Growing malignant tumors must evade destruction by the immune system, a hurdle some malignancies overcome by attracting immune-suppressive regulatory T-cells (Tregs)1. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Tregs, and IKZF2 deficiency enhances immune responses to tumors in mice2, suggesting IKZF2 may be an attractive target for cancer immunotherapy. Here we describe the discovery and characterization of DKY709, the first molecular glue degrader of IKZF2/4 which spares IKZF1/3. DKY709 was identified through a recruitment-guided medicinal chemistry campaign that redirected the degradation selectivity of CRBN binders towards IKZF2. The IKZF transcription factor selectivity of DKY709 was rationalized by the X-ray structure of the CRBN-DKY709-IKZF2(ZF2) ternary complex. Upon exposure to DKY709, human Tregs showed reduced suppressive activity and exhausted T-effector cells recovered IFNγ production. In vivo, oral treatment with DKY709 drove a rapid and sustained degradation of IKZF2 including in humans and led to delayed tumor growth in mice with humanized immune systems and enhanced immunization responses in monkeys. DKY709 is a first-in-class, potent and selective oral IKZF2/4 degrader currently being investigated in a phase 1 clinical trial as an immune-enhancing agent for cancer immunotherapy.

Balancing post-operative adequate pain control, respiratory depression, and return of bowel function can be particularly challenging in infants receiving the Kasai procedure (hepatoportoenterostomy). We performed a retrospective chart review of all patients who underwent the Kasai procedure from a single surgeon at Children’s Healthcare of Atlanta from 1 January 2018, to 1 September 2022. 12 patients received the Kasai procedure within the study period. Average weight was 4.47 kg and average age was 7.4 weeks. Most patients received multimodal pain management including dexmedetomidine and/or ketorolac along with intravenous opioids. A balance of colloid and crystalloids were used for all patients; 57% received blood products as well. All patients were extubated in the OR and transferred to the general surgical floor without complications. Return of bowel function occurred in all patients by POD2, and enteral feeds were started by POD3. One patient had a presumed opioid overdose while admitted requiring a rapid response and brief oxygen supplementation. Simultaneously optimizing pain control, respiratory safety, and bowel function is possible in infants receiving the Kasai procedure. Based on our experience and the current pediatric literature, we propose an enhanced recovery protocol to improve patient outcomes in this fragile population. Larger, prospective studies implementing an enhanced recovery protocol in the Kasai population are required for stronger evidence and recommendations.

Purpose As self-advocate leaders, the authors aim to present the perspective of people with learning disabilities on “Behaviour that Challenges: A Unified Approach”. Building on firsthand accounts which reveal compassion and cruelty in the health-care system, the authors propose ways of working, which confirm and add to the thinking in “A Unified Approach”, especially “Capable Environments”. Design/methodology/approach To ensure integrity, the authors engaged contributors with lived experience of admission to secure care after acting in ways that put themselves or others at risk. The authors included the perspective of people whose severe learning disabilities limit them to few or no words as best they could by interviewing their parents. The authors were supported and advised in the writing of this commentary while retaining full control throughout. Findings While recognising compassionate care, the authors suggest the provider’s power over a person’s life is a central reason for the care system’s vulnerability to the cruelty evident in firsthand accounts. The authors propose practical ways to offset this power. Firsthand accounts suggest the key features of capable environments are communication, valuing families and developing a valued, caring, well-trained workforce. Lived experience in workforce training and peer-support to individuals offer great potential to transform outcomes. Originality/value The perspectives of diverse contributors with learning disabilities bring lived experience insight to the challenges of “behaviour that challenges”. The authors aim to add value by blending lived experience viewpoints with the emotion of firsthand accounts of care. The insights of lived experience – too often a marginal consideration in health-care design – are presented here as central to care that fully achieves what people want and need.

Purpose Inspired by the work of the Keep Safe Advisory Group, this paper aims to explain and make the case for co-production as a powerful model for working alongside people with learning disabilities. Design/methodology/approach The collaborative approach of the Keep Safe advisory group is the authors’ springboard for a deep dive into the power and potential of co-production as a model. As organisational leaders – one with and one without a learning disability – the authors draw on their personal experience to argue that co-production is essential to recognising the adulthood of people with learning disabilities. Findings Co-production means the equal sharing of power and responsibility from the start, best served by the leap of faith of a blank agenda. Co-production values different kinds of expertise as complementary – broadly considered as expertise from lived experience and professional expertise. When working co-productively, a deep investment of time to understand people pays dividends in outcomes and everyone’s personal and professional growth. Co-production enriches the lives of everyone taking part. Originality/value Co-production, though common currency in health and social care, remains too rarely understood and practiced. Readers will benefit from this reflective viewpoint, which aims to clarify and deepen what co-production really means. In particular, enabling people with learning disabilities to take responsibility for themselves and others is rarely considered but is presented here as foundational to human maturity and adulthood.