A systematic review of tools for predicting complications in patients with influenza-like illness.

Objective: To identify tools that predict the risk of complications for patients presenting to an outpatient clinic or an emergency department (ED) with influenza-like illness. Methods: We searched Medline, Embase, Cochrane Library and CINAHL from inception to July 2023. We included articles reporting on the derivation or validation of a score or algorithm used to stratify the risk of hospitalization or mortality among patients with influenza-like illness in the ED or outpatient clinic. Results: Twelve articles reporting on eight scores and six predictive models were identified. For predicting the need for hospitalization, the area under the curve (AUC) of the PMEWS and the CURB-65 ranged respectively from 0.76 to 0.94, and 0.65 to 0.88. The Community Assessment Tool had an AUC of 0.62. For predicting inpatient mortality, AUC was 0.66 for PMEWS and 0.79 for CURB-65, 0.79 for the SIRS criteria and 0.86 for the qSOFA score. Two scores were developed without external validation during the Covid-19 pandemic. The CovHos score and the Canadian Covid discharge score had an AUC ranged from 0.70 to 0.91. The predictive models performed adequately (AUC from 0.76 to 0.92) but will require external validation for clinical use. Tool diversity and study population heterogeneity precluded meta-analysis. Conclusion: Although the CURB, PMEWS and qSOFA scores appear to predict accurately the risk of complications of influenza-like illness, none were reliable enough to justify their widespread ED use. Refinement of an existing tool or development of a new tool to optimize the management of these patients is needed.

Development and Validation of an Instrument to Measure Health-Related Out-of-Pocket Costs: The Cost for Patients Questionnaire.

OBJECTIVE: The growth of healthcare spending is a major concern for insurers and governments but also for patients whose health problems may result in costs going beyond direct medical costs. To develop a comprehensive tool to measure direct and indirect costs of a health condition for patients and their families to various outpatient contexts. METHODS: We conducted a content and face validation including results of a systematic review to identify the items related to direct and indirect costs for patients or their families and an online Delphi to determine the cost items to retain. We conducted a pilot test-retest with 18 naive participants and analyzed data calculating intraclass correlation and kappa coefficients. RESULTS: An initial list of 34 items was established from the systematic review. Each round of the Delphi panel incorporated feedback from the previous round until a strong consensus was achieved. After 4 rounds of the Delphi to reach consensus on items to be included and wording, the questionnaire had a total of 32 cost items. For the test-retest, kappa coefficients ranged from -0.11 to 1.00 (median = 0.86), and intraclass correlation ranged from -0.02 to 0.99 (median = 0.62). CONCLUSIONS: A rigorous process of content and face development was implemented for the Cost for Patients Questionnaire, and this study allowed to set a list of cost elements to be considered from the patient's perspective. Additional research including a test-retest with a larger sample will be part of a subsequent validation strategy.

Acute health care among Indigenous patients in Canada: a scoping review.

A recent report by the Chief Public Health Officer of Canada demonstrates the inferior health status of Indigenous Peoples in Canada when compared to non-Indigenous populations. This scoping review maps out the available literature concerning acute health care for Indigenous Peoples in Canada in order to better understand the health care issues they face. All existing articles concerning health care provided to Indigenous Peoples in Canada in acute settings were included in this review. The targeted studied outcomes were access to care, health care satisfaction, hospital visit rates, mortality, quality of care, length of stay and cost per hospitalisation. 114 articles were identified. The most studied outcomes were hospitalisation rates (58.8%), length of stay (28.0%), mortality (25.4%) and quality of care (24.6%) Frequently studied topics included pulmonary disease, injuries, cardiovascular disease and mental illness. Indigenous Peoples presented lower levels of satisfaction and access to care although they tend to be over-represented in hospitalisation rates for acute care. Greater inclusion of Indigenous Peoples in the health care system and in the training of health care providers is necessary to ensure a better quality of care that is culturally safe for Indigenous Peoples.

High Users of Healthcare Services: Development and Alpha Testing of a Patient Decision Aid for Case Management.

BACKGROUND: Some patients with complex healthcare needs become high users of healthcare services. Case management allows these patients and their interprofessional team to work together to evaluate their needs, priorities and available resources. High-user patients must make an informed decision when choosing whether to engage in case management and currently there is no tool to support them. OBJECTIVE: The objective of this study was to develop and conduct a pilot alpha testing of a patient decision aid that supports high-user patients with complex needs and the teams who guide those patients in shared decision making when engaging in case management. METHODS: We chose a user-centered design to co-develop a patient decision aid with stakeholders informed by the Ottawa Research Institute and International Patient Decision Aid Standards frameworks. Perceptions and preferences for the patient decision aid's content and format were assessed with patients and clinicians and were iteratively collected through interviews and focus groups. We developed a prototype and assessed its acceptability by using a think-aloud method and a questionnaire with three patient-partners, six clinicians and seven high-user patients with complex needs. RESULTS: The three rounds of evaluation to assess the decision aid's acceptability highlighted comments related to simplicity, readability and visual aspect. A section presenting clinical vignettes including story telling was identified as the most helpful. CONCLUSIONS: We created and evaluated a patient decision aid. Considering the positive comments, we believe that this aid has the potential to help high-user patients with complex care needs make better choices concerning case management.

Some patients are living with physical and mental health problems. They also may have handicaps and unsuitable backgrounds. This may lead them to use health services more often. Case management is a service offered by a team of health professionals. They help patients to decide what is important to them based on their values and preferences. Currently, no tools exist for that service. We built and assessed a tool to support patients in their decisions. With this tool, they think about engaging in case management or continuing with usual care. They can also postpone their decision to a later time. This tool will present data based on scientific studies about case management. It will help patients to clarify their values and preferences to make the best decision for them. This tool was built with a team of researchers, healthcare professionals, managers and patient-partners. It was built according to several guidelines. We met participants and they answered questions that helped us to build our tool. We also ensured the tool was acceptable to them. The most frequent comments were to make it simpler and to use simple vocabulary. The look was also important for the participants. The latter found that the section where patients could write their own story was useful. Patients also found that reading stories about other patients like them was helpful. Our tool will help patients with complex care needs make better choices concerning their health based on their values and scientific data.

"They heard our voice!" patient engagement councils in community-based primary care practices: a participatory action research pilot study.

BACKGROUND: Patient engagement could improve the quality of primary care practices. However, we know little about effective patient engagement strategies. We aimed to assess the acceptability and feasibility of embedding advisory councils of clinicians, managers, patients and caregivers to conduct patient-oriented quality improvement projects in primary care practices. METHODS: Using a participatory action research approach, we conducted our study in two non-academic primary care practices in Quebec City (Canada). Patient-experts (patients trained in research) were involved in study design, council recruitment and meeting facilitation. Advisory councils were each to include patients and/or caregivers, clinicians and managers. Over six meetings, councils would identify quality improvement priorities and plan projects accordingly. We assessed acceptability and feasibility of the councils using non-participant observations, audio-recordings and self-administered questionnaires. We used descriptive analyses, triangulated qualitative data and performed inductive thematic analysis. RESULTS: Between December 2017 and June 2018, two advisory councils were formed, each with 11 patients (36% male, mean age 53.8 years), a nurse and a manager practising as a family physician (25% male, mean age 45 years). The six meetings per practice occurred within the study period with a mean of eight patients per meeting. Councils worked on two projects each: the first council on a new information leaflet about clinic organization and operation, and on communications about local public health programs; the second on methods to further engage patients in the practice, and on improving the appointment scheduling system. Median patient satisfaction was 8/10, and 66.7% perceived councils had an impact on practice operations. They considered involvement of a manager, facilitation by patient-experts, and the fostering of mutual respect as key to this impact. Clinicians and managers liked having patients as facilitators and the respect among members. Limiting factors were difficulty focusing on a single feasible project and time constraints. Managers in both practices were committed to pursuing the councils post-study. CONCLUSION: Our results indicated that embedding advisory councils of clinicians, managers, patients and caregivers to conduct patient-oriented quality improvement projects in primary care practices is both acceptable and feasible. Future research should assess its transferability to other clinical contexts.

Decisional needs assessment of patients with complex care needs in primary care.

RATIONALE: Patients with complex care needs who frequently use health services often face challenges in managing their health and with integrated care, leading to frequent decision making. These complex care needs require a good understanding of health issues and their impact on daily life. As the decisional needs of this particular clientele have yet to be described in scientific literature, they warrant further study. OBJECTIVES: To assess the decision-making needs of patients with complex care needs (PCCN) who frequently use health care services. METHODS: We performed a multicenter cross-sectional qualitative descriptive study in four institutions of the health and social services network of Quebec (Canada). We enrolled a convenience sample of PCCNs who frequently use health care services, health care providers, case managers, and decision-makers. We conducted interviews and focus groups and investigated decisional needs according to the Ottawa decision support framework: roles played and desired in the decision-making process, facilitators, and barriers. We conducted qualitative data collection and qualitative deductive/inductive thematic analysis within and across participating groups. RESULTS: In total, 16 patients, 38 clinicians, six case managers, and 14 decision-makers participated in the study. The decisional needs of this clientele are numerous, varied and different from those of the general population. We identified 26 decisional needs grouped under five themes. The most frequent decisions related to visiting the emergency department, moving to a nursing home, and adhering to a plan or treatment. In addition, we identified new themes such as patients' fear and mistrust of health professionals, differences of opinion between health professionals and health professionals' preconceived opinions of patients. CONCLUSION: We observed a wide range of types of decisions that patients face and differences in decision-making needs across participating groups. Our results should inform future research on the development of a patient decision aid tool.

How to engage patients in research and quality improvement in community-based primary care settings: protocol for a participatory action research pilot study.

PLAIN ENGLISH SUMMARY: Making primary care clinics more patient-centered is key to improving patients' experience of care. If patients themselves were engaged in helping define priorities and suggesting quality improvements in the clinic, care would respond better to their needs. However, patient engagement is a new phenomenon, particularly in community based primary care clinics. How to engage patients in quality improvement in these clinics, or what effect this might have, is not well known. The involvement of patients needs to be adapted to the way these clinics function. The aim of this study is to create and evaluate a new model of patient engagement for quality improvement in community based primary care clinics. Patients, primary care professionals and researchers will create advisory councils in two primary care clinics in Quebec City (Canada). In each clinic, the advisory council will include 12 patients or caregivers registered at the clinic, a clinician and a clinic manager. The advisory council will meet every 6 weeks for a total of six meetings. Two patient-experts will facilitate meetings. During meetings, members of the council will list their needs in order of importance. Then they will suggest improvements in line with these needs. We will study if our advisory council model is well adapted to community based primary care settings and meets participants' expectations. At the end of the study we will be able to offer guidance about engaging patients with health professionals in quality improvement in primary care clinics. ABSTRACT: Background Involvement of end-users, including patients, managers and clinicians, in identifying quality improvement and research priorities might improve the relevance of projects and increase their impact. Few patient engagement initiatives have taken place in community based primary care practices (CBPCPs) and best practices for engaging patients in such settings are not well defined. The aim of this pilot study is to develop and assess the feasibility of a new collaborative model of advisory council involving clinicians, managers, patients and caregivers in CBPCP to strengthen their capacity to conduct quality improvement and patient-oriented research projects. Methods We will conduct a participatory action research project in two non-academic CBPCPs in Quebec City (Canada). In each CBPCP, the advisory council will include 12 patients or caregivers, a clinician and a clinic manager. Patients or their caregivers will be identified by clinicians and contacted by patient-experts. They will be eligible if they are registered at the practice, motivated, and available to attend meetings. The council will meet every 6 weeks for a total of six meetings. Two patient-experts will guide council members to identify quality improvement priorities and patient-oriented research questions based on their experience in the clinic. They will then be supported to plan actions to target these priorities. Analysis of meetings will be based on feasibility criteria, notes by non-participant observers in log books, audio-recording of the meetings and questionnaires to evaluate council members' perceptions and the likelihood they would engage in such councils. Discussion The results of this study will  be a model of patient engagement and a discussion of factors to improve the model to fit the needs of primary care patients and professionals. This will lay the foundation for a sustainable structure for long-term patient engagement and contribute to the development of a patient-centered and quality-improvement culture in CBPCPs.

Caring for seniors living with dementia means caring for their caregivers too.

To improve the care of seniors living with dementia, current initiatives typically target better identification and treatment of the patient. Our recent survey, however, shows we should also focus more on the needs of the informal caregivers who care for this population in primary care settings. This three-round Delphi survey sought caregivers' views on the most frequent and difficult decisions that seniors with dementia, their informal caregivers, and health care providers face in primary care settings in the province of Quebec. Respondents consisted of 31 health care professionals, informal caregivers, managers, representatives of community-based organizations devoted to these seniors, and clinical researchers involved in the organization of care or services to seniors with dementia. When we asked respondents to rank 27 common but difficult decisions involving benefit/harm trade-offs, 83% ranked the decision to choose an option to reduce the burden of informal caregivers as one of the five most important decisions. Choosing a treatment to manage agitation, aggression or psychotic symptoms followed closely, with 79% of respondents selecting it as one of the five most important decisions. Our results point to the importance of attending to the needs of informal caregivers and improving the management of behavioural and psychological symptoms of dementia.

Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter.

Induction of the antiviral interferon response is initiated upon recognition of viral RNA structures by the RIG-I or Mda-5 DEX(D/H) helicases. A complex signaling cascade then converges at the mitochondrial adapter MAVS, culminating in the activation of the IRF and NF-kappaB transcription factors and the induction of interferon gene expression. We have previously shown that MAVS recruits IkappaB kinase epsilon (IKKepsilon) but not TBK-1 to the mitochondria following viral infection. Here we map the interaction of MAVS and IKKepsilon to the C-terminal region of MAVS and demonstrate that this interaction is ubiquitin dependent. MAVS is ubiquitinated following Sendai virus infection, and K63-linked ubiquitination of lysine 500 (K500) of MAVS mediates recruitment of IKKepsilon to the mitochondria. Real-time PCR analysis reveals that a K500R mutant of MAVS increases the mRNA level of several interferon-stimulated genes and correlates with increased NF-kappaB activation. Thus, recruitment of IKKepsilon to the mitochondria upon MAVS K500 ubiquitination plays a modulatory role in the cascade leading to NF-kappaB activation and expression of inflammatory and antiviral genes. These results provide further support for the differential role of IKKepsilon and TBK-1 in the RIG-I/Mda5 pathway.

Roles of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling.

Post-translational protein modifications are involved in all functions of living cells. This includes the ability of cells to recognize pathogens and regulate genes involved in their clearance, a concept known as innate immunity. While phosphorylation mechanisms play essential roles in regulating different aspects of the innate immune response, ubiquitination is now recognized as another post-translational modification that works in parallel with phosphorylation to orchestrate the final proper innate immune response against invading pathogens. More precisely, this review will discuss the most recent advances that address the role of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling.

Phosphorylation of IRF-3 on Ser 339 generates a hyperactive form of IRF-3 through regulation of dimerization and CBP association.

The IkappaB kinase-related kinases, TBK1 and IKKi, were recently shown to be responsible for the C-terminal phosphorylation of IRF-3. However, the identity of the phosphoacceptor site(s) targeted by these two kinases remains unclear. Using a biological assay based on the IRF-3-mediated production of antiviral cytokines, we demonstrate here that all Ser/Thr clusters of IRF-3 are required for its optimal transactivation capacity. In vitro kinase assays using full-length His-IRF-3 as a substrate combined with mass spectrometry analysis revealed that serine 402 and serine 396 are directly targeted by TBK1. Analysis of Ser/Thr-to-Ala mutants revealed that the S396A mutation, located in cluster II, abolished IRF-3 homodimerization, CBP association, and nuclear accumulation. However, production of antiviral cytokines was still present in IRF-3 S396A-expressing cells. Interestingly, mutation of serine 339, which is involved in IRF-3 stability, also abrogated CBP association and dimerization without affecting gene transactivation as long as serine 396 remained available for phosphorylation. Complementation of IRF-3-knockout mouse embryonic fibroblasts also revealed a compensatory mechanism of serine 339 and serine 396 in the ability of IRF-3 to induce expression of the interferon-stimulated genes ISG56 and ISG54. These data lead us to reconsider the current model of IRF-3 activation. We propose that conventional biochemical assays used to measure IRF-3 activation are not sensitive enough to detect the small fraction of IRF-3 needed to elicit a biological response. Importantly, our study establishes a molecular link between the role of serine 339 in IRF-3 homodimerization, CBP association, and its destabilization.

Involvement of the IkappaB kinase (IKK)-related kinases tank-binding kinase 1/IKKi and cullin-based ubiquitin ligases in IFN regulatory factor-3 degradation.

Activation of the innate arm of the immune system following pathogen infection relies on the recruitment of latent transcription factors involved in the induction of a subset of genes responsible for viral clearance. One of these transcription factors, IFN regulatory factor 3 (IRF-3), is targeted for proteosomal degradation following virus infection. However, the molecular mechanisms involved in this process are still unknown. In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection. Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3. Inactivation of NEDD8-activating E1 enzyme also results in stabilization of IRF-3 suggesting the NEDDylation also plays a role in IRF-3 degradation following Sendai virus infection. In agreement with this observation, IRF-3 is recruited to Cullin1 following virus infection and overexpression of a dominant-negative mutant of Cullin1 significantly inhibits the degradation of IRF-3 observed in infected cells. We also asked whether the C-terminal cluster of phosphoacceptor sites of IRF-3 could serve as a destabilization signal and we therefore measured the half-life of C-terminal phosphomimetic IRF-3 mutants. Interestingly, we found them to be short-lived in contrast to wild-type IRF-3. In addition, no degradation of IRF-3 was observed in TBK1(-/-) mouse embryonic fibroblasts. All together, these data demonstrate that virus infection stimulates a host cell signaling pathway that modulates the expression level of IRF-3 through its C-terminal phosphorylation by the IkappaB kinase-related kinases followed by its polyubiquitination, which is mediated in part by a Cullin-based ubiquitin ligase.

Signaling pathways involved in the cardioprotective effects of cannabinoids.

The aim of the present article is to review the cardioprotective properties of cannabinoids, with an emphasis on the signaling pathways involved. Cannabinoids have been reported to protect against ischemia in rat isolated hearts, as well as in rats and mice in vivo. Although these effects have been observed mostly with a pre-treatment of a cannabinoid, we report that the selective CB(2)-receptor agonist JWH133 is able to reduce infarct size when administered either before ischemia, during the entire ischemic period, or just upon reperfusion. Little is known about the signaling pathways involved in these cardioprotective effects. Likely candidates include protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) since they are activated during ischemia-reperfusion and contribute to the protective effect ischemic preconditioning. The use of pharmacological inhibitors suggests that PKC, p38 MAPK, and p42/p44 MAPK (ERK1/2) contribute to the protective effect of cannabinoids. In addition, perfusion with JWH133 in healthy hearts caused an increase in both p38 MAPK phosphorylation level and activity, whereas the CB(1)-receptor agonist ACEA was associated with an increase in the phosphorylation status of both ERK1 and ERK2 without any change in activity. During ischemia, both agonists doubled p38 MAPK activity, whereas ERK1/2 phosphorylation level and activity during reperfusion were enhanced only by the CB(1)-receptor agonist. Finally, although nitric oxide (NO) was shown to exert both pro and anti-apoptotic effects on cardiomyocytes, with an apparently controversial effect on myocardial survival, our data suggest that NO may contribute to the cardioprotective effect of some cannabinoids.

The proinflammatory actions of angiotensin II are dependent on p65 phosphorylation by the IkappaB kinase complex.

The vasoactive hormone angiotensin II (Ang II) probably triggers inflammatory cardiovascular diseases by activating transcription factors such as NF-kappaB. We describe here a novel mode of NF-kappaB activation in cultured vascular smooth muscle cells exposed to Ang II. Ang II treatment resulted in an increase in the phosphotransferase activity of the IKK complex, which was mediated through the AT1 receptor subtype. The typical phosphorylation and proteasome-dependent degradation of the NF-kappaB inhibitor IkappaBalpha were not observed. Rather, Ang II treatment of vascular smooth muscle cells led to the phosphorylation of p65 on serine 536, a signal detected in both the cytoplasm and the nuclear compartments. The use of pharmacological inhibitors that inhibit the activation of MEK by Ang II revealed that phosphorylation of p65 on serine 536 did not require the MEK-ERK-RSK signaling pathway. On the other hand, specifically targeting the IKKbeta subunit of the IKK complex by overexpression of a dominant negative version of IKKbeta (IKKbeta K44A) or silencing RNA technology demonstrated that the IKKbeta subunit of the IKK complex was responsible for the detected phosphoserine 536 signal in Ang II-treated cells. Characterization of the signaling pathway leading to activation of the IKK complex by Ang II revealed that neither epidermal growth factor receptor transactivation nor the phosphatidylinositol 3-kinase-AKT signaling cascade were involved. Collectively, our data demonstrate that the proinflammatory activity of Ang II is independent of the classical pathway leading to IkappaBalpha phosphorylation and degradation but clearly depends on the recruitment of an IKK complex signaling cascade leading to phosphorylation of p65 on serine 536.

Time course of airway mechanics of the (+)insert myosin isoform knockout mouse.

Two smooth muscle myosin heavy chain isoforms that differ by the presence ([+]insert) or the absence ([-]insert) of a 7-amino acid insert in the motor domain have a 2-fold difference in their in vitro actin filament velocity. We hypothesized that a preferential expression of the fast (+)insert isoform in airway smooth muscle would increase the rate of bronchoconstriction. To verify our hypothesis we measured the time course of bronchoconstriction following a bolus injection of methacholine (160 microg/kg) in (+)insert isoform knockout (KO) and corresponding wild-type (WT) mice. Neither baseline airway resistance (Raw) (0.424 +/- 0.04 for WT and 0.374 +/- 0.01 cm H(2)O.s.ml(-1) for KO) nor peak Raw (4.1 +/- 0.9 for WT and 4.0 +/- 0.5 cm H(2)O.s.ml(-1) for KO) differed between groups. However, the time to peak Raw was significantly longer in the KO (17.2 +/- 0.6 s) compared with the WT (14.6 +/- 0.8 s) mice (P < 0.05). Differentiating Raw with respect to time revealed a greater rate of bronchoconstriction for the WT during the initial 4 s, presumably reflecting the faster shortening velocities under these relatively unloaded conditions. Reverse transcriptase-polymerase chain reaction analysis revealed that the (+)insert myosin isoform mRNA content in the WT airways was 47.8 +/- 5.6%. We conclude that the presence of the (+)insert myosin isoform in the airways increases the rate of bronchoconstriction.