Identifying value arguments and deployment avenues of primary care innovations using a deliberative multidimensional approach.

Context: The increasing pressure on primary care services calls for efficient approaches to assess the potential value of innovations and identify facilitators to their deployment in local contexts. Objective: To explore the value arguments of innovations in primary care identified as promising during Quebec College of Family Physicians' Symposia on Innovations and to propose avenues for their improvement and deployment. Methods: Ten innovations were selected using their ranking at the Symposia and pre-established criteria to ensure diversity. An evidence-informed multidimensional deliberative approach (clinical, populational, economic, organizational and sociocultural dimensions) was applied by a panel of 12 clinicians, managers, patients and citizens. Using data synthesized by dimension, each participant identified arguments on the value of each innovation and appraised them on a numerical scale. The arguments were discussed by the group, and a qualitative analysis with inter-rater validation of the deliberation was performed and the mean appraisal scores at the group level were calculated. These qualitative and quantitative data were synthesized and used as a basis for a second discussion with the group during which avenues for deployment were organized by thematic analysis. Results: Innovations fell into three categories: support for clinical processes (n=5), adaptation of the organization of care to vulnerable populations (n=3), and support for quality improvement (n=2). Innovations aiming at adapting the organization of care for vulnerable populations were considered of highest value overall. Quality improvement innovations received mixed appraisals and needed to be further developed in terms of their value proposition and organizational fit. Innovations to support clinical processes also received mixed appraisals; proposals for further development included keeping them up to date and integrating them with information systems. Conclusions: This study highlights the factors that influence the value of certain categories of primary care innovations as well as avenues for their improvement and implementation that can guide innovators. This work demonstrates that exploring complex innovations with a multidimensional deliberative approach including patients and citizens is useful to identify their value arguments from a comprehensive standpoint, which is essential to identify the best implementation avenues to optimize the creation of value in real life.

GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease.

Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17ß-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-κB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory "M2" immunophenotype reducing MPP(+)-induced NF-κB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies.

Examining nursing processes in primary care settings using the Chronic Care Model: an umbrella review.

BACKGROUND: While there is clear evidence that nurses can play a significant role in responding to the needs of populations with chronic conditions, there is a lack of consistency between and within primary care settings in the implementation of nursing processes for chronic disease management. Previous reviews have focused either on a specific model of care, populations with a single health condition, or a specific type of nurses. Since primary care nurses are involved in a wide range of services, a comprehensive perspective of effective nursing processes across primary care settings and chronic health conditions could allow for a better understanding of how to support them in a broader way across the primary care continuum. This systematic overview aims to provide a picture of the nursing processes and their characteristics in chronic disease management as reported in empirical studies, using the Chronic Care Model (CCM) conceptual approach. METHODS: We conducted an umbrella review of systematic reviews published between 2005 and 2021 based on the recommendations of the Joanna Briggs Institute. The methodological quality was assessed independently by two reviewers using the AMSTAR 2 tool. RESULTS: Twenty-six systematic reviews and meta-analyses were included, covering 394 primary studies. The methodological quality of most reviews was moderate. Self-care support processes show the most consistent positive outcomes across different conditions and primary care settings. Case management and nurse-led care show inconsistent outcomes. Most reviews report on the clinical components of the Chronic Care Model, with little mention of the decision support and clinical information systems components. CONCLUSIONS: Placing greater emphasis on decision support and clinical information systems could improve the implementation of nursing processes. While the need for an interdisciplinary approach to primary care is widely promoted, it is important that this approach not be viewed solely from a clinical perspective. The organization of care and resources need to be designed to support contributions from all providers to optimize the full range of services available to patients with chronic conditions. PROSPERO REGISTRATION: CRD42021220004.

Strategies to engage family physicians in primary care research: A systematic review.

RATIONALE: Moving towards high quality primary health care, involving family physicians in primary care research becomes an essential prerequisite to ensures a better adoption and routinization of patient-centred, evidence-based practices. AIM: To assess the effectiveness of strategies to engage family physicians in primary care research. METHODS: We systematically reviewed evidence for strategies used to engage family physicians in primary care research. We included any study design that reported at least one quantitative outcome. Searches were carried out on MEDLINE, Embase, PsycINFO and Web of Science. Pairs of reviewers independently screened for publications in two stages using standardized forms. We performed data analysis through a narrative synthesis approach, using the Reasoned-action approach as framework. RESULTS: A total of 4859 deduped records were identified of which 41 studies met the eligibility criteria and were included for analysis. The majority of studies (n = 35) investigated family physician's participation in a research project. They aimed to influence family physicians' intention (n = 7) or their ability (n = 3) to participate in a research project. Three types of strategies (compensation/incentive, recruitment by a peer and support from a research network or an academic institution) demonstrated a significant increase in participation rate. Methodological quality of the studies evaluating these strategies was relatively low. Few studies (n = 6) targeted research capacity-building programmes with no significant impact noted. CONCLUSION: Numerous strategies have been used to engage family physicians in primary care research, but few studies evaluated their effectiveness in a rigorous way. REGISTRATION: The protocol of this review was registered with the SPOR Evidence Alliance and on the PROSPERO platform (registration number: CRD42020189322).

Differential contribution of estrogen receptors to the intestinal therapeutic effects of 17ß-estradiol in a murine model of Parkinson's disease.

Beneficial effects of estrogens have been reported in Parkinson's disease (PD) for many years. We previously reported their neuroprotective and anti-inflammatory potentials in the enteric nervous system of the intestine, a region possibly affected during the early stages of the disease according to Braak's hypothesis. Three different estrogen receptors have been characterized to date: the estrogen receptor alpha (ERα), the estrogen receptor beta (ERß) and the G protein coupled estrogen receptor 1 (GPER1). The aim of the present study was to decipher the individual contribution of each estrogen receptor to the therapeutic properties of 17ß-estradiol (E2) in the myenteric plexus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Different agonists, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ERß), G1 (GPER1), and antagonists, ICI 182,780 (ERα and ERß), G15 (GPER1), were used to analyze the involvement of each receptor. We confirmed that G1 protects dopamine (DA) neurons to a similar extent as E2. An anti-inflammatory effect on proinflammatory macrophages and cultured human monocytes was also demonstrated with E2 and G1. The effects of PPT and DPN were less potent than G1 with only a partial neuroprotection of DA neurons by PPT and a partial reduction of interleukin (IL)- 1ß production in monocytes by PPT and DPN. Overall, the present results indicate that the positive outcomes of estrogens are mainly through activation of GPER1. Therefore, this suggests that targeting GPER1 could be a promising approach for future estrogen-based hormone therapies during early PD.

Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson's Disease Models.

Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.

Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson's disease.

Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10 days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5 days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro-inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8 mg kg-1 progesterone administered after MPTP. In the brain of MPTP mice, brain-derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection. In the myenteric plexus, increased BDNF levels compared to controls were measured in MPTP mice treated with 8 mg kg-1 progesterone started post MPTP, whereas GFAP levels remained unchanged. In conclusion, the results obtained in the present study show neuroprotective and anti-inflammatory effects of progesterone in the myenteric plexus of MPTP mice that are similar to our previous findings in the brain. Progesterone is non-feminising and could be used for both men and women in the pre-symptomatic stages of the disease.

Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease.

Motor symptoms in Parkinson's disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastric emptying. These gastrointestinal impairments are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric plexus of the gut. Recently, we demonstrated the anti-inflammatory properties of estrogens to treat intestinal neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The present study aimed to investigate the neuroprotective and anti-inflammatory roles of raloxifene, a selective estrogen receptor modulator (SERM) already commercialized for osteoporosis treatment. In MPTP-treated mice, we found that raloxifene decreased the loss of DAergic neurons and prevented the increase in proinflammatory macrophage density in the myenteric plexus. Interestingly, raloxifene activity was prevented by the G protein-coupled estrogen receptor 1 (GPER1) antagonist G15, suggesting that raloxifene effects were mainly mediated by GPER1. Moreover, monocytic cell proinflammatory polarization, nuclear factor-kappa B (NF-κB) response, nitric oxide (NO), and proinflammatory cytokines production following 1-methyl-4-phenylpyridinium (MPP+) treatment were also prevented by raloxifene in vitro. Overall, the present results suggest that raloxifene may help preventing the loss of DAergic neurons in the myenteric plexus in an MPTP mouse model of PD, at least in part through its anti-inflammatory effects. This suggests that drug repurposing of raloxifene might represent a promising therapeutic avenue to prevent systemic inflammation and peripheral neuronal dysfunction at early PD stages.

Gastrointestinal Dysfunctions in Parkinson's Disease: Symptoms and Treatments.

A diagnosis of Parkinson's disease is classically established after the manifestation of motor symptoms such as rigidity, bradykinesia, and tremor. However, a growing body of evidence supports the hypothesis that nonmotor symptoms, especially gastrointestinal dysfunctions, could be considered as early biomarkers since they are ubiquitously found among confirmed patients and occur much earlier than their motor manifestations. According to Braak's hypothesis, the disease is postulated to originate in the intestine and then spread to the brain via the vagus nerve, a phenomenon that would involve other neuronal types than the well-established dopaminergic population. It has therefore been proposed that peripheral nondopaminergic impairments might precede the alteration of dopaminergic neurons in the central nervous system and, ultimately, the emergence of motor symptoms. Considering the growing interest in the gut-brain axis in Parkinson's disease, this review aims at providing a comprehensive picture of the multiple gastrointestinal features of the disease, along with the therapeutic approaches used to reduce their burden. Moreover, we highlight the importance of gastrointestinal symptoms with respect to the patients' responses towards medical treatments and discuss the various possible adverse interactions that can potentially occur, which are still poorly understood.