DR5 disulfide bonding as a sensor and effector of protein folding stress.

New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity, but TRAIL analogs or agonistic antibodies targeting these receptors have not received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may bypass some of the pharmacological limitations of these protein drugs. Previously described Disulfide bond Disrupting Agents (DDAs) activate DR5 by altering its disulfide bonding through inhibition of the Protein Disulfide Isomerases (PDIs) ERp44, AGR2, and PDIA1. Work presented here extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of Caspase 8-Caspase 3 mediated pro-apoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy. Disulfide-defective DR5 mutants do not activate the ER stress response or stimulate autophagy, indicating that these DDA-mediated responses are separable from DR5 activation and pro-apoptotic signaling. Importantly, other ER stressors, including Thapsigargin and Tunicamycin also alter DR5 disulfide bonding in various cancer cell lines and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the Integrated Stress Response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands.

A Clinically Significant Difference on the COPM: A Review.

Background. The Canadian Occupational Performance Measure (COPM) assists occupational therapists to identify occupational performance problems using a client-centred approach. Since its first publication in 1991, there has been abundant evidence of the ability of the COPM to detect a statistically significant difference as an outcome measure. There has also been a tacit understanding that a difference of 2 points from pre-test to post-test on either Performance or Satisfaction COPM score represents a clinically significant difference. There is however, some confusion about the origins of this claim. Purpose. To ascertain empirical evidence for the claim that a clinically significant difference is a change score ≥2 points. Method. We conducted a scoping review of peer-reviewed literature (1991-2020) for intervention studies using the COPM as an outcome measure and examined intervention type and change scores. Findings. One hundred studies were identified. The COPM was used to assess effectiveness of eight types of occupational therapy interventions. The common belief, however, was not empirically supported that clinical significance can be asserted on the basis of a two-point change in COPM scores. Implications. Further research is needed to test alternative approaches to asserting clinical significance or a minimal clinically important difference.

Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.

The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells.

Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.

Reported are structure-property-function relationships associated with a class of cyclic thiosulfonate molecules-disulfide-bond disrupting agents (DDAs)-with the ability to downregulate the Epidermal Growth Factor Receptor (HER) family in parallel and selectively induce apoptosis of EGFR+ or HER2+ breast cancer cells. Recent findings have revealed that the DDA mechanism of action involves covalent binding to the thiol(ate) from the active site cysteine residue of members of the protein disulfide isomerase (PDI) family. Reported is how structural modifications to the pharmacophore can alter the anticancer activity of cyclic thiosulfonates by tuning the dynamics of thiol-thiosulfonate exchange reactions, and the studies reveal a correlation between the biological potency and thiol-reactivity. Specificity of the cyclic thiosulfonate ring-opening reaction by a nucleophilic attack can be modulated by substituent addition to a parent scaffold. Lead compound optimization efforts are also reported, and have resulted in a considerable decrease of the IC50 /IC90 values toward HER-family overexpressing breast cancer cells.

Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death.

Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.

Degree of Correspondence Between Retrospective and Proximal Reports of Borderline Personality Disorder Symptoms, Symptom Triggers, and Emotions.

This study investigated the degree of correspondence of retrospective reports of personality disorder symptoms, triggers, and emotions with reports closer in time to the actual experiences. Retrospective reports of symptoms, triggers, and emotions are heavily used in both clinical and research settings, yet no study has investigated the correspondence for symptoms or triggers of personality disorders. A total of 257 participants, including 75 with BPD, completed overlapping daily, weekly, monthly, and semi-annual questionnaires. Retrospective reports showed: (1) systematic biases, reporting fewer symptom and situational trigger occurrences, and greater emotion intensities; but (2) little unsystematic error, largely reproducing bias-adjusted individual levels of symptoms, situational triggers, and emotions (rs generally .70-.80). People with BPD did not retrospectively misremember their symptoms, triggers, or emotions much more than others. Thus, retrospective reports of symptoms, triggers, and emotions should be adjusted for systematic bias, but after such adjustment can be taken as relatively faithful accounts of individuals' experiences.

Repurposing Tranexamic Acid as an Anticancer Agent.

Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.

Disulfide bond-disrupting agents (DDAs) are a new chemical class of agents recently shown to have activity against breast tumors in animal models. Blockade of tumor growth is associated with downregulation of EGFR, HER2, and HER3 and reduced Akt phosphorylation, as well as the induction of endoplasmic reticulum stress. However, it is not known how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, DDAs are the first compounds identified that upregulate the TRAIL receptor DR5 through transcriptional and post-transcriptional mechanisms to activate the extrinsic cell death pathway. At the protein level, DDAs alter DR5 disulfide bonding to increase steady-state DR5 levels and oligomerization, leading to downstream caspase 8 and 3 activation. DDAs and TRAIL synergize to kill cancer cells and are cytotoxic to HER2+ cancer cells with acquired resistance to the EGFR/HER2 tyrosine kinase inhibitor Lapatinib. Investigation of the mechanisms responsible for DDA selectivity for cancer cells reveals that DDA-induced upregulation of DR5 is enhanced in the context of EGFR overexpression. DDA-induced cytotoxicity is strongly amplified by MYC overexpression. This is consistent with the known potentiation of TRAIL-mediated cell death by MYC. Together, the results demonstrate selective DDA lethality against oncogene-transformed cells, DDA-mediated DR5 upregulation, and protein stabilization, and that DDAs have activity against drug-resistant cancer cells. Our results indicate that DDAs are unique in causing DR5 accumulation and oligomerization and inducing downstream caspase activation and cancer cell death through mechanisms involving altered DR5 disulfide bonding. DDAs thus represent a new therapeutic approach to cancer therapy.

A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers.

While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

Personal, environmental, and family factors of participation among young children.

OBJECTIVE: The purpose of this study is to assess the influences of environment, population characteristics, and service utilization on participation frequency and involvement in the home setting among children 0 to 5 years. METHOD: Data were collected from parents of 236 children (mean age 3 years and 5 months, SD = 1.30, girls = 152 and boys = 84) using a children's treatment centre in Ontario through an online survey. Two path models measuring home frequency and home involvement were assessed using structural equation modelling. The exogenous factors in the models included child's age, child's sex, child's complexity, number of environmental barriers, income, mother's participation, and service utilization. In addition to participation as the primary outcome, each model explored predictors of service utilization and mother's participation. RESULTS: The involvement model (R2  = 0.46) explained more variance than the frequency model (R2  = 0.33). Age (0.35, P < 0.001) and barriers (0.07, P = 0.001) predicted participation frequency in the home, χ2 (9) = 8.51, P < 0.4, root mean square error of approximation (RMSEA) = 0.00, comparative fit index (CFI) = 1.00. The home involvement model, χ2 (6) = 9.79, P < 0.13, RMSEA = 0.06, CFI = 0.97, showed that increasing age (0.09, P < 0.001), lower complexity (0.13, P = 0.001), and higher mother's participation (0.057, P = 0.001) were significantly related to higher participation. An increase in child's age or complexity significantly influenced service utilization across both models. Complexity reduced mother's participation in both the frequency and involvement models. CONCLUSIONS: This study is one of the first in Canada to examine participation of young children. The aggregation of each unit factor, particularly barriers and complexity, can accrue a large impact on the child's and mother's participation. The potential to mediate this impact by removing environmental barriers and promoting mother's participation merits further study.

The unfolded protein response as a target for anticancer therapeutics.

The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells, responsible for protein synthesis, folding, sorting, and transportation. ER stress is initiated when the unfolded or misfolded protein load exceeds the capacity of the ER to properly fold protein. Tumor microenvironmental conditions, such as nutrient deprivation, hypoxia, and oxidative stress perturb protein folding and trigger chronic ER stress. Cancer cells can tolerate mild ER stress, however, persistent and severe ER stress kills cancer cells by inducing their autophagy, apoptosis, necroptosis, or immunogenic cell death. Based on this rationale, many drugs have been developed for triggering irremediable ER stress in cancer cells by targeting various processes in the secretory pathway. This review discusses the mechanisms of protein targeting to the ER, the key signaling cassettes that are involved in the ER stress response, and their correlation with cancer formation and progression. Importantly, this review discusses current experimental and FDA approved anti-cancer drugs that induce ER stress, and emerging targets within the secretory pathway for the development of new anticancer drugs.

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers.

Ischemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age-mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23-26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near-complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co-overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C-terminus of MFN2, leading to autophagy activation. The SIRT1-MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

The effectiveness of the Pathways and Resources for Engagement and Participation (PREP) intervention: improving participation of adolescents with physical disabilities.

AIM: This study examined the effectiveness of the Pathways and Resources for Engagement and Participation (PREP) intervention in improving the participation of adolescents in community-based activities. METHOD: Twenty-eight adolescents (14 males, 14 females), aged 12 to 18 years (mean 14y 6mo, SD 21.6mo) with moderate physical disabilities participated in a 12-week PREP intervention. An interrupted time series design with multiple baselines was employed, replicating the intervention effect across three chosen activities and all participants. An occupational therapist worked individually with adolescents and parents to identify and implement strategies to remove environmental barriers that impede participation in selected activities. Activity performance was repeatedly measured using the Canadian Occupational Performance Measure (COPM) at baseline, intervention, and follow-up (20wks). For each activity, the trajectory representing change in performance was analyzed descriptively. Segmented regression combined with a mixed-effects modeling approach was used to statistically estimate the overall effectiveness of the intervention within and across 79 activities. RESULTS: A statistically significant improvement (B=2.08, p<0.001) was observed across all activities, 59 per cent of which also indicated a clinically significant change of more than 2 points on the COPM scale. Levels of performance were maintained during follow-up with an additional increase of 0.66 points on the COPM scale (t=3.04, p=0.004). Intervention was most effective for males and those with a higher number of functional issues. INTERPRETATION: Findings illustrate that participation can be improved by changing the environment only. Such evidence further supports emerging therapeutic approaches that are activity-based, goal-oriented, and ecological in nature. WHAT THIS PAPER ADDS: Environment-based intervention strategies, guided by the Pathways and Resources for Engagement and Participation, are effective in improving and maintaining adolescent participation. Intervention was most effective for males and those with a higher number of functional issues. The study design serves as an example for future pragmatic studies accounting for individual-based changes and contexts.

Psychometric Evaluation of the Young Children's Participation and Environment Measure (YC-PEM) for use in Singapore.

AIMS: To estimate the psychometric properties of a culturally adapted version of the Young Children's Participation and Environment Measure (YC-PEM) for use among Singaporean families. METHODS: This is a prospective cohort study. Caregivers of 151 Singaporean children with (n = 83) and without (n = 68) developmental disabilities, between 0 and 7 years, completed the YC-PEM (Singapore) questionnaire with 3 participation scales (frequency, involvement, and change desired) and 1 environment scale for three settings: home, childcare/preschool, and community. Setting-specific estimates of internal consistency, test-retest reliability, and construct validity were obtained. RESULTS: Internal consistency estimates varied from .59 to .92 for the participation scales and .73 to .79 for the environment scale. Test-retest reliability estimates from the YC-PEM conducted on two occasions, 2-3 weeks apart, varied from .39 to .89 for the participation scales and from .65 to .80 for the environment scale. Moderate to large differences were found in participation and perceived environmental support between children with and without a disability. CONCLUSIONS: YC-PEM (Singapore) scales have adequate psychometric properties except for low internal consistency for the childcare/preschool participation frequency scale and low test-retest reliability for home participation frequency scale. The YC-PEM (Singapore) may be used for population-level studies involving young children with and without developmental disabilities.

Relationships between Adaptive Behaviours, Personal Factors, and Participation of Young Children.

AIM: To examine the extent to which personal factors (age, socioeconomic grouping, and preterm birth) and adaptive behaviour explain the participation patterns of young children. METHODS: 65 Children 2-5 years old with and without a history of preterm birth and no physical or intellectual disability were selected by convenience sampling from Galway University Hospital, Ireland. Interviews with parents were conducted using the Adaptive Behaviour Assessment System, Second Edition (ABAS-II) and the Assessment of Preschool Children's Participation (APCP). Linear regression models were used to identify associations between the ABAS-II scores, personal factors, and APCP scores for intensity and diversity of participation. RESULTS: Adaptive behaviour explained 21% of variance in intensity of play, 18% in intensity of Skill Development, 7% in intensity of Active Physical Recreation, and 6% in intensity of Social Activities controlling for age, preterm birth, and socioeconomic grouping. Age explained between 1% and 11% of variance in intensity of participation scores. Adapted behaviour (13%), Age (17%), and socioeconomic grouping (5%) explained a significant percentage of variance in diversity of participation controlling for the other variables. CONCLUSIONS: Adaptive behaviour had a unique contribution to children's intensity and diversity of participation, suggesting its importance.

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells.

Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and "Triple-Negative" Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR). Thus agents that selectively kill EGFR+ and HER2+ tumors would provide new options for breast cancer therapy. We previously identified a class of compounds we termed Disulfide bond Disrupting Agents (DDAs) that selectively kill EGFR+ and HER2+ breast cancer cells in vitro and blocked the growth of HER2+ breast tumors in an animal model. DDA-dependent cytotoxicity was found to correlate with downregulation of HER1-3 and Akt dephosphorylation. Here we demonstrate that DDAs activate the Unfolded Protein Response (UPR) and that this plays a role in their ability to kill EGFR+ and HER2+ cancer cells. The use of breast cancer cell lines ectopically expressing EGFR or HER2 and pharmacological probes of UPR revealed all three DDA responses: HER1-3 downregulation, Akt dephosphorylation, and UPR activation, contribute to DDA-mediated cytotoxicity. Significantly, EGFR overexpression potentiates each of these responses. Combination studies with DDAs suggest that they may be complementary with EGFR/HER2-specific receptor tyrosine kinase inhibitors and mTORC1 inhibitors to overcome drug resistance.

Measuring Participation of Children and Environmental Factors at Home, School, and in Community: Construct Validation of the Korean PEM-CY.

AIMS: To determine construct validity of the Korean Participation and Environment Measure for Children and Youth (KPEM-CY) in South Korea. METHODS: A total of 184 parents of children with (n = 80) and without disabilities (n = 104) aged 5 to 13 years completed the KPEM-CY. Construct validity was analyzed by assessing differences in the participation and environment scores for children with and without disabilities across age and gender. RESULTS: Validity of the KPEM-CY was supported by significant differences in participation and environmental factors for subgroups (p < .05). Children with disabilities participated less in typical activities and had more environmental barriers than those without disabilities across all settings. Parents of children with disabilities reported a higher level of desire to change their children's participation patterns. Similar participation patterns and environmental factors, which were influenced by interaction effects between disability and age, were confirmed at home and in the community. CONCLUSIONS: KPEM-CY is a valid measure to assess participation and environmental factors in home, school, and community settings for Korean children, aged 5-13 years, with and without disabilities.

Leisure participation-preference congruence of children with cerebral palsy: a Children's Assessment of Participation and Enjoyment International Network descriptive study.

AIM: To examine participation-preference congruence, regional differences in participation-preference congruence, and predictors of whether children with cerebral palsy participate in preferred activities. METHOD: The sample (n=236) included 148 males and 88 females aged 10 to 13 years, living in Victoria, Australia (n=110), Ontario (n=80), or Quebec (n=46), Canada. Ninety-nine (41.9%) were classed at Gross Motor Function Classification System (GMFCS) level I; 89 (37.7%) at GMFCS level II/III; and 48 (20.3%) at GMFCS level IV/V. Participants completed the Children's Assessment of Participation and Enjoyment and Preferences for Activity of Children questionnaires. Regional comparisons were performed using one-way analyses of variance and factors influencing participation-preference congruence were explored using multiple linear regression. RESULTS: The proportion of children doing non-preferred activities in each activity type was generally low (2-17%), with only one regional difference. Higher proportions were not doing preferred active physical (range 23.2-29.1% across regions), skill-based (range 21.7-27.9% across regions), and social activities (range 12.8-14.5% across regions). GMFCS level was the most important predictor associated with not doing preferred activities. INTERPRETATION: Children with cerebral palsy did not always participate in preferred active physical and skill-based activities. Understanding discrepancies between preferences and actual involvement may allow families and rehabilitation professionals to address participation barriers.

Current Rehabilitation Practices for Children with Cerebral Palsy: Focus and Gaps.

AIMS: To describe the focus of therapy practices in occupational and physical therapy for school-aged children with cerebral palsy, and better understand whether it is congruent with recommended practices. METHODS: A Canada-wide Web-based survey was completed by 62 occupational and 61 physical therapists to identify problems, assessments, and treatment interventions for two case-based scenarios. Data were coded using the International Classification of Functioning, Disability and Health (ICF) definitions for "body functions and structure," "activity and participation," and "environment." RESULTS: Physical therapists, in comparison to occupational therapists, were more likely to select interventions classed in the "body functions and structure" category (34-42% and 18-20%, respectively). Both professions focused on "activity and participation" (34-61%) when identifying problems, assessing, and intervening; attention, however, was mainly directed towards task-oriented activities such as activities of daily living and mobility. Participation in leisure or community-based activities received less attention (2-15%). The environment received limited attention for problems and assessments (4-25%), though it was an important focus of intervention (19-37%). CONCLUSIONS: While body functions and structure are well-addressed, other ICF elements, specifically participation, are poorly integrated into practice. The emerging focus on the environment in therapy intervention, by modifying the context rather than changing aspects of the child, is consistent with current approaches and evidence. Knowledge translation implementation initiatives are recommended to bridge identified gaps.

Participation in Out-of-Home Environments for Young Children With and Without Developmental Disabilities.

This study examines caregivers' perceptions of participation patterns and environmental supports and barriers for young children with and without developmental disabilities within their child care/preschool and community settings. The Young Children's Participation and Environment Measure (YC-PEM) was completed by 151 parents of Singaporean children (0-7 years old) with and without developmental disabilities. Setting-specific summary and item-level scores of these children were compared using ANCOVA, Mann-Whitney U, and Pearson chi-square tests. Children with developmental disabilities had significantly lower participation and environment summary scores in both settings as compared with children without developmental disabilities (p < .05; [Formula: see text] = 0.03-0.31). Group differences were also evident at the item level, particularly when comparing the percentage of parents who desire change in their child's activity participation. Adequate financial support, public awareness, programs, and services have been identified as environmental factors that are potentially important to parents of children with developmental disabilities.