Focused Jurisdictional Scan of Glomerulonephritis Medication Access in Canada: A Program Report.

Purpose of Program: Glomerulonephritis (GN) is a group of rare kidney diseases that is increasingly being managed with higher cost immunosuppressive (IS) agents in Canada. Ontario Health's Ontario Renal Network (ORN) oversees the management and delivery of GN services in the province. Stakeholder surveys previously conducted by ORN identified that both clinicians and patients do not perceive access to GN medications as comprehensive or timely. The program conducted a focused jurisdictional scan among 7 provinces to inform ORN initiatives to improve access to GN medications. Specifically, the program examined clinician experience with GN access, public drug coverage criteria, and timelines for public coverage for select IS agents (ie, tacrolimus, cyclosporine, mycophenolate mofetil [MMF], mycophenolate sodium, rituximab, and eculizumab) used to manage GN in adults who live in Canada. Methods: For the selected IS agents, a focused jurisdictional scan on medication access was conducted by ORN in 2018 and updated in July 2022. Information was obtained by searching the gray literature and/or credible online sources for public funding policies and eligibility criteria. Findings were supplemented by personal communications with provincial drug programs and consulting GN clinical experts from 7 provinces (ie, Alberta, British Columbia, Saskatchewan, Manitoba, Ontario, Nova Scotia, and Quebec). Key Findings: Clinicians from different provinces prescribe IS agents similarly for GN indications, despite distinctions in public drug funding policies. While patients can obtain public funding for many IS agents, for GN, most provinces rely on case-by-case review processes. In addition, provinces can vary in their funding criteria and which IS agents are listed on the public formulary. For IS agents that require prior authorization or case-by-case review, timelines vary by province with decisions taking a few days to weeks. British Columbia, with a GN-specific drug formulary, had the most integrated and efficient system for patients and prescribers. Limitations: This scan primarily relied on publicly available information for drug coverage criteria and clinician experience with access in their province. Since this scan was conducted, public drug coverage criteria and/or application processes may have changed. Implications: While patients in most provinces have similar needs and nephrologists similar prescribing patterns, gaps still exist for publicly funded GN medications. Interprovincial differences in the drugs funded, funding criteria, and application process may affect timely and equitable access to GN medications across Canada. Given the rarity of GN, a pan-Canadian funding approach may be warranted to improve the current state.

Objectif du programme: Les glomérulonéphrites (GN) sont un groupe de néphropathies rares qui sont de plus en plus fréquemment traitées avec les agents immunosuppresseurs (IS) coûteux au Canada. Le Réseau rénal de l'Ontario (ORN­Ontario Renal Network) de Santé Ontario supervise la gestion et la prestation des services liés à la GN dans cette province. Des enquêtes menées précédemment par l'ORN auprès des parties prenantes ont révélé que tant les cliniciens que les patients ne percevaient pas l'accès aux médicaments pour traiter la GN comme complet ou opportun. Le programme a mené une analyse ciblée des territoires de compétences dans sept provinces afin d'orienter les initiatives de l'ORN ayant pour objectif d'améliorer l'accès aux médicaments pour traiter la GN. Plus précisément, le programme a examiné l'expérience des cliniciens en matière d'accès aux médicaments pour traiter la GN, les critères d'admissibilité au régime public d'assurance-médicaments et les délais de couverture publique de certains agents IS (p. ex., tacrolimus, cyclosporine, mycophénolate mofétil [MMF], mycophénolate sodique, Rituximab, éculizumab) utilisés pour traiter la GN chez les adultes canadiens. Méthodologie: Une analyse ciblée des territoires de compétences quant à l'accès aux médicaments a été réalisée par l'ORN en 2018 et mise à jour en juillet 2022. L'information quant aux politiques de financement public et aux critères d'admissibilité a été obtenue en effectuant une recherche dans la littérature grise et des sources crédibles en ligne. Les résultats ont été complétés par des communications directes avec les régimes provinciaux d'assurance-médicaments et des experts cliniques de la GN de sept provinces (Alberta, Colombie-Britannique, Saskatchewan, Manitoba, Ontario, Nouvelle-Écosse et Québec). Principaux résultats: Les cliniciens des différentes provinces prescrivent des agents IS de façon similaire pour les indications liées à la GN, malgré des distinctions dans les politiques publiques de financement des médicaments. Bien que les patients bénéficient d'une couverture publique pour de nombreux agents IS, pour le traitement de la GN, la plupart des provinces s'appuient sur des processus d'examen au cas par cas. De plus, il peut exister des différences entre les provinces en ce qui concerne les critères de financement et les agents IS qui figurent sur leur formulaire public. Dans le cas des agents IS nécessitant une autorisation au préalable ou un examen au cas par cas, les délais varient d'une province à l'autre; les décisions pouvant prendre de quelques jours à quelques semaines. La Colombie-Britannique, qui dispose d'un formulaire de médicaments pour traiter spécifiquement la GN, présente le système le plus intégré et le plus efficace pour les patients et les prescripteurs. Limites: Cette analyse s'est principalement appuyée sur des renseignements accessibles au public en ce qui concerne les critères de couverture des médicaments et l'expérience des cliniciens en matière d'accès dans leur province. Les critères de couverture des médicaments publics et les processus de demande pourraient avoir changé depuis que cette analyse a été effectuée. Conclusion: Bien que les patients de la plupart des provinces aient des besoins similaires et que les néphrologues aient des habitudes de prescription similaires, des lacunes subsistent en ce qui concerne le financement public des médicaments pour traiter la GN. Les différences interprovinciales entre les médicaments financés, les critères de financement et le processus de demande peuvent avoir une incidence sur l'accès opportun et équitable aux médicaments pour traiter la GN à travers le Canada. Étant donné la rareté de cette maladie, une approche de financement pancanadienne pourrait être justifiée afin d'améliorer l'état actuel.

Community pharmacists' perspectives on assessing kidney function and medication dosing for patients with advanced chronic kidney disease: A qualitative study using the theoretical domains framework.

Background: The kidneys are responsible for the elimination of many drugs. Chronic kidney disease (CKD) is common, and medications may require adjustment to avoid adverse outcomes. Despite the availability of kidney drug dosing resources, people with CKD are at risk of inappropriate drug prescribing. Community pharmacists are in the ideal position to mitigate harm from inappropriate prescribing in this population. Methods: In this qualitative study, community pharmacists were interviewed on their perspective on kidney function assessment and dose adjustment in people with advanced CKD (estimated glomerular filtration rate <30 mL/min/1.73 m2). The theoretical domains framework for targeting behavioural change was used to inform the interview guide and analysis. Purposeful sampling was employed until data saturation. Semistructured virtual interviews were audio-recorded, transcribed verbatim and uploaded into NVIVO 12 Pro to facilitate thematic analysis. Deductive and inductive iterative coding approaches were employed to determine categories and themes. Results: Twelve pharmacists were interviewed, with a mean age of 42 years and 16 years of experience. Four themes comprising 10 categories were identified to influence kidney function assessment and dosing, including resources (information access, technology, references), environment (pharmacy infrastructure, practice setting), reflection (triggers, experience and training, collaboration) and leadership and governance (pharmacist role, advocacy). Feedback on an optimal CKD tool was collected, and enabling themes (categories) for implementation included knowledge and skills (education, training) and reflection (role, support, integration). Conclusions: Findings will inform the interventions needed to improve implementation of kidney assessment and dosing of high-risk medications in people with kidney impairment into community pharmacy practice. Can Pharm J (Ott) 2023;156:xx-xx.

Phosphorylation status of Bß subunit acts as a switch to regulate the function of phosphatase PP2A in ethylene-mediated root growth inhibition.

The various combinations and regulations of different subunits of phosphatase PP2A holoenzymes underlie their functional complexity and importance. However, molecular mechanisms governing the assembly of PP2A complex in response to external or internal signals remain largely unknown, especially in Arabidopsis thaliana. We found that the phosphorylation status of Bß of PP2A acts as a switch to regulate the activity of PP2A. In the absence of ethylene, phosphorylated Bß leads to an inactivation of PP2A; the substrate EIR1 remains to be phosphorylated, preventing the EIR1-mediated auxin transport in epidermis, leading to normal root growth. Upon ethylene treatment, the dephosphorylated Bß mediates the formation of the A2-C4-Bß protein complex to activate PP2A, resulting in the dephosphorylation of EIR1 to promote auxin transport in epidermis of elongation zone, leading to root growth inhibition. Altogether, our research revealed a novel molecular mechanism by which the dephosphorylation of Bß subunit switches on PP2A activity to dephosphorylate EIR1 to establish EIR1-mediated auxin transport in the epidermis in elongation zone for root growth inhibition in response to ethylene.

EIN2-directed histone acetylation requires EIN3-mediated positive feedback regulation in response to ethylene.

Ethylene is an important phytohormone with pleotropic roles in plant growth, development, and stress responses. ETHYLENE INSENSITIVE2 (EIN2) mediates the transduction of the ethylene signal from the endoplasmic reticulum membrane to the nucleus, where its C-terminus (EIN2-C) regulates histone acetylation to mediate transcriptional regulation by EIN3. However, no direct interaction between EIN2-C and EIN3 has been detected. To determine how EIN2-C and EIN3 act together, we followed a synthetic approach and engineered a chimeric EIN2-C with EIN3 DNA-binding activity but lacking its transactivation activity (EIN2C-EIN3DB). The overexpression of EIN2C-EIN3DB in either wild-type or in the ethylene-insensitive mutant ein3-1 eil1-1 led to a partial constitutive ethylene response. Chromatin immunoprecipitation sequencing showed that EIN2C-EIN3DB has DNA-binding activity, indicating that EIN3DB is functional in EIN2C-EIN3DB. Furthermore, native EIN3 protein levels determine EIN2C-EIN3DB binding activity and binding targets in a positive feedback loop by interacting with EIN2C-EIN3DB to form a heterodimer. Additionally, although EIN3 does not direct affect histone acetylation levels in the absence of EIN2, it is required for the ethylene-induced elevation of H3K14Ac and H3K23Ac in the presence of EIN2. Together, we reveal efficient and specific DNA-binding by dimerized EIN3 in the presence of ethylene to mediate positive feedback regulation, which is required for EIN2-directed elevation of histone acetylation to integrate into an EIN3-dependent transcriptional activation.

TREE1-EIN3-mediated transcriptional repression inhibits shoot growth in response to ethylene.

Ethylene is an important plant hormone that regulates plant growth, in which the master transcriptionactivator EIN3 (Ethylene Insensitive 3)-mediated transcriptional activation plays vital roles. However, the EIN3-mediated transcriptional repression in ethylene response is unknown. We report here that a Transcriptional Repressor of EIN3-dependent Ethylene-response 1 (TREE1) interacts with EIN3 to regulate transcriptional repression that leads to an inhibition of shoot growth in response to ethylene. Tissue-specific transcriptome analysis showed that most of the genes are down-regulated by ethylene in shoots, and a DNA binding motif was identified that is important for this transcriptional repression. TREE1 binds to the DNA motif to repress gene expression in an EIN3-dependent manner. Genetic validation demonstrated that repression of TREE1-targeted genes leads to an inhibition of shoot growth. Overall, this work establishes a mechanism by which transcriptional repressor TREE1 interacts with EIN3 to inhibit shoot growth via transcriptional repression in response to ethylene.

Genome-wide identification, characterization, interaction network and expression profile of GAPDH gene family in sweet orange (Citrus sinensis).

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that plays important roles in multiple cellular processes including phytohormone signaling, plant development, and transcriptional regulation. Although GAPDH genes have been well characterized in various plant species such as Arabidopsis, tobacco, wheat, rice, and watermelon, comprehensive analysis has yet to be completed at the whole genome level in sweet orange (Citrus sinensis). In this study, six GAPDH genes distributed across four chromosomes were identified within the sweet orange genome. Their gene structures, conserved subunits, and subcellular localization were also characterized. Cis-element analysis of CsGAPDHs' promoter regions and the results of dark treatments indicate that CsGAPDH may be involved in photosynthesis. CsGAPDH genes expressed either in a tissue-specific manner or constitutively were ultimately identified along with their expression response to phosphorus deficiency treatments. In addition, a dual-luciferase transient assay was performed to reveal the transcriptional activation of CsGAPDH proteins. Gene Ontology (GO) analysis for proteins interacting with CsGAPDHs helped to uncover the roles these CsGAPDHs play in other plant processes such as citrus seed germination. This study provides a systematic analysis of the CsGAPDH gene family in the sweet orange genome, which can serve as a strong foundation for further research into the biochemical properties and physiological functions of CsGAPDHs.

Ambulatory Medication Reconciliation in Dialysis Patients: Benefits and Community Practitioners' Perspectives.

BACKGROUND: Ambulatory medication reconciliation can reduce the frequency of medication discrepancies and may also reduce adverse drug events. Patients receiving dialysis are at high risk for medication discrepancies because they typically have multiple comorbid conditions, are taking many medications, and are receiving care from many practitioners. Little is known about the potential benefits of ambulatory medication reconciliation for these patients. OBJECTIVES: To determine the number, type, and potential level of harm associated with medication discrepancies identified through ambulatory medication reconciliation and to ascertain the views of community pharmacists and family physicians about this service. METHODS: This retrospective cohort study involved patients initiating hemodialysis who received ambulatory medication reconciliation in a hospital renal program over the period July 2014 to July 2016. Discrepancies identified on the medication reconciliation forms for study patients were extracted and categorized by discrepancy type and potential level of harm. The level of harm was determined independently by a pharmacist and a nurse practitioner using a defined scoring system. In the event of disagreement, a nephrologist determined the final score. Surveys were sent to 52 community pharmacists and 44 family physicians involved in the care of study patients to collect their opinions and perspectives on ambulatory medication reconciliation. RESULTS: Ambulatory medication reconciliation was conducted 296 times for a total of 147 hemodialysis patients. The mean number of discrepancies identified per patient was 1.31 (standard deviation 2.00). Overall, 30% of these discrepancies were deemed to have the potential to cause moderate to severe patient discomfort or clinical deterioration. Survey results indicated that community practitioners found ambulatory medication reconciliation valuable for providing quality care to dialysis patients. CONCLUSIONS: This study has provided evidence that ambulatory medication reconciliation can increase patient safety and potentially prevent adverse events associated with medication discrepancies.

CONTEXTE: Le bilan comparatif des médicaments en soins ambulatoires peut réduire les divergences au chapitre des médicaments et les événements indésirables liés aux médicaments. Les divergences relatives aux médicaments représentent un risque élevé pour les patients dialysés, car ils souffrent normalement de multiples troubles comorbides, ils prennent souvent de nombreux médicaments et ils sont soignés par bon nombre de praticiens. Peu d'information existe sur les possibles avantages du bilan comparatif des médicaments en soins ambulatoires pour ces patients. OBJECTIFS: Déterminer le nombre et la catégorie des divergences concernant les médicaments constatées lors d'un bilan comparatif des médicaments en soins ambulatoires ainsi que la gravité potentielle des préjudices consécutifs. De plus, établir la position des pharmaciens communautaires et des médecins de famille sur cette modalité du bilan comparatif des médicaments. MÉTHODES: La présente étude de cohorte rétrospective a été menée auprès de patients amorçant un traitement par hémodialyse pour qui un bilan comparatif des médicaments en soins ambulatoires a été réalisé dans le cadre d'un programme hospitalier des maladies du rein, entre juillet 2014 et juillet 2016. Les divergences trouvées dans les formulaires de bilan comparatif des médicaments ont été classées par catégorie et selon la gravité potentielle des préjudices. Le niveau du préjudice a été déterminé de manière indépendante par un pharmacien et un membre du personnel infirmier praticien à l'aide d'un système de notation défini. En cas de désaccord, le score final était établi par un néphrologue. Des sondages ont été envoyés à 52 pharmaciens communautaires et à 44 médecins de famille prodiguant des soins aux participants afin qu'ils expriment leurs opinions et leurs points de vue sur le bilan comparatif des médicaments en soins ambulatoires. RÉSULTATS: En tout, 296 bilans comparatifs des médicaments en soins ambulatoires ont été effectués auprès de 147 patients hémodialysés. Le nombre moyen de divergences constatées par patient était de 1,31 (écart-type de 2,00). Dans l'ensemble, 30 % de ces divergences ont été considérées comme une source potentielle d'un inconfort allant de modéré à grave ou de dégradation clinique. Selon les résultats du sondage, les praticiens communautaires ont jugé le bilan comparatif des médicaments en soins ambulatoires utile à la prestation de soins de qualité aux patients dialysés. CONCLUSIONS: D'après les résultats de l'étude, le bilan comparatif des médicaments en soins ambulatoires augmenterait la sécurité des patients et pourrait prévenir les événements indésirables liés aux divergences relatives aux médicaments.