Evaluation of Digital Technologies Tailored to Support Young People's Self-Management of Musculoskeletal Pain: Mixed Methods Study.

BACKGROUND: Digital technologies connect young people with health services and resources that support their self-care. The lack of accessible, reliable digital resources tailored to young people with persistent musculoskeletal pain is a significant gap in the health services in Australia. Recognizing the intense resourcing required to develop and implement effective electronic health (eHealth) interventions, the adaptation of extant, proven digital technologies may improve access to pain care with cost and time efficiencies. OBJECTIVE: This study aimed to test the acceptability and need for adaptation of extant digital technologies, the painHEALTH website and the iCanCope with Pain app, for use by young Australians with musculoskeletal pain. METHODS: A 3-phased, mixed methods evaluation was undertaken from May 2019 to August 2019 in Australia. Young people aged 15 to 25 years with musculoskeletal pain for >3 months were recruited. Phases were sequential: (1) phase 1, participant testing (3 groups, each of n=5) of co-designed website prototypes compared with a control website (painHEALTH), with user tasks mapped to eHealth quality and engagement criteria; (2) phase 2, participants' week-long use of the iCanCope with Pain app with engagement data captured using a real-time analytic platform (daily check-ins for pain, interference, sleep, mood, physical activity, and energy levels; goal setting; and accessing resources); and (3) phase 3, semistructured interviews were conducted to gain insights into participants' experiences of using these digital technologies. RESULTS: Fifteen young people (12/15, 80% female; mean age 20.5 [SD 3.3] years; range 15-25 years) participated in all 3 phases. The phase 1 aggregated group data informed the recommendations used to guide 3 rapid cycles of prototype iteration. Adaptations included optimizing navigation, improving usability (functionality), and enhancing content to promote user engagement and acceptability. In phase 2, all participants checked in, with the highest frequency of full check-ins attributed to pain intensity (183/183, 100.0%), pain interference (175/183, 95.6%), and mood (152/183, 83.1%), respectively. Individual variability was evident for monitoring progress with the highest frequency of history views for pain intensity (51/183, 32.3%), followed by pain interference (24/183, 15.2%). For the goals set feature, 87% (13/15) of participants set a total of 42 goals covering 5 areas, most frequently for activity (35/42, 83%). For phase 3, metasynthesis of qualitative data highlighted that these digital tools were perceived as youth-focused and acceptable. A total of 4 metathemes emerged: (1) importance of user-centered design to leverage user engagement; (2) website design (features) promoting user acceptability and engagement; (3) app functionality supporting self-management; and (4) the role of wider promotion, health professional digital prescriptions, and strategies to ensure longer-term engagement. CONCLUSIONS: Leveraging extant digital tools, with appropriate user-informed adaptations, can help to build capacity tailored to support young people's self-management of musculoskeletal pain.

Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia.

Phosphatidylserine (PS) exposure increases as red cells age, and is an important signal for the removal of senescent cells from the circulation. PS exposure is elevated in red cells from sickle cell anaemia (SCA) patients and is thought to enhance haemolysis and vaso-occlusion. Although precise conditions leading to its externalisation are unclear, high intracellular Ca2+ has been implicated. Red cells from SCA patients are also exposed to an increased oxidative challenge, and we postulated that this stimulates PS exposure, through increased Ca2+ levels. We tested four different ways of generating oxidative stress: hypoxanthine and xanthine oxidase, phenazine methosulphate, nitrite and tert-butyl hydroperoxide, together with thiol modification with N-ethylmaleimide (NEM), dithiothreitol and hypochlorous acid (HOCl), in red cells permeabilised to Ca2+ using bromo-A23187. Unexpectedly, our findings showed that the four oxidants significantly reduced Ca2+ -induced PS exposure (by 40-60%) with no appreciable effect on Ca2+ affinity. By contrast, NEM markedly increased PS exposure (by about 400%) and slightly but significantly increased the affinity for Ca2+ . Dithiothreitol modestly reduced PS exposure (by 25%) and HOCl had no effect. These findings emphasise the importance of thiol modification for PS exposure in sickle cells but suggest that increased oxidant stress alone is not important.

Genotoxic stress-induced expression of p53 and apoptosis in leukemic clam hemocytes with cytoplasmically sequestered p53.

In nature, the soft shell clam, Mya arenaria, develops a fatal blood cancer in which a highly conserved homologue for wild-type human p53 protein is rendered nonfunctional by cytoplasmic sequestration. In untreated leukemic clam hemocytes, p53 is complexed throughout the cytoplasm with overexpressed variants for both clam homologues (full-length variant, 1,200-fold and truncated variant, 620-fold above normal clam hemocytes) of human mortalin, an Hsp70 family protein. In vitro treatment with etoposide only and in vivo treatment with either etoposide or mitoxantrone induces DNA damage, elevates expression (600-fold) and promotes nuclear translocation of p53, and results in apoptosis of leukemic clam hemocytes. Pretreatment with wheat germ agglutinin followed by etoposide treatment induces DNA damage and elevates p53 expression (893-fold) but does not overcome cytoplasmic sequestration of p53 or induce apoptosis. We show that leukemic clam hemocytes have an intact p53 pathway, and that maintenance of this tumor phenotype requires nuclear absence of p53, resulting from its localization in the cytoplasm of leukemic clam hemocytes. The effects of these topoisomerase II poisons may result as mortalin-based cytoplasmic tethering is overwhelmed by de novo expression of p53 protein after DNA damage induced by genotoxic stress. Soft shell clam leukemia provides excellent in vivo and in vitro models for developing genotoxic and nongenotoxic cancer therapies for reactivating p53 transcription in human and other animal cancers displaying mortalin-based cytoplasmic sequestration of the p53 tumor suppressor, such as colorectal cancers and primary and secondary glioblastomas, though not apparently leukemias or lymphomas.

Mortalin-based cytoplasmic sequestration of p53 in a nonmammalian cancer model.

In nature the soft shell clam Mya arenaria develops a fatal neoplasm that shares molecular similarity with an unrelated group of human cancers. In leukemic clam hemocytes, wild-type p53 and mortalin proteins co-localize in the cytoplasm. A similar phenotype, characterized by cytoplasmic sequestration of wild-type p53 protein, has been observed in several human cancers (undifferentiated neuroblastoma, retinoblastoma, colorectal and hepatocellular carcinomas, and glioblastoma). In some of these cancers p53 is tethered in the cytoplasm by mortalin when the latter protein is overexpressed. Using co-immunoprecipitation we have demonstrated that mortalin and p53 proteins are complexed in the cytoplasm of leukemic clam hemocytes (and not in normal hemocytes). In addition, treatment of leukemic clam hemocytes with MKT-077, a cationic inhibitor of mortalin, disrupts the interaction of mortalin and p53 proteins, resulting in translocation of some p53 to the nucleus. Based on these data, we introduce leukemic clam hemocytes as novel and easily accessible, in vivo and in vitro models for human cancers displaying a similar mortalin-based phenotype. Treatment of these models with novel chemotherapeutics may help reveal the molecular mechanism(s) involved in inactivating p53 by this form of cytoplasmic sequestration.