Healthcare Utilization and Costs in Children Receiving Home Mechanical Ventilation in Ontario: A 14-Year Cohort Study.

RATIONALE: Home mechanical ventilation (HMV) is an advanced medical therapy offered to children with medical complexity. Despite the growing pediatric HMV population in North America, there are limited studies describing healthcare utilization and predictors of highest costs using robust health administrative data. OBJECTIVES: To describe patterns of healthcare utilization and costs in children receiving HMV over a 14-year period in Ontario, Canada. METHODS: We conducted a retrospective population-based cohort study (April 1, 2003 to March 31, 2017) of children aged 0-18 years receiving HMV via invasive mechanical ventilation (IMV) or non-invasive ventilation (NIV). Paired t-tests compared healthcare system utilization and costs two years before and two years after HMV approval. We developed linear models to analyze variables associated with children in the top quartile of health service utilization and costs. RESULTS: We identified 835 children receiving HMV. In the two years after HMV approval compared to the 2 years prior, children had decreased hospitalization days (median 9 (IQR 3-30) versus 29 (6-99), p<0.0001) and ICU admission days (6.6 (1.9-18.0) versus 17.1 (3.3-70.9), p<0.0001) but had increased homecare service approvals (195 (24-522) versus 40 (12-225), p<0.0001) and outpatient Pulmonology visits (3 (1-4) versus 2 (1-3), p<0.0001). Total healthcare costs were higher in the two years after HMV approval (mean $164,892 (SD $214,187) versus $128,941 ($194,199), p<0.0001). However, all-cause hospital admission costs were reduced ($66,546 ($142,401) versus $81,578 ($164,672), p<0.0001). Highest total 2-year costs were associated with IMV (OR 3.45, 95% CI 2.24-5.31; reference NIV), number of medical devices at home (OR 1.63, 95% CI 1.35-1.96; reference no technology), and increased healthcare costs in the year prior to HMV initiation (OR 2.23, 95% CI 1.84-2.69). CONCLUSIONS: Children progressing to the need for HMV represent a worsening in their respiratory status that will undoubtedly increase healthcare utilization and costs. We found that the initiation of HMV in these children can reduce inpatient healthcare utilization and costs but can still increase overall healthcare expenditures, especially in the outpatient setting.

Impact evaluation of guidelines on antibiotic utilisation & appropriateness in Malaysian public primary care: an interrupted time series analysis.

Background: The National Antimicrobial Guidelines (NAG) 2014 and NAG2019 in Malaysia targeted rational and judicious use of antimicrobials. In this study, we assessed the change in antibiotic utilisation and appropriateness due to the guidelines that were implemented from 2011 to 2019. Methods: Interrupted time series analyses on rates of antibiotic appropriateness and utilisation were performed using prescription data from public primary care clinics in Malaysia between January 2011 and December 2019. Rates of antibiotic utilisation, reported as Defined Daily Dose (DDD) per 1000 patients per day, were stratified by antibiotic classes. Results: Of the 16,081,492 prescriptions recorded during the study period, 4.98% (n = 800,899) contained antibiotics. NAG2014 resulted in a significant increase in antibiotic utilisation trend by 0.029 (p < 0.0001) while NAG2019 had a substantial impact on antibiotic utilisation, decreasing DDD by 1778 and increasing appropriateness by 54.6% (p < 0.0001). Variation in the number of antibiotic molecules being prescribed also decreased after NAG2019. Conclusion: Our findings indicate that the introduction of NAG2019 led to a substantial improvement in antibiotic appropriateness. At the same time, antibiotic utilisation decreased. Further research is needed to ascertain and ensure the sustainability of these changes and to establish targeted improvement strategies focusing on reducing inappropriate and unnecessary prescribing.

A comparison between antibiotic utilisation in public and private community healthcare in Malaysia.

BACKGROUND: There are two parallel systems in Malaysian primary healthcare services: government funded public primary care and privately-owned practices. While there have been several studies evaluating antibiotic utilisation in Malaysian public healthcare, there is a lack of literature on the use of antibiotics in the private sector. There is a dire need to evaluate the more recent performance of public vs. private community healthcare in Malaysia. As such, this study aimed at measuring and comparing the utilisation of antibiotics in the public and private community healthcare sectors of Malaysia in 2018-2021. METHODS: This study was a retrospective analysis of antibiotic utilisation in Malaysian primary care for the period of 1 January 2018 until 31 December 2021 using the nationwide pharmaceutical procurement and sales data from public and private health sectors. Rates of antibiotic utilisation were reported as Defined Daily Doses per 1000 inhabitants per day (DID) and stratified by antibiotic classes. The secondary analysis included proportions of AWaRe antibiotic category use for each sector and proportion of antibiotic utilisation for both sectors. RESULTS: The overall national antibiotic utilisation for 2018 was 6.14 DID, increasing slightly to 6.56 DID in 2019, before decreasing to 4.54 DID in 2020 and 4.17 DID in 2021. Private primary care antibiotic utilisation was almost ten times higher than in public primary care in 2021. The public sector had fewer (four) antibiotic molecules constituting 90% of the total antibiotic utilisation as compared to the private sector (eight). Use of Access antibiotics in the public sector was consistently above 90%, while use of Access category antibiotics by the private sector ranged from 64.2 to 68.3%. Although use of Watch antibiotics in the private sector decreased over the years, the use of Reserve and 'Not Recommended' antibiotics increased slightly over the years. CONCLUSION: Antibiotic consumption in the private community healthcare sector in Malaysia is much higher than in the public sector. These findings highlight the need for more rigorous interventions targeting both private prescribers and the public with improvement strategies focusing on reducing inappropriate and unnecessary prescribing.

Development of a compensation-aware virtual rehabilitation system for upper extremity rehabilitation in community-dwelling older adults with stroke.

BACKGROUND: Compensatory movements are commonly observed in older adults with stroke during upper extremity (UE) motor rehabilitation, which could limit their motor recovery. AIM: This study aims to develop a compensation-aware virtual rehabilitation system (VRS) that can detect compensatory movements and improve the outcome of UE rehabilitation in community-dwelling older adults with stroke. METHODS: The VRS development includes three main components: (1) the use of thresholds for determining compensatory movements, (2) the algorithm for processing the kinematic data stream from Kinect to detect compensation in real-time, and (3) the audio-visual feedback to assist older adults with stroke to be aware of the compensation. Two studies were conducted following the VRS development, where Study 1 identified the value of thresholds for determining compensatory movements in two planar motor exercises, and Study 2 provided preliminary validation for the developed VRS by comparing two groups undergoing VR training or conventional training (CT) in a community rehabilitation center. RESULTS: The VRS could effectively detect all determined compensatory movements and timely trigger feedback in response to the detected compensatory movements. The VR participants showed significant improvements in Fugl-Meyer Assessment-Upper Extremity (FMA-UE, p = 0.045) and Wolf Motor Function Test (WMFT, p = 0.009). However, the VR and CT groups had no significant differences in outcome measures. CONCLUSION: The VRS demonstrates the ability to detect compensation and the potential of assisting older adults with stroke to improve motor functions. Suggestions are given for further improvements of the VRS to support the older adult with stroke to reduce compensation.

Tubomanometry in measurement of velopharyngeal closure: A pilot study.

Objective: To investigate the differences in velum closure pattern in people with and without a history of middle ear disease using intranasal pressure curves recorded with the tubomanometer, a Eustachian tube (ET) testing device. Study Design: Case control study. Setting: Tertiary referral center. Subjects and Methods: Tubomanometry nasopharyngeal pressure curves from 20 controls (Group 1) and 20 people with history of otitis media (OM) and possible ongoing ET dysfunction (ETD) (Group 2 or OM/ETD group) were compared. The variables included in the analysis were: (a) ratio of signal amplitude relative to the delivered nasal pressure (C2/delivered pressure x 10); (b) time (s) to achieve maximal signal amplitude (C2-C1); (c) duration of velum closure (s) and (d) plateau decay during the isometric contraction of the velum (C3-C2) and (e) swallow duration (s) (C4-C1). Statistical analysis was conducted using mixed models for the normalized values of individual characteristics. Results: Age, race and sex distribution in each group was as follows: 24 ± 8 years, 15 whites and 12 females in Group 1; 20 ± 10 years, 19 whites and 15 females in Group 2. Group 2 demonstrated a greater velopharyngeal pressure decay (p = .13), longer swallow duration (p = .10), and longer duration of velum closure (p = .14). Conclusion: This is the first study using tubomanometry to investigate differences in velopharyngeal closure between controls and individuals with OM/ETD. Although not statistically significant, our results showed that those with OM/ETD demonstrated a longer swallow and velum closure duration, and a higher degree of leakage during velum contraction compared to controls.

Impact of COVID-19 Pandemic on Antibiotic Utilisation in Malaysian Primary Care Clinics: An Interrupted Time Series Analysis.

The COVID-19 pandemic has resulted in a dramatic change in the delivery of primary healthcare across the world, presumably changing trends in consultations for infectious diseases and antibiotic use. This study aimed at describing and evaluating the impact of COVID-19 on antibiotic use in public primary care clinics in Malaysia between 2018 and 2021. Data from the nationwide procurement database of systemic antibiotics from public primary care clinics in Malaysia between January 2018 and December 2021 were analysed using interrupted time series analysis. The monthly number of defined daily doses per 1000 inhabitants per day (DID) was calculated and grouped by antibiotic class. The trend of antibiotic utilisation rates had been decreasing by 0.007 DID monthly before March 2020 (p = 0.659). With the introduction of national lockdown due to COVID-19 beginning March 2020, there was a significant reduction in the level of antibiotic utilisation rates of 0.707 (p = 0.022). Subsequently, the monthly trend showed a slight upward change until the end of the study period (p = 0.583). Our findings indicate that there was a significant decrease in antibiotic utilisation for systemic use in primary care following the COVID-19 pandemic compared with the preceding years (January 2018-March 2020).

Effectiveness of Structured Care Coordination for Children With Medical Complexity: The Complex Care for Kids Ontario (CCKO) Randomized Clinical Trial.

Importance: Children with medical complexity (CMC) have chronic conditions and high health needs and may experience fragmented care. Objective: To compare the effectiveness of a structured complex care program, Complex Care for Kids Ontario (CCKO), with usual care. Design, Setting, and Participants: This randomized clinical trial used a waitlist variation for randomizing patients from 12 complex care clinics in Ontario, Canada, over 2 years. The study was conducted from December 2016 to June 2021. Participants were identified based on complex care clinic referral and randomly allocated into an intervention group, seen at the next available clinic appointment, or a control group that was placed on a waitlist to receive the intervention after 12 months. Intervention: Assignment of a nurse practitioner-pediatrician dyad partnering with families in a structured complex care clinic to provide intensive care coordination and comprehensive plans of care. Main Outcomes and Measures: Co-primary outcomes, assessed at baseline and at 6, 12, and 24 months postrandomization, were service delivery indicators from the Family Experiences With Coordination of Care that scored (1) coordination of care among health care professionals, (2) coordination of care between health care professionals and families, and (3) utility of care planning tools. Secondary outcomes included child and parent health outcomes and child health care system utilization and cost. Results: Of 144 participants randomized, 141 had complete health administrative data, and 139 had complete baseline surveys. The median (IQR) age of the participants was 29 months (9-102); 83 (60%) were male. At 12 months, scores for utility of care planning tools improved in the intervention group compared with the waitlist group (adjusted odds ratio, 9.3; 95% CI, 3.9-21.9; P < .001), with no difference between groups for the other 2 co-primary outcomes. There were no group differences for secondary outcomes of child outcomes, parent outcomes, and health care system utilization and cost. At 24 months, when both groups were receiving the intervention, no primary outcome differences were observed. Total health care costs in the second year were lower for the intervention group (median, CAD$17 891; IQR, 6098-61 346; vs CAD$37 524; IQR, 9338-119 547 [US $13 415; IQR, 4572-45 998; vs US $28 136; IQR, 7002-89 637]; P = .01). Conclusions and Relevance: The CCKO program improved the perceived utility of care planning tools but not other outcomes at 1 year. Extended evaluation periods may be helpful in assessing pediatric complex care interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT02928757.

Incidence and Mortality of Children Receiving Home Mechanical Ventilation.

OBJECTIVES: The incidence, as well as the predictors of mortality, for children receiving home mechanical ventilation (HMV) using population-based data in Canada is a current knowledge gap. Our objectives were to describe HMV incidence and mortality rates, and associations of demographic and clinical variables on mortality. METHODS: Using Ontario health and demographic administrative databases, we conducted a retrospective cohort study (April 1, 2003-March 31, 2017) of children aged 0 to 17 years receiving HMV via invasive mechanical ventilation and noninvasive ventilation. We identified children with complex chronic conditions. We used data from Census Canada to calculate incidence rates and Cox proportional hazards modeling to assess for predictors of mortality. RESULTS: We identified 906 children with a mean (SD) crude incidence rate of 2.4 (0.6) per 100 000 for pediatric HMV approvals that increased by 37% over the 14-year study period. Compared with children who were invasively ventilated, we found mortality was associated with noninvasive ventilation (adjusted hazard ratio [aHR], 1.9; 95% confidence interval [CI], 1.3-2.8). Mortality was highest in children from families in the lowest income quintile (aHR, 2.5; 95% CI, 1.5-4.0), those with neurologic impairment complex chronic conditions (aHR, 2.9; 95% CI, 1.4-6.4), those aged 11 to 17 years at HMV initiation (aHR, 1.5; 95% CI, 1.1-2.0), and those with higher health care costs in the 1 year before HMV initiation (aHR, 1.5; 95% CI, 1.3-1.7). CONCLUSIONS: The incidence of children receiving HMV increased substantially over the 14-year period. Demographic variables associated with increased mortality were identified, suggesting areas requiring greater attention for care providers.

Conjoint analyses of patients' preferences for primary care: a systematic review.

BACKGROUND: While patients' preferences in primary care have been examined in numerous conjoint analyses, there has been little systematic effort to synthesise the findings. This review aimed to identify, to organise and to assess the strength of evidence for the attributes and factors associated with preference heterogeneity in conjoint analyses for primary care outpatient visits. METHODS: We searched five bibliographic databases (PubMed, Embase, PsycINFO, Econlit and Scopus) from inception until 15 December 2021, complemented by hand-searching. We included conjoint analyses for primary care outpatient visits. Two reviewers independently screened papers for inclusion and assessed the quality of all included studies using the checklist by ISPOR Task Force for Conjoint Analysis. We categorized the attributes of primary care based on Primary Care Monitoring System framework and factors based on Andersen's Behavioural Model of Health Services Use. We then assessed the strength of evidence and direction of preference for the attributes of primary care, and factors affecting preference heterogeneity based on study quality and consistency in findings. RESULTS: Of 35 included studies, most (82.4%) were performed in high-income countries. Each study examined 3-8 attributes, mainly identified through literature reviews (n = 25). Only six examined visits for chronic conditions, with the rest on acute or non-specific / other conditions. Process attributes were more commonly examined than structure or outcome attributes. The three most commonly examined attributes were waiting time for appointment, out-of-pocket costs and ability to choose the providers they see. We identified 24/58 attributes with strong or moderate evidence of association with primary care uptake (e.g., various waiting times, out-of-pocket costs) and 4/43 factors with strong evidence of affecting preference heterogeneity (e.g., age, gender). CONCLUSIONS: We found 35 conjoint analyses examining 58 attributes of primary care and 43 factors that potentially affect the preference of these attributes. The attributes and factors, stratified into evidence levels based on study quality and consistency, can guide the design of research or policies to improve patients' uptake of primary care. We recommend future conjoint analyses to specify the types of visits and to define their attributes clearly, to facilitate consistent understanding among respondents and the design of interventions targeting them. Word Count: 346/350 words. TRIAL REGISTRATION: On Open Science Framework: https://osf.io/m7ts9.

Cost effectiveness analyses of pharmacological treatments in heart failure.

In a rapidly growing and aging population, heart failure (HF) has become recognised as a public health concern that imposes high economic and societal costs worldwide. HF management stems from the use of highly cost-effective angiotensin converting enzyme inhibitors (ACEi) and ß-blockers to the use of newer drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2i), ivabradine, and vericiguat. Modelling studies of pharmacological treatments that report on cost effectiveness in HF is important in order to guide clinical decision making. Multiple cost-effectiveness analysis of dapagliflozin for heart failure with reduced ejection fraction (HFrEF) suggests that it is not only cost-effective and has the potential to improve long-term clinical outcomes, but is also likely to meet conventional cost-effectiveness thresholds in many countries. Similar promising results have also been shown for vericiguat while a cost effectiveness analysis (CEA) of empagliflozin has shown cost effectiveness in HF patients with Type 2 diabetes. Despite the recent FDA approval of dapagliflozin and empagliflozin in HF, it might take time for these SGLT2i to be widely used in real-world practice. A recent economic evaluation of vericiguat found it to be cost effective at a higher cost per QALY threshold than SGLT2i. However, there is a lack of clinical or real-world data regarding whether vericiguat would be prescribed on top of newer treatments or in lieu of them. Sacubitril/valsartan has been commonly compared to enalapril in cost effectiveness analysis and has been found to be similar to that of SGLT2i but was not considered a cost-effective treatment for heart failure with reduced ejection fraction in Thailand and Singapore with the current economic evaluation evidences. In order for more precise analysis on cost effectiveness analysis, it is necessary to take into account the income level of various countries as it is certainly easier to allocate more financial resources for the intervention, with greater effectiveness, in high- and middle-income countries than in low-income countries. This review aims to evaluate evidence and cost effectiveness studies in more recent HF drugs i.e., SGLT2i, ARNi, ivabradine, vericiguat and omecamtiv, and gaps in current literature on pharmacoeconomic studies in HF.

A Novel Hospital-to-Home System for Children With Medical Complexities: Usability Testing Study.

BACKGROUND: Children with medical complexity (CMC) are a group of young people who have severe complex chronic conditions, substantial family-identified service needs, functional limitations, and high health care resource use. Technology-enabled hospital-to-home interventions designed to deliver comprehensive care in the home setting are needed to ease CMC family stress, provide proactive and comprehensive care to this fragile population, and avoid hospital admissions, where possible. OBJECTIVE: In this usability testing study, we aimed to assess areas of strength and opportunity within the DigiComp Kids system, a hospital-to-home intervention for CMC and their families and care providers. METHODS: Hospital-based clinicians, family members of medically complex children, and home-based clinicians participated in DigiComp Kids usability testing. Participants were recorded and tasked to think aloud while completing usability testing tasks. Participants were scored on the metrics of effectiveness, efficiency, and satisfaction, and the total usability score was calculated using the Single Usability Metric. Participants also provided insights into user experiences during the postusability testing interviews. RESULTS: A total of 15 participants (5 hospital-based clinicians, 6 family members, and 4 home-based clinicians) participated in DigiComp Kids usability testing. The participants were able to complete all assigned tasks independently. Error-free rates for tasks ranged from 58% to 100%; the average satisfaction rating across groups was ≥80%, as measured by the Single Ease Question. Task times of participants were variable compared with the task times of an expert DigiComp Kids user. Single Usability Metric scores ranged from 80.5% to 89.5%. In qualitative interviews, participants stressed the need to find the right fit between user needs and the effort required to use the system. Interviews also revealed that the value of the DigiComp Kids system was in its ability to create a digital bridge between hospital and home, enabling participants to foster and maintain connections across boundaries. CONCLUSIONS: Usability testing revealed strong scores across the groups. Insights gained include the importance of tailoring the implementation of the system to match individual user needs, streamlining key system features, and consideration of the meaning attached to system use by participants to allow for insight into system adoption and sustainment.

Evaluation of BNT162b2 vaccine effectiveness in Malaysia: test negative case-control study.

There is a notable lack of vaccine effectiveness studies using test-negative case-controlled approach in low- and middle-income countries which have different logistic, demographic and socio-economic conditions from high-income countries. We aimed to estimate the effectiveness of BNT162b2 vaccine against COVID-19 infection over time, intensive care unit admission, severe or critical disease and death due to COVID-19. This study was conducted in the resident population of Labuan aged ≥18 years who had been tested for SARS-CoV-2 by Reverse-Transcriptase Polymerase Chain Reaction between 1 March 2021 and 31 October 2021. We used a test-negative case-control design where 2644 pairs of cases and controls were matched by age, sex, testing date, nationality and testing reason. Analysis was stratified by age group to estimate age effect (<60 years and ≥60 years). Of 22217 individuals tested by Reverse-Transcriptase Polymerase Chain Reaction, 5100 were positive for SARS-CoV-2 and aged 18 years and above. Overall vaccine effectiveness ≥ 14 days after the second dose was 65.2% (95% CI: 59.8-69.9%) against COVID-19 infection, 92.5% (95% CI: 72.3-98.8%) against intensive care unit admission, and 96.5% (95% CI: 82.3-99.8%) against COVID-19 deaths. Among infected individuals, vaccine effectiveness was 79.2% (95% CI: 42.3-94.1%) in preventing severe or critical disease due to COVID-19. Vaccine effectiveness for ≥60 years was 72.3% (95% CI: 53.4-83.9%) in fully vaccinated individuals, higher than 64.8% (95% CI: 49.3-59.1%) for those <60 years. Two doses of BNT162b2 were highly effective against COVID-19 infection, severe or critical disease, intensive care unit admission and death due to COVID-19. This study addresses a gap in literature on BNT162b2 vaccine effectiveness in low- and middle-income populations and demonstrates the feasibility of such a study design in a resource limited setting while supporting evidence of waning immunity.

Molecular basis of the key regulator WRINKLED1 in plant oil biosynthesis.

Vegetable oils are not only major components of human diet but also vital for industrial applications. WRINKLED1 (WRI1) is a pivotal transcription factor governing plant oil biosynthesis, but the underlying DNA-binding mechanism remains incompletely understood. Here, we resolved the structure of Arabidopsis WRI1 (AtWRI1) with its cognate double-stranded DNA (dsDNA), revealing two antiparallel ß sheets in the tandem AP2 domains that intercalate into the adjacent major grooves of dsDNA to determine the sequence recognition specificity. We showed that AtWRI1 represented a previously unidentified structural fold and DNA-binding mode. Mutations of the key residues interacting with DNA element affected its binding affinity and oil biosynthesis when these variants were transiently expressed in tobacco leaves. Seed oil content was enhanced in stable transgenic wri1-1 expressing an AtWRI1 variant (W74R). Together, our findings offer a structural basis explaining WRI1 recognition and binding of DNA and suggest an alternative strategy to increase oil yield in crops through WRI1 bioengineering.

Optimizing Antimicrobial Therapy by Integrating Multi-Omics With Pharmacokinetic/Pharmacodynamic Models and Precision Dosing.

In the era of "Bad Bugs, No Drugs," optimizing antibiotic therapy against multi-drug resistant (MDR) pathogens is crucial. Mathematical modelling has been employed to further optimize dosing regimens. These models include mechanism-based PK/PD models, systems-based models, quantitative systems pharmacology (QSP) and population PK models. Quantitative systems pharmacology has significant potential in precision antimicrobial chemotherapy in the clinic. Population PK models have been employed in model-informed precision dosing (MIPD). Several antibiotics require close monitoring and dose adjustments in order to ensure optimal outcomes in patients with infectious diseases. Success or failure of antibiotic therapy is dependent on the patient, antibiotic and bacterium. For some drugs, treatment responses vary greatly between individuals due to genotype and disease characteristics. Thus, for these drugs, tailored dosing is required for successful therapy. With antibiotics, inappropriate dosing such as insufficient dosing may put patients at risk of therapeutic failure which could lead to mortality. Conversely, doses that are too high could lead to toxicities. Hence, precision dosing which customizes doses to individual patients is crucial for antibiotics especially those with a narrow therapeutic index. In this review, we discuss the various strategies in optimizing antimicrobial therapy to address the challenges in the management of infectious diseases and delivering personalized therapy.

Implementing a Care Coordination Strategy for Children with Medical Complexity in Ontario, Canada: A Process Evaluation.

Introduction: A provincial strategy to expand care coordination and integration of care for children with medical complexity (CMC) was launched in Ontario, Canada in 2015. A process evaluation of the roll-out examined the processes, mechanisms of impact, and contextual factors affecting the implementation of the Complex Care for Kids Ontario (CCKO) intervention strategy. Methods: This process evaluation was conducted and analyzed according to the United Kingdom Medical Research Council (UK-MRC) process evaluation framework. To evaluate the implementation of the CCKO intervention, a multi-method study design was used, including semi-structured interviews with 38 key informants and 10 families of CMC involved in CCKO. To further understand implementation details across regional sites, provincial-level implementation plans, and process documents were reviewed. Discussion: Strengths of CCKO included novel collaborations and partnerships between complex care teams, community partners and regional sites. Issues relating to communication and coordination across care sectors created challenges to holistic care coordination objectives. Provincial system fragmentation limited the ability of CCKO to provide seamless care coordination due to the multiple care sectors involved. Conclusion: This study adds to the understanding of the processes involved in a population-level care coordination intervention for CMC. Lessons learned through CCKO can help facilitate reproducibility and necessary adjustments of the intervention in different settings.

Transcriptional regulation of oil biosynthesis in seed plants: Current understanding, applications, and perspectives.

Plants produce and accumulate triacylglycerol (TAG) in their seeds as an energy reservoir to support the processes of seed germination and seedling development. Plant seed oils are vital not only for the human diet but also as renewable feedstocks for industrial use. TAG biosynthesis consists of two major steps: de novo fatty acid biosynthesis in the plastids and TAG assembly in the endoplasmic reticulum. The latest advances in unraveling transcriptional regulation have shed light on the molecular mechanisms of plant oil biosynthesis. We summarize recent progress in understanding the regulatory mechanisms of well-characterized and newly discovered transcription factors and other types of regulators that control plant fatty acid biosynthesis. The emerging picture shows that plant oil biosynthesis responds to developmental and environmental cues that stimulate a network of interacting transcriptional activators and repressors, which in turn fine-tune the spatiotemporal regulation of the pathway genes.

Sunflower WRINKLED1 Plays a Key Role in Transcriptional Regulation of Oil Biosynthesis.

Sunflower (Helianthus annuus) is one of the most important oilseed crops worldwide. However, the transcriptional regulation underlying oil accumulation in sunflower is not fully understood. WRINKLED1 (WRI1) is an essential transcription factor governing oil accumulation in plant cells. Here, we identify and characterize a sunflower ortholog of WRI1 (HaWRI1), which is highly expressed in developing seeds. Transient production of HaWRI1 stimulated substantial oil accumulation in Nicotiana benthamiana leaves. Dual-luciferase reporter assay, electrophoretic mobility shift assay, fatty acid quantification, and gene expression analysis demonstrate that HaWRI1 acts as a pivotal transcription factor controlling the expression of genes involved in late glycolysis and fatty acid biosynthesis. HaWRI1 directly binds to the cis-element, AW-box, in the promoter of biotin carboxyl carrier protein isoform 2 (BCCP2). In addition, we characterize an 80 amino-acid C-terminal domain of HaWRI1 that is crucial for transactivation. Moreover, seed-specific overexpression of HaWRI1 in Arabidopsis plants leads to enhanced seed oil content as well as upregulation of the genes involved in fatty acid biosynthesis. Taken together, our work demonstrates that HaWRI1 plays a pivotal role in the transcriptional control of seed oil accumulation, providing a potential target for bioengineering sunflower oil yield improvement.

Functional Antagonism of WRI1 and TCP20 Modulates GH3.3 Expression to Maintain Auxin Homeostasis in Roots.

Auxin is a well-studied phytohormone, vital for diverse plant developmental processes. The GH3 genes are one of the major auxin responsive genes, whose expression changes lead to modulation of plant development and auxin homeostasis. However, the transcriptional regulation of these GH3 genes remains largely unknown. WRI1 is an essential transcriptional regulator governing plant fatty acid biosynthesis. Recently, we identified that the expression of GH3.3 is increased in the roots of wri1-1 mutant. Nevertheless, in this study we found that AtWRI1 did not activate or repress the promoter of GH3.3 (proGH3.3) despite of its binding to proGH3.3. Cross-family transcription factor interactions play pivotal roles in plant gene regulatory networks. To explore the molecular mechanism by which WRI1 controls GH3.3 expression, we screened an Arabidopsis transcription factor library and identified TCP20 as a novel AtWRI1-interacting regulator. The interaction between AtWRI1 and TCP20 was further verified by several approaches. Importantly, we found that TCP20 directly regulates GH3.3 expression via binding to TCP binding element. Furthermore, AtWRI1 repressed the TCP20-mediated transactivation of proGH3.3. EMSAs demonstrated that AtWRI1 antagonized TCP20 from binding to proGH3.3. Collectively, we provide new insights that WRI1 attenuates GH3.3 expression through interaction with TCP20, highlighting a new mechanism that contributes to fine-tuning auxin homeostasis.

Transition to adult care for youth with medical complexity: Assessing needs and setting priorities for a health care improvement initiative.

BACKGROUND: Technological advances have led to more youth with medical complexity (YMC) who are living into adulthood and being transferred from pediatric to adult care. The transition to adult care is a complex and challenging process, partly due to differences in how pediatric and adult systems deliver health care. YMC and their families need support from their health care providers to ease this transition. To identify how to better support transitioning YMC, a needs assessment was conducted to examine the current state of transitional support for youth and families cared for by a pediatric Complex Care Program. AIMS: The aims of this needs assessment were to understand the transition practices of pediatric Complex Care Programs, explore transition-related needs of YMC and their families, and identify priorities for future quality improvement. METHODS: This project involved three components: a literature review, a benchmarking survey of pediatric Complex Care Programs in Ontario, and key informant interviews. FINDINGS: The benchmarking survey identified transition planning and transfer of care as areas of strength in the Complex Care Program, while transition readiness and transfer completion provided opportunities for improvement. Stakeholder collaboration, an early start, and knowledgeable providers facilitated a successful transition. Barriers included lack of time, poor access to adult services and resources, higher medical complexity, and inadequate support for adult health care providers. CONCLUSIONS: Recommendations for improving transitional care for YMC are provided, along with resources, tools, and considerations for implementation.