings and conclusions can be found in the main project report

ESPON ACTAREA Guide to developing soft territorial cooperation

This handbook builds on the lessons distilled from 24 case studies on soft territorial cooperation in different parts of Europe that were undertaken in the scope of the ESPON ACTAREA project on “Thinking and planning in areas of territorial cooperation”. Case studies focused on analysing and characterising soft territorial cooperation areas regarding - the strategic purpose they pursue; - approaches to region-building they take; - organisational structures they have set up and resources they draw on; - strategies to motivate actors to participate and overcome barriers to cooperation they have developed; and - the policy frameworks and strategies under which they have been create

Yield of Screening for COVID-19 in Asymptomatic Patients Before Elective or Emergency Surgery Using Chest CT and RT-PCR (SCOUT): Multicenter Study

OBJECTIVE: To determine the yield of preoperative screening for COVID-19 with chest CT and RT-PCR in patients without COVID-19 symptoms. SUMMARY OF BACKGROUND DATA: Many centers are currently screening surgical patients for COVID-19 using either chest CT, RT-PCR or both, due to the risk for worsened surgical outcomes and nosocomial spread. The optimal design and yield of such a strategy are currently unknown. METHODS: This multicenter study included consecutive adult patients without COVID-19 symptoms who underwent preoperative screening using chest CT and RT-PCR before elective or emergency surgery under general anesthesia. RESULTS: A total of 2093 patients without COVID-19 symptoms were included in 14 participating centers; 1224 were screened by CT and RT-PCR and 869 by chest CT only. The positive yield of screening using a combination of chest CT and RT-PCR was 1.5% [95% confidence interval (CI): 0.8-2.1]. Individual yields were 0.7% (95% CI: 0.2-1.1) for chest CT and 1.1% (95% CI: 0.6-1.7) for RT-PCR; the incremental yield of chest CT was 0.4%. In relation to COVID-19 community prevalence, up to ∼6% positive RT-PCR was found for a daily hospital admission rate >1.5 per 100,000 inhabitants, and around 1.0% for lower prevalence. CONCLUSIONS: One in every 100 patients without COVID-19 symptoms tested positive for SARS-CoV-2 with RT-PCR; this yield increased in conjunction with community prevalence. The added value of chest CT was limited. Preoperative screening allowed us to take adequate precautions for SARS-CoV-2 positive patients in a surgical population, whereas negative patients needed only routine procedures

Yield of Screening for COVID-19 in Asymptomatic Patients Before Elective or Emergency Surgery Using Chest CT and RT-PCR (SCOUT): Multicenter Study

OBJECTIVE: To determine the yield of preoperative screening for COVID-19 with chest CT and RT-PCR in patients without COVID-19 symptoms. SUMMARY OF BACKGROUND DATA: Many centers are currently screening surgical patients for COVID-19 using either chest CT, RT-PCR or both, due to the risk for worsened surgical outcomes and nosocomial spread. The optimal design and yield of such a strategy are currently unknown. METHODS: This multicenter study included consecutive adult patients without COVID-19 symptoms who underwent preoperative screening using chest CT and RT-PCR before elective or emergency surgery under general anesthesia. RESULTS: A total of 2093 patients without COVID-19 symptoms were included in 14 participating centers; 1224 were screened by CT and RT-PCR and 869 by chest CT only. The positive yield of screening using a combination of chest CT and RT-PCR was 1.5% [95% confidence interval (CI): 0.8-2.1]. Individual yields were 0.7% (95% CI: 0.2-1.1) for chest CT and 1.1% (95% CI: 0.6-1.7) for RT-PCR; the incremental yield of chest CT was 0.4%. In relation to COVID-19 community prevalence, up to ∼6% positive RT-PCR was found for a daily hospital admission rate >1.5 per 100,000 inhabitants, and around 1.0% for lower prevalence. CONCLUSIONS: One in every 100 patients without COVID-19 symptoms tested positive for SARS-CoV-2 with RT-PCR; this yield increased in conjunction with community prevalence. The added value of chest CT was limited. Preoperative screening allowed us to take adequate precautions for SARS-CoV-2 positive patients in a surgical population, whereas negative patients needed only routine procedures

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study

Background: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak. Methods: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342). Findings: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7–7·1), PEEP was 14·0 cm H2O (IQR 11·0–15·0), and driving pressure was 14·0 cm H2O (11·2–16·0). Median respiratory system compliance was 31·9 mL/cm H2O (26·0–39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0–15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. Interpretation: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19. Funding: Amsterdam University Medical Centers, location Academic Medical Center