Development, implementation and impact of an immunoglobulin stewardship programme in Saskatchewan, Canada.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulin (IVIG) is one of the most costly and limited-supply blood products. Judicious use of this therapy is important to ensure a continued supply is available for patients in need. The Saskatchewan IG Stewardship Program was initiated to monitor and reduce inappropriate IG use. MATERIALS AND METHODS: The Program was developed and implemented through the collaborative efforts of a multidisciplinary, inter-organizational team. Funding was provided from provincial organizations to create new positions within the Program and to support stakeholder engagement throughout the process of implementation. Data were collected from local and national databases regarding the amount of IVIG used and appropriateness of orders based on published criteria. RESULTS: Over 20 months, the Program helped to reduce unnecessary IVIG use from pre-intervention levels by more than 20%. Interventions from nurse navigators alone reduced inappropriate IVIG use by 2.6%. During the 20-month period following Program initiation, more than 4 million CAD less was spent on IVIG compared with the previous 20 months. CONCLUSION: The Saskatchewan IG Stewardship Program has led to more appropriate IVIG use across the province, more effective preservation of this limited healthcare resource, and cost savings that more than cover the cost of administering the Program.

The viral prescription pad - a mixed methods study to determine the need for and utility of an educational tool for antimicrobial stewardship in primary health care.

BACKGROUND: In order to combat rising rates of antimicrobial resistant infections, it is vital that antimicrobial stewardship become embedded in primary health care (PHC). Despite the high use of antimicrobials in PHC settings, there is a lack of data regarding the integration of antimicrobial stewardship programs (ASP) in non-hospital settings. Our research aimed to determine which antimicrobial stewardship interventions are optimal to introduce into PHC clinics beginning to engage with an ASP, as well as how to optimize those interventions. This work became focused specifically around management of viral upper respiratory tract infections (URTIs), as these infections are one of the main sources of inappropriate antibiotic use. METHODS: This mixed methods study of sequential explanatory design was developed through three research projects over 3 years in Regina, Saskatchewan, Canada. First, a survey of PHC providers was performed to determine their perceived needs from a PHC-based ASP. From this work, a "viral prescription pad" was developed to provide a tool to help PHC providers engage in patient education regarding appropriate antimicrobial use, specifically for URTIs. Next, interviews were performed with family physicians to discuss their perceived utility of this tool. Finally, we performed a public survey to determine preferences for the medium by which information is received regarding symptom management for viral URTIs. RESULTS: The majority of PHC providers responding to the initial survey indicated they were improperly equipped with tools to aid in promoting conversations with patients and providing education about the appropriate use of antimicrobials. Following dissemination of the viral prescription pad and semi-structured interviews with family physicians, the viral prescription pad was deemed to be a useful educational tool. However, about half of the physicians interviewed indicated they did not actually provide a viral prescription to patients when providing advice on symptom management for viral URTIs. When asked about their preferences, 76% of respondents to the public survey indicated they would prefer to receive written or a combination of verbal and written information in this circumstance. CONCLUSIONS: PHC providers indicated a need for educational tools to promote conversations with patients and provide education about the appropriate use of antimicrobials. Viral prescription pads were regarded by family physicians and patients as useful tools in facilitating discussion on the appropriate use of antimicrobials. PHC providers should exercise caution in opting out of providing written forms of information, as many respondents to the general public survey indicated their preference in receiving both verbal and written information.

Identification of Staphylococci by Polymerase Chain Reaction Directly from a Positive Blood Culture and Effect on Patient Care.

BACKGROUND: As one of the most common bloodstream infections worldwide, Staphylococcus aureus bacteremia places a major burden on health care. Implementation of a rapid, genetic-based diagnostic test may have important implications in the clinical management of patients with S. aureus bacteremia. OBJECTIVES: The primary objective was to assess concordance between testing based on polymerase chain reaction (PCR) and the current gold standard, culture and sensitivity testing; the secondary objective was to assess the impact of this technology on patient care. METHODS: A pre-post intervention retrospective chart review was used to document the hospital course of patients with a diagnosis of S. aureus bacteremia before and after implementation of the PCR-based diagnostic system. Laboratory results from all patient samples subjected to PCR-based analysis following implementation of this system were compared with culture and sensitivity data for the same samples to determine accuracy of the new system. In addition, time to optimal therapy for each patient was calculated as the interval between the initiation of empiric and terminal therapies. The appropriateness of antimicrobial treatment was characterized as guideline-concordant, nonconcordant with the guidelines, or nonconcordant yet still clinically appropriate. RESULTS: In total, 98 and 99 patients met the inclusion criteria before and after implementation of the PCR-based diagnostic system, respectively. PCR-based results displayed 99.8% concordance (440/441 total samples) with results from culture and sensitivity testing. The time to optimal therapy was significantly shorter after implementation, by a mean of 22.8 h (p < 0.001). Overall, 97% of empiric and 99% of terminal antimicrobial regimens were either guideline-concordant or clinically appropriate for treatment of S. aureus bacteremia; 3% of empiric and 1% of terminal antimicrobial regimens were nonconcordant with clinical guidelines without any explanation based on other clinical considerations. CONCLUSIONS: The study findings support the utility of using a direct-from-positive-blood-culture PCR-based diagnostic tool as the primary method of identifying S. aureus bacteremia in patients, as well as the acceptance of and acting upon the new assay's results by our local clinicians. PCR-based assays can help reduce the time to optimal terminal therapy for patients with bacteremia.

CONTEXTE: La bactériémie à Staphylococcus aureus (BAC-SA), qui est l'une des infections du sang les plus répandues dans le monde, fait peser une lourde charge sur les soins de santé. La mise en place d'un test diagnostique génétique rapide pourrait avoir des retombées importantes sur la gestion clinique des patients présentant une BAC-SA. OBJECTIFS: L'objectif principal consistait à évaluer la concordance entre les tests basés sur la réaction en chaîne par polymérase (PCR) et le test de sensibilité et de culture, qui est la référence absolue actuelle; l'objectif secondaire consistait à évaluer l'impact de cette technologie sur les soins des patients. MÉTHODES: Un examen rétrospectif des dossiers pré-et post-intervention a servi à décrire le séjour à l'hôpital des patients ayant reçu un diagnostic de BAC-SA avant et après la mise en place du système de diagnostic de la PCR. Les résultats de laboratoire de tous les échantillons des patients soumis à une analyse de la PCR à la suite de la mise en place de ce système ont été comparés avec les données relatives à la culture et à la sensibilité de ces mêmes échantillons afin de déterminer la précision du nouveau système. De plus, l'évaluation du délai d'atteinte du traitement optimal de chaque patient repose sur le calcul de l'intervalle entre le début des thérapies empiriques et terminales. La pertinence du traitement antimicrobien était caractérisée comme suit : concordance avec les lignes directrices, non-concordance avec les lignes directrices ou non-concordance mais encore approprié d'un point de vue clinique. RÉSULTATS: Au total, 98 et 99 patients ont satisfait au critère d'inclusion respectivement avant et après la mise en place du système de diagnostic de la PCR. Les résultats basés sur la PCR affichaient une concordance de 99,8 % (440/441 échantillons au total) avec les résultats des tests de sensibilité et de culture. La diminution du délai d'atteinte du traitement optimal était importante après la mise en place du système, puisqu'elle atteignait en moyenne 22,8 h (p < 0,001). De manière générale, 97 % des régimes antimicrobiens empiriques et 99 % des régimes antimicrobiens terminaux concordaient avec les lignes directrices ou étaient cliniquement appropriés pour le traitement de la BAC-SA; 3 % des régimes antimicrobiens empiriques et 1 % des régimes antimicrobiens terminaux n'étaient pas conformes aux lignes directrices cliniques sans qu'aucune explication basée sur d'autres considérations cliniques n'ait été donnée. CONCLUSIONS: Les résultats de l'étude confirment la nécessité d'utiliser un outil diagnostique basé sur la PCR directement de l'hémoculture positive en guise de méthode principale pour déterminer la présence de BAC-SA chez les patients ainsi que l'acceptation et l'utilisation des nouveaux résultats du test par nos cliniciens locaux. Les tests basés sur la PCR peuvent aider à réduire le délai d'attente du traitement optimal pour les patients atteints de BAC-SA.

Development of a Patient-Oriented Intervention to Support Patient-Provider Conversations about Unnecessary Lower Back Pain Imaging.

BACKGROUND: despite the efforts of multiple stakeholders to promote appropriate care throughout the healthcare system, studies show that two out of three lower back pain (LBP) patients expect to receive imaging. We used the Choosing Wisely Canada patient-oriented framework, prioritizing patient engagement, to develop an intervention that addresses lower back pain imaging overuse. METHODS: to develop this intervention, we collaborated with a multidisciplinary advisory team, including two patient partners with lower back pain, researchers, clinicians, healthcare administrators, and the Choosing Wisely Canada lead for Saskatchewan. For this qualitative study, data were collected through two advisory team meetings, two individual interviews with lower back pain patient partners, and three focus groups with lower back pain patient participants. A lower back pain prescription pad was developed as an outcome of these consultations. RESULTS: participants reported a lack of interactive and informative communication was a significant barrier to receiving appropriate care. The most cited content information for inclusion in this intervention was treatments known to work, including physical activity, useful equipment, and reliable sources of educational material. Participants also suggested it was important that benefits and risks of imaging were explained on the pad. Three key themes derived from the data were also used to guide development of the intervention: (a) the role of imaging in LBP diagnosis; (b) the impact of the patient-physician relationship on LBP diagnosis and treatment; and (c) the lack of patient awareness of Choosing Wisely Canada and their recommendations. CONCLUSIONS: the lower back pain patient-developed prescription pad may help patients and clinicians engage in informed conversations and shared decision making that could support reduce unnecessary lower back pain imaging.

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

BACKGROUND: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. RESULTS: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. CONCLUSIONS: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion.

Mutations of FBXL4, which encodes an orphan mitochondrial F-box protein, are a recently identified cause of encephalomyopathic mtDNA depletion. Here, we describe the detailed clinical and biochemical phenotype of a neonate presenting with hyperlactatemia, leukoencephalopathy, arrhythmias, pulmonary hypertension, dysmorphic features, and lymphopenia. Next-generation sequencing in the proband identified a homozygous frameshift, c.1641_1642delTG, in FBXL4, with a surrounding block of SNP marker homozygosity identified by microarray. Muscle biopsy showed a paucity of mitochondria with ultrastructural abnormalities, mitochondrial DNA depletion, and profound deficiency of all respiratory chain complexes. Cell-based mitochondrial phenotyping in fibroblasts showed mitochondrial fragmentation, decreased basal and maximal respiration, absence of ATP-linked respiratory and leak capacity, impaired survival under obligate aerobic respiration, and reduced mitochondrial inner membrane potential, with relative sparing of mitochondrial mass. Cultured fibroblasts from the patient exhibited a more oxidized glutathione ratio, consistent with altered cellular redox poise. High-resolution respirometry of permeabilized muscle fibers showed marked deficiency of oxidative phosphorylation using a variety of mitochondrial energy substrates and inhibitors. This constitutes the fourth and most detailed report of FBXL4 deficiency to date. In light of our patient's clinical findings and genotype (homozygous frameshift), this phenotype likely represents the severe end of the FBXL4 clinical spectrum.

DNM1L-related mitochondrial fission defect presenting as refractory epilepsy.

Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.