RIOK3 is an adaptor protein required for IRF3-mediated antiviral type I interferon production.

Detection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-ß production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-ß. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3. Importance: The innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.

Optimal Therapeutic Drug Monitoring Strategy for IV Aminoglycosides and IV Vancomycin in People with Cystic Fibrosis: A Systematic Review.

Background: Given altered pharmacokinetics in people with cystic fibrosis (pwCF), there is debate regarding optimal strategies for therapeutic drug monitoring (TDM) for aminoglycosides and vancomycin administered intravenously. Objectives: To determine the TDM strategy for IV aminoglycosides and IV vancomycin associated with optimal clinical outcomes in pwCF. Data Sources: Several databases (MEDLINE, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov ) were searched from inception to November 15, 2020, with searches rerun on February 13, 2023. Study Selection and Data Extraction: Full articles evaluating TDM strategies and clinical outcomes in pwCF receiving IV aminoglycosides or IV vancomycin were included. Data Synthesis: Three studies met the inclusion criteria for IV aminoglycosides, and 1 study met the inclusion criteria for IV vancomycin. Data are presented with descriptive analyses. Conclusions: The available evidence is insufficient to determine an optimal TDM strategy for IV aminoglycoside or IV vancomycin therapy in pwCF.

Contexte: Étant donné que la pharmacocinétique des personnes atteintes de fibrose kystique est altérée, un débat existe concernant les stratégies optimales de suivi thérapeutique des médicaments (STM) pour les aminoglycosides et la vancomycine administrés par voie intraveineuse. Objectif: Déterminer la stratégie de suivi thérapeutique des médicaments pour les aminoglycosides et la vancomycine par voie intraveineuse associée aux résultats cliniques optimaux chez les personnes atteintes de fibrose kystique. Sources des données: Plusieurs bases de données (MEDLINE, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials et ClinicalTrials.gov ) ont été consultées depuis leur création jusqu'au 15 novembre 2020, avec des recherches répétées le 13 février 2023. Sélection des études et extraction des données: Les articles en texte intégral évaluant les stratégies de suivi thérapeutique des médicaments et les résultats cliniques chez les personnes atteintes de fibrose kystique recevant des aminoglycosides ou de la vancomycine par voie intraveineuse ont été inclus. Synthèse des données: Trois études répondaient aux critères d'inclusion pour les aminoglycosides par voie intraveineuse, et une étude répondait aux critères d'inclusion pour la vancomycine par voie intraveineuse. Les données s'accompagnent d'analyses descriptives. Conclusions: Les éléments probants disponibles sont insuffisants pour déterminer une stratégie optimale de suivi thérapeutique des médicaments pour la thérapie par aminoglycosides par voie intraveineuse ou la vancomycine par voie intraveineuse chez les personnes atteintes de fibrose kystique.

Belatacept: a new biologic and its role in kidney transplantation.

OBJECTIVE: To review the pharmacology, efficacy, safety, and role of belatacept in maintenance immunosuppression in adult kidney transplant recipients (KTR). DATA SOURCES: PubMed, EMBASE, International Pharmaceutical Abstracts, Web of Knowledge (1990-November 2011), and Google were searched using the terms belatacept, kidney or renal, and transplant. STUDY SELECTION AND DATA EXTRACTION: Relevant articles (English language and human subjects) were reviewed. Selected studies included 3 Phase 2 and 2 Phase 3 trials. Data were compared with Food and Drug Administration (FDA) briefing documents and belatacept full prescribing information. DATA SYNTHESIS: Belatacept, a cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin, is the first marketed intravenous maintenance immunosuppressant. It is approved for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids to prevent rejection in adult KTR. Belatacept exhibits linear pharmacokinetics and first-order elimination. The less intensive regimen used in Phase 3 trials is approved by the FDA. In low-moderate immunologic risk KTR, short-term patient and allograft survival appear comparable with that seen with cyclosporine, with improved renal function despite more frequent and severe early acute rejection. Preliminary data from Phase 2 corticosteroid-avoidance and conversion trials suggest that better renal function, acceptable rejection rates, and comparable patient and allograft survival may be achieved with belatacept compared with calcineurin inhibitors (CNIs). Common adverse effects of belatacept include anemia, neutropenia, urinary tract infection, headache, and peripheral edema. While a more favorable cardiovascular and metabolic profile and lack of requirement for therapeutic drug monitoring are attractive, a higher frequency of posttransplant lymphoproliferative disorder is concerning. Belatacept drug costs are significantly higher than those of standard CNI- or sirolimus-based regimens. CONCLUSIONS: Belatacept provides a new option for maintenance immunosuppression in adult KTR. Further research is needed to compare its efficacy and safety with standard tacrolimus-based regimens, to evaluate whether increased drug costs are offset by long-term improvements in patient and allograft survival, and to establish its role in the immunosuppression armamentarium.

Correction: Dagenais et al. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J. Clin. Med. 2021, 10, 23.

In the original article [...].

Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review.

OBJECTIVE: To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. DATA SOURCES: PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. DATA SYNTHESIS: Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. CONCLUSIONS: Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.

Evaluating a Pharmacist-Led Opioid Stewardship Initiative at an Urban Teaching Hospital.

BACKGROUND: Deaths due to overdose from illicit drugs have risen in Canada, despite various community-led harm reduction programs. There have been limited pharmacist-led inpatient initiatives aimed at reducing opioid harm. The authors' group recently developed and implemented the Medication and Risk Factor Review, Optimize, Refer at Risk Patients, Educate and Plan (MORE) tool, a systematic checklist designed to help pharmacists follow and enhance the safety of in-hospital opioid prescribing. OBJECTIVES: To evaluate the impact of a pharmacist-led opioid stewardship program utilizing the MORE tool in the care of patients at one tertiary teaching hospital. METHODS: This study involved a review of health care records for patients admitted to general surgery and internal medicine clinical teaching units at a tertiary hospital between September 10 and December 31, 2018, for whom opioids were prescribed during the hospital stay. A descriptive data analysis was performed for patients who underwent assessment with the MORE tool. RESULTS: Of the 210 patients who met the initial eligibility criteria, including in-hospital opioid therapy for at least 3 days, 50 were assessed by a pharmacist using the MORE tool. For 40 (80%) of these patients, the pharmacist recommended an intervention, and 35 (87.5%) of these interventions were accepted by the prescriber. Among all 50 patients, the most common pharmacist interventions were adding or optimizing non-opioid pain medications (23 patients [46%]), decreasing opioid dose or frequency (15 patients [30%]), and adding a bowel regimen (9 patients [18%]). CONCLUSIONS: Most patients who underwent assessment by a pharmacist had risk factors for adverse events from opioid prescriptions and/or suboptimal orders and drug combinations. The MORE tool provided a guided approach for pharmacists to make targeted interventions aimed at improving opioid safety. A dedicated opioid stewardship pharmacist might be able to provide additional benefit.

CONTEXTE: Les décès provoqués par les surdoses de drogues illégales ont augmenté au Canada, malgré les divers programmes communautaires axés sur la réduction des risques. Le nombre d'initiatives menées par les pharmaciens auprès des patients hospitalisés visant à réduire les dommages causés par les opioïdes est limité. Le groupe d'auteurs de cette étude a récemment élaboré et mis en place l'outil Medication and Risk Factor Review, Optimize, Refer at Risk Patients, Educate and Plan (MORE): une liste de contrôle systématique conçue pour aider les pharmaciens à respecter et à renforcer la sécurité de la prescription d'opioïdes en milieu hospitalier. OBJECTIFS: Évaluer l'impact d'un programme de gestion des opioïdes dirigé par des pharmaciens à l'aide de l'outil MORE pour les soins des patients résidant dans un hôpital d'enseignement tertiaire. MÉTHODES: Cette étude impliquait l'examen des dossiers de santé des patients admis dans les unités d'enseignement clinique de chirurgie générale et de médecine interne d'un hôpital tertiaire entre le 10 septembre et le 31 décembre 2018. Des opioïdes ont été prescrits à ces patients lors de leur séjour hospitalier. Une analyse descriptive des données a été menée auprès des patients ayant fait l'objet d'une évaluation à l'aide de l'outil MORE. RÉSULTATS: Sur les 210 patients qui répondaient aux critères d'admissibilité initiaux, notamment à celui d'un traitement aux opioïdes à l'hôpital pendant au moins trois jours, 50 ont fait l'objet d'une évaluation à l'aide de l'outil MORE. Le pharmacien a recommandé une intervention auprès de 40 de ces patients (80 %), et le prescripteur a accepté 35 de ces interventions (87,5 %). Les interventions des pharmaciens les plus répandues réalisées auprès des 50 patients consistaient en l'ajout ou en l'optimisation des analgésiques sans opioïdes (23 patients [46 %]); en la diminution de la dose d'opioïdes ou de leur fréquence (15 patients [30 %]); et en l'ajout d'un régime d'hygiène intestinale (9 patients [18 %]). CONCLUSIONS: La plupart des patients ayant fait l'objet d'une évaluation menée par un pharmacien présentaient des facteurs de risque d'effets indésirables découlant des prescriptions d'opioïdes et/ou d'ordonnances et de combinaisons médicamenteuses sous-optimales. L'outil MORE a permis aux pharmaciens d'adopter une approche guidée pour qu'ils puissent effectuer des interventions ciblées visant à améliorer l'innocuité des opioïdes. Un pharmacien affecté spécifiquement à la gestion des opioïdes pourrait offrir des avantages supplémentaires.

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and are generally well-tolerated; however, real-world studies indicate the frequency of discontinuation and adverse events (AEs) may be higher than what was observed in clinical trials. The objectives of this systematic review were to summarize real-world AEs reported for market-available CFTR modulators (i.e., ivacaftor (IVA), lumacaftor/ivacaftor (LUM/IVA), tezacaftor/ivacaftor (TEZ/IVA), and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)), and to identify ways in which the pharmacist on CF healthcare teams may contribute to mitigating and managing these AEs. The MEDLINE, EMBASE, CINAHL, and Web of Science Core Collection online databases were searched from 2012 to Aug 1, 2020. Full manuscripts or conference abstracts of observational studies, case series, and case reports were eligible for inclusion. The included full manuscripts and conference abstracts comprised of 54 observational studies, 5 case series, and 9 case reports. The types of AEs reported generally aligned with what have been observed in clinical trials. LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. A systematic approach to monitoring for AEs in people with CF on CFTR modulators in the real-world setting is necessary to help better understand potential AEs, as well as patient characteristics that may be associated with higher risk of certain AEs. Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies.

Postpartum Psychosis in a Young VA Patient: Diagnosis, Implications, and Treatment Recommendations.

Consider including a mood stabilizer with an antipsychotic medication because of the close association with bipolar disorder.

Impact of PharmaNet-Based Admission Medication Reconciliation on Best Possible Medication Histories for Warfarin.

BACKGROUND: Inaccurate documentation of medication histories may lead to medication discrepancies during hospital admissions. Obtaining a best possible medication history (BPMH) for warfarin can be challenging because of frequent dosage changes and nonspecific directions of use (e.g., "take as directed"). On February 27, 2012, the study hospital implemented an admission medication reconciliation (MedRec) process using a form that compiled the most recent 6 months of outpatient prescription dispensing history from a provincial electronic database called PharmaNet. It was unclear whether admission MedRec had improved the process of obtaining warfarin BPMHs and the quality of their documentation. OBJECTIVE: To compare the rates of complete warfarin BPMH documentation before and after implementation of PharmaNet-based admission MedRec. METHODS: A single-centre, retrospective chart review was conducted using the health records of patients receiving warfarin who were admitted to the hospital's Internal Medicine service before and after implementation of admission MedRec. The study periods were October 1, 2009, to February 26, 2012, and February 27, 2012, to July 31, 2014, respectively. The primary outcome was the rate of complete warfarin BPMH documentation during each period. RESULTS: Data were recorded for 100 patients in the pre-implementation phase and 100 patients in the post-implementation phase. The rates of complete warfarin BPMH documentation were 65% and 84% in these 2 phases, respectively (p = 0.002). CONCLUSION: Implementation of PharmaNet-based admission MedRec was associated with a statistically significant increase in the rate of complete warfarin BPMH documentation.

La consignation inexacte des schémas thérapeutiques peut mener à des divergences au chapitre des médicaments durant l'hospitalisation. Il peut être difficile d'établir un meilleur schéma thérapeutique possible (MSTP) pour la warfarine à cause de fréquents changements de posologie et de modes d'emploi imprécis (par exemple, « usage connu ¼). Le 27 février 2012, l'hôpital où s'est déroulée l'étude a mis en place un processus de bilan comparatif des médicaments (BCM) à l'admission. Celui-ci emploie un formulaire dressant la liste des médicaments d'ordonnance délivrés aux patients externes au cours des six derniers mois selon PharmaNet, une base de données numérique provinciale. On ignorait si les BCM à l'admission avaient amélioré le processus d'obtention et la qualité de la consignation des MSTP liés à la warfarine.

Characterization of Venous Thromboembolism Risk in Medical Inpatients Using Different Clinical Risk Assessment Models.

BACKGROUND: Symptomatic venous thromboembolism (VTE) occurs in about 1% of patients within 3 months after admission to a medical unit. Recent evidence for thromboprophylaxis in an unselected medical inpatient population has suggested only a modest net benefit. Consequently, guidelines recommend careful risk stratification to guide thromboprophylaxis. OBJECTIVES: To compare candidacy for thromboprophylaxis according to 4 risk stratification models: a regional preprinted order (PPO) set used in the study institution, the Padua Prediction Score, and the IMPROVE predictive and associative risk assessment models. METHODS: A retrospective review of health records was undertaken for patients with no contraindication to pharmacologic thromboprophylaxis who were admitted to the internal medicine service of a teaching hospital between April and July 2013. RESULTS: Of the 298 patients in the study cohort, 238 (80.0%) received pharmacologic thromboprophylaxis on admission, ordered according to the regional PPO. However, according to the Padua and the IMPROVE predictive risk assessment models, only 64 (21.5%) and 21 (7.0%) of the patients, respectively, were eligible for thromboprophylaxis at the time of admission. On the basis of risk factors identified during the subsequent hospital stay, 54 (18.1%) of the patients were eligible for thromboprophylaxis according to the IMPROVE associative model. Chance-corrected agreement between the PPO and the published risk assessment models was generally poor, with kappa coefficients of 0.109 for the PPO compared with the Padua Prediction Score and 0.013 for the PPO compared with the IMPROVE predictive model. CONCLUSIONS: These data suggest that quantitative models such as the Padua Prediction Score and the IMPROVE models identify more patients at low risk of venous thromboembolism than do in-hospital qualitative risk assessment models. Adoption of these guideline-based risk assessment models for predicting thromboembolic risk in medical inpatients could reduce the use of pharmacologic thromboprophylaxis from 80% to as low as 7%. Further external prognostic validation of risk assessment models and impact analysis studies may show improvements in safety and resource utilization.

La thromboembolie veineuse symptomatique se produit chez environ 1 % des patients dans les trois mois suivant leur admission à un service médical. Des données récentes portant sur la thromboprophylaxie chez une population non sélectionnée de patients hospitalisés ne suggéraient qu'un modeste avantage. Par conséquent, les lignes directrices recommandent une stratification du risque rigoureuse pour guider l'emploi d'une thromboprophylaxie.

Approach to the pharmacological management of chronic pain in patients with an alcohol use disorder.

This paper provides an overview of research, guidelines, and clinical considerations for the use of medications for chronic pain in the management of patients with an alcohol use disorder. A review of the literature identified randomized controlled trials, epidemiological cohort studies, consensus guidelines, and one systematic review and meta-analysis. Where gaps in the literature existed, clinical experience of the authors is included. Use of nonopioid medications should be given priority and may offer a more favorable risk profile as well as benefits beyond pain management, such as improvement in anxiety, depression, or insomnia. Pregabalin and gabapentin have additional benefits to decrease alcohol cravings or time to relapse after a period of abstinence from alcohol. Drug interactions between selected analgesics and alcohol, disulfiram, or naltrexone require careful consideration.