Soluble CD4 and low molecular weight CD4-mimetic compounds sensitize cells to be killed by anti-HIV cytotoxic immunoconjugates.

IMPORTANCE: HIV infection can be effectively treated to prevent the development of AIDS, but it cannot be cured. We have attached poisons to anti-HIV antibodies to kill the infected cells that persist even after years of effective antiviral therapy. Here we show that the killing of infected cells can be markedly enhanced by the addition of soluble forms of the HIV receptor CD4 or by mimics of CD4.

Breaking the cycle: extending the persistent pain cycle diagram using an affective pictorial metaphor.

The persistent pain cycle diagram is a common feature of pain management literature. but how is it designed and is it fulfilling its potential in terms of providing information to motivate behavioral change? This article examines on-line persistent pain diagrams and critically discusses their purpose and design approach. By using broad information design theories by Karabeg and particular approaches to dialogic visual communications in business, this article argues the need for motivational as well as cognitive diagrams. It also outlines the design of a new persistent pain cycle that is currently being used with chronic pain patients in NHS Bradford, UK. This new cycle adopts and then visually extends an established verbal metaphor within acceptance and commitment therapy (ACT) in an attempt to increase the motivational aspects of the vicious circle diagram format.

Confidence of practitioners to support self-management of pain: A multidisciplinary survey.

Background: Supported self-management is an important component of management for persistent pain according to current recommendations and guidelines. However, it is unclear whether staff from differing disciplines who may be in early contact with people with established or developing persistent pain are confident to introduce and support self-management for this patient group. Aim: To determine the confidence of staff across professional disciplines to introduce and support self-management. Design and Setting: Cross-sectional online survey. Methods: Charts were constructed to represent information on professional grouping, prior training in self-management and confidence in supporting key components of self-management for persistent pain. Analysis of variance was used to test for differences between groups. Results: Overall, 165 practitioners reported confidence to support self-management below the midpoint of a ten-point scale and 93 above. There were few differences between different professions apart from in explaining pain (f = 6.879 p < .001), managing activity levels (f = 6.340 p < .001) and supporting healthy habits (f = 4.700, p = .001) in which physiotherapists expressed higher confidence than other professional groups. There was no difference in confidence expressed between staff who had or had not received previous training in self-management (f = 1.357, p = .233). Conclusions: Many front-line staff who might be expected to introduce and deliver self-management support for persistent pain lack the confidence and skills to do so. This is consistent with a known lack of education about pain across disciplinary boundaries in primary and community-based care. In order to meet treatment priorities for persistent pain there is an urgent need to upskill the workforce by providing access to good quality training and resources.

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191.

Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655.

'Power to the People, to the people': Training for social prescribers improves support of persistent pain.

Introduction: Supported self-management is an important aspect of managing pain, however widely held beliefs about the biomedical nature of pain and limited time availability can make it a tricky concept to introduce to patients. Social prescribers are in an ideal position to support self-management of pain if appropriate training is available to support them. This study aimed to evaluate training for social prescribers and to explore their opinions and experiences about providing self-management support. Methods: This was a mixed methods study. Repeated measures t-tests were used to compare the reported confidence of attendees in supporting different facets of self-management before and after the training. Thematic analysis of interviews was used to develop a deeper understanding of how participants related the training to their work with patients. Results: Average confidence improved in all aspects of supporting self-management, and particularly with regard to supporting understanding pain, acceptance, pacing, setting goals, sleep and managing setbacks. Challenges were identified around explaining pain in an accurate and accessible way in order to provide a meaningful rationale for self-management. Conclusion: Training for social prescribers in self-management support is feasible and leads to improvements in self-reported confidence. Further research is needed to determine the impact on patients and over a longer period of time.

Identification of Anti-gp41 Monoclonal Antibodies That Effectively Target Cytotoxic Immunoconjugates to Cells Infected with Human Immunodeficiency Virus, Type 1.

We are developing cytotoxic immunoconjugates (CICs) targeting the envelope protein (Env) of the Human Immunodeficiency Virus, type 1 (HIV) to purge the persistent reservoirs of viral infection. We have previously studied the ability of multiple monoclonal antibodies (mAbs) to deliver CICs to an HIV-infected cell. We have found that CICs targeted to the membrane-spanning gp41 domain of Env are most efficacious, in part because their killing is enhanced in the presence of soluble CD4. The ability of a mAb to deliver a CIC does not correlate with its ability to neutralize nor mediate Ab-dependent cellular cytotoxicity. In the current study, we seek to define the most effective anti-gp41 mAbs for delivering CICs to HIV-infected cells. To do this, we have evaluated a panel of human anti-gp41 mAbs for their ability to bind and kill two different Env-expressing cell lines: persistently infected H9/NL4-3 and constitutively transfected HEK293/92UG. We measured the binding and cytotoxicity of each mAb in the presence and absence of soluble CD4. We found that mAbs to the immunodominant helix-loop-helix region (ID-loop) of gp41 are most effective, whereas neutralizing mAbs to the fusion peptide, gp120/gp41 interface, and the membrane proximal external region (MPER) are relatively ineffective at delivering CICs. There was only a weak correlation between antigen exposure and killing activity. The results show that the ability to deliver an effective IC and neutralization are distinct functions of mAbs.

Pain through the perspective of art and creativity: insights from the Unmasking Pain project.

People struggle to tell their story of living with pain and when they do it is articulated in a way that may not be understood, heard or taken seriously. Unmasking Pain is an artist-led project that explored creative approaches to tell stories of life with pain. The project was led by a dance theatre company that specialises in storytelling and emotional experiences for players and audiences. The project involved artists and people living with ongoing pain co-creating activities and environments to curiously explore "oneself", through imagination and creative expression. This article discusses insights and perspectives emerging from the project. The project revealed the power of art to make-sense of oneself with or without pain, and how art facilitates expression of complex inner experience and personal stories. People described Unmasking Pain as "explorative joy despite pain", and "a new set of rules" that contrasts with those experienced during clinical encounters. We discuss how art has the potential to improve clinical encounters and promote health and well-being, and whether artist-led activities are an intervention, therapy, or something else. Pain rehabilitation specialists from the project described Unmasking Pain as "freeing-up thinking", allowing conceptual thought beyond the biopsychosocial model of pain. We conclude that art has the potential to shift people living with pain from "I can't do, I am not willing to do it" to "Perhaps I can, I'll give it a go, I enjoyed".

Developmental aspects of temporal and spatial visual attention: insights from the attentional blink and visual search tasks.

Frontal regions of the human cortex are thought to reach full maturation last in the course of development. The present report examines such development in the context of attentional tasks in the temporal (e.g., the attentional blink, AB, paradigm) and spatial (e.g., the visual search, VS, paradigm) domains. Here we show that the recovery from AB is progressively longer with younger age by studying 7-, 12-, 15-year-olds, and adults participating on a modified AB task. By contrast, we found no difference between 7-year-olds and adults in a VS task using the same target stimuli as in the AB task. This differential pattern of development between temporal and spatial attention is discussed in relation to visual working memory development, clinical populations, and general mechanisms of cortical development.