Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma: A CONNECT pediatric neuro-oncology consortium report.

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Pediatric tectal plate gliomas: a review of clinical outcomes, endocrinopathies, and neuropsychological sequelae.

Pediatric tectal plate gliomas are indolent slow-growing gliomas that often present with increased intracranial pressure or incidentally on routine brain imaging. We investigated clinical outcomes, endocrinopathies, and neuropsychological sequelae associated with tectal plate gliomas. Twenty-six patients with tectal plate glioma were identified in a 20-year retrospective review. Clinical outcomes, treatments, endocrine function, neuropsychological testing outcomes and radiographic imaging were reviewed for possible signs correlating with tumor progression. Among 26 patients, 19 presented with signs or symptoms of increased intracranial pressure (73 %) versus an incidental finding in 7 (27 %). Median follow-up was 46 months (range 8-143 months). Six of 26 (23 %) experienced progressive disease after diagnosis. Five of 26 (19 %) required more than one surgical procedure due to failure of initial endoscopic third ventriculostomy. Seven of 26 had history of endocrine dysfunction, of which, five presented with endocrine dysfunction (precocious puberty or short stature), 1 developed menstrual irregularities after surgical intervention and 1 had preexisting pan hypopituitarism. Of 12 patients with available neuropsychological testing, eleven had at least one indicator of executive functioning in the low-average to impaired range. While tectal plate gliomas have been considered indolent tumors that are rarely progressive, 23 % of patients in our cohort experienced disease progression and required further therapy. Neurocognitive deficits may occur, while endocrine deficiency is uncommon. Regular multidisciplinary oncology follow-up, routine monitoring with MRI and formal neurocognitive evaluation are imperative to provide early recognition of disease progression or recurrent hydrocephalus and to improve school functioning in this population.

Ribosome profiling reveals a cell-type-specific translational landscape in brain tumors.

Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5'-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation.

Mapping the coverage of attributes in validated instruments that evaluate primary healthcare from the patient perspective.

BACKGROUND: Primary healthcare in developed countries is undergoing important reforms, and these require evaluation strategies to assess how well the population's expectations are being met. Although numerous instruments are available to evaluate primary healthcare (PHC) from the patient perspective, they do not all measure the same range of constructs. To analyze the extent to which important PHC attributes are covered in validated instruments measuring quality of care from the patient perspective. METHOD: We systematically identified validated instruments from the literature and by consulting experts. Using a Delphi consensus-building process, Canadian PHC experts identified and operationally defined 24 important PHC attributes. One team member mapped instrument subscales to these operational definitions; this mapping was then independently validated by members of the research team and conflicts were resolved by the PHC experts. RESULTS: Of the 24 operational definitions, 13 were evaluated as being best measured by patients, 10 by providers, three by administrative databases and one by chart audits (some being best measured by more than one source). Our search retained 17 measurement tools containing 118 subscales. After eliminating redundancies, we mapped 13 unique measurement tools to the PHC attributes. Accessibility, relational continuity, interpersonal communication, management continuity, respectfulness and technical quality of clinical care were the attributes widely covered by available instruments. Advocacy, management of clinical information, comprehensiveness of services, cultural sensitivity, family-centred care, whole-person care and equity were poorly covered. CONCLUSIONS: Validated instruments to evaluate PHC quality from the patient perspective leave many important attributes of PHC uncovered. A complete assessment of PHC quality will require adjusting existing tools and/or developing new instruments.

Canadian Experts' Views on the Importance of Attributes within Professional and Community-Oriented Primary Healthcare Models.

PURPOSE: The aim of this study was to rate the importance of primary healthcare (PHC) attributes in evaluations of PHC organizational models in Canada. METHODS: Using the Delphi process, we conducted a consensus consultation with 20 persons recognized by peers as Canadian PHC experts, who rated the importance of PHC attributes within professional and community-oriented models of PHC. RESULTS: ATTRIBUTES RATED AS ESSENTIAL TO ALL MODELS WERE DESIGNATED CORE ATTRIBUTES: first-contact accessibility, comprehensiveness of services, relational continuity, coordination (management) continuity, interpersonal communication, technical quality of clinical care and clinical information management. Overall, while all were important, non-core attributes - except efficiency/productivity - were rated as more important in community-oriented than in professional models. Attributes rated as essential for community-oriented models were equity, client/community participation, population orientation, cultural sensitivity and multidisciplinary teams. CONCLUSION: Evaluation tools should address core attributes and be customized in accordance with the specific organizational models being evaluated to guide health reforms.

Validation of instruments to evaluate primary healthcare from the patient perspective: overview of the method.

UNLABELLED: Patient evaluations are an important part of monitoring primary healthcare reforms, but there is little comparative information available to guide evaluators in the choice of instruments or to determine their relevance for Canada. OBJECTIVE: To compare values and the psychometric performances of validated instruments thought to be most pertinent to the Canadian context for evaluating core attributes of primary healthcare. METHOD: AMONG VALIDATED INSTRUMENTS IN THE PUBLIC DOMAIN, WE SELECTED SIX: the Primary Care Assessment Survey (PCAS); the Primary Care Assessment Tool - Short Form (PCAT-S); the Components of Primary Care Index (CPCI); the first version of the EUROPEP (EUROPEP-I); the Interpersonal Processes of Care Survey, version II (IPC-II); and part of the Veterans Affairs National Outpatient Customer Satisfaction Survey (VANOCSS). We mapped subscales to operational definitions of attributes. All were administered to a sample of adult service users balanced by English/French language (in Nova Scotia and Quebec, respectively), urban/rural residency, high/low education and overall care experience. The sample was recruited from previous survey respondents, newspaper advertisements and community posters. We used common factor analysis to compare our factor resolution for each instrument to that of the developers. RESULTS: Our sample of 645 respondents was approximately balanced by design variables, but considerable effort was required to recruit low-education and poor-experience respondents. Subscale scores are statistically different by excellent, average and poor overall experience, but interpersonal communication and respectfulness scores were the most discriminating of overall experience. We found fewer factors than did the developers, but when constrained to the number of expected factors, our item loadings were largely similar to those found by developers. Subscale reliability was equivalent to or higher than that reported by developers. CONCLUSION: These instruments perform similarly in the Canadian context to their original development context, and can be used with confidence. Interpersonal and respectfulness scores are most discriminating of excellent, average or poor overall experience and are crucial dimensions of patient evaluations.

An overview of confirmatory factor analysis and item response analysis applied to instruments to evaluate primary healthcare.

This paper presents an overview of the analytic approaches that we used to assess the performance and structure of measures that evaluate primary healthcare; six instruments were administered concurrently to the same set of patients. The purpose is (a) to provide clinicians, researchers and policy makers with an overview of the psychometric methods used in this series of papers to assess instrument performance and (b) to articulate briefly the rationale, the criteria used and the ways in which results can be interpreted. For illustration, we use the case of instrument subscales evaluating accessibility. We discuss (1) distribution of items, including treatment of missing values, (2) exploratory and confirmatory factor analysis to identify how items from different subscales relate to a single underlying construct or sub-dimension and (3) item response theory analysis to examine whether items can discriminate differences between individuals with high and low scores, and whether the response options work well. Any conclusion about the relative performance of instruments or items will depend on the type of analytic technique used. Our study design and analytic methods allow us to compare instrument subscales, discern common constructs and identify potentially problematic items.

Accessibility from the patient perspective: comparison of primary healthcare evaluation instruments.

UNLABELLED: The operational definition of first-contact accessibility is "the ease with which a person can obtain needed care (including advice and support) from the practitioner of choice within a time frame appropriate to the urgency of the problem"; accommodation is "the way healthcare resources are organized to accommodate a wide range of patients' abilities to contact healthcare providers and reach healthcare services, that is to say telephone services, flexible appointment systems, hours of operation, and walk-in periods." OBJECTIVE: To compare how well accessibility is measured in validated subscales that evaluate primary healthcare from the patient's perspective. METHOD: 645 adults with at least one healthcare contact in the previous 12 months responded to six instruments that evaluate primary healthcare with four subscales that measure accessibility: the Primary Care Assessment Survey (PCAS), the Primary Care Assessment Tool - Short Form (PCAT-S, two subscales) and the first version of the EUROPEP (EUROPEP-I). Scores were normalized to a 0-to-10 scale for descriptive comparison. Exploratory and confirmatory (structural equation modelling) factor analysis examined fit to operational definition, and item response theory analysis examined item performance on common constructs. RESULTS: The subscales demonstrate similar psychometric measures to those reported by developers. The PCAT-S First-Contact Utilization subscale does not fit the accessibility construct. The remaining three subscales load reasonably onto a single factor, presumed to be accessibility, but the best-fitting model has two factors: "timeliness of obtaining needed care" (PCAT-S First-Contact Access, some EUROPEP-I items) and "how resources are organized to accommodate clients" (PCAS Organizational Access and most of EUROPEP-I organization of care). Items in the PCAS and PCAT-S subscales have good discriminability. CONCLUSION: Only three of the four subscales measure accessibility; all are appropriate for use in Canada. The PCAT-S First-Contact Access subscale is the best measure for first-contact accessibility, and PCAS Organizational Accessibility has good metric properties and measures for accommodation.

Respectfulness from the patient perspective: comparison of primary healthcare evaluation instruments.

UNLABELLED: Respectfulness is one measurable and core element of healthcare responsiveness. The operational definition of respectfulness is "the extent to which health professionals and support staff meet users' expectations about interpersonal treatment, demonstrate respect for the dignity of patients and provide adequate privacy." OBJECTIVE: To examine how well respectfulness is captured in validated instruments that evaluate primary healthcare from the patient's perspective, whether or not their developers had envisaged these as representing respectfulness. METHOD: 645 adults with at least one healthcare contact with their own regular doctor or clinic in the previous 12 months responded to six instruments, two subscales that mapped to respectfulness: the Interpersonal Processes of Care, version II (IPC-II, two subscales) and the Primary Care Assessment Survey (PCAS). Additionally, there were individual respectfulness items in subscales measuring other attributes in the Components of Primary Care Index (CPCI) and the first version of the EUROPEP (EUROPEP-I). Scores were normalized for descriptive comparison. Exploratory and confirmatory (structural equation modelling) factor analyses examined fit to operational definition. RESULTS: Respectfulness scales correlate highly with one another and with interpersonal communication. All items load adequately on a single factor, presumed to be respectfulness, but the best model has three underlying factors corresponding to (1) physician's interpersonal treatment (eigenvalue=13.99), (2) interpersonal treatment by office staff (eigenvalue=2.13) and (3) respect for the dignity of the person (eigenvalue=1.16). Most items capture physician's interpersonal treatment (IPC-II Compassionate, Respectful Interpersonal Style, IPC-II Hurried Communication and PCAS Interpersonal Treatment). The IPC-II Interpersonal Style (Disrespectful Office Staff) captures treatment by staff, but only three items capture dignity. CONCLUSION: Various items or subscales seem to measure respectfulness among currently available validated instruments. However, many of these items related to other constructs, such as interpersonal communication. Further studies should aim at developing more refined measures - especially for privacy and dignity - and assess the relevance of the broader concept of responsiveness.

Operational definitions of attributes of primary health care: consensus among Canadian experts.

PURPOSE: In 2004, we undertook a consultation with Canadian primary health care experts to define the attributes that should be evaluated in predominant and proposed models of primary health care in the Canadian context. METHOD: Twenty persons considered to be experts in primary health care or recommended by at least 2 peers responded to an electronic Delphi process. The expert group was balanced between clinicians (principally family physicians and nurses), academics, and decision makers from all regions in Canada. In 4 iterative rounds, participants were asked to propose and modify operational definitions. Each round incorporated the feedback from the previous round until consensus was achieved on most attributes, with a final consensus process in a face-to-face meeting with some of the experts. RESULTS: Operational definitions were developed and are proposed for 25 attributes; only 5 rate as specific to primary care. Consensus on some was achieved early (relational continuity, coordination-continuity, family-centeredness, advocacy, cultural sensitivity, clinical information management, and quality improvement process). The definitions of other attributes were refined over time to increase their precision and reduce overlap between concepts (accessibility, quality of care, interpersonal communication, community orientation, comprehensiveness, multidisciplinary team, responsiveness, integration). CONCLUSION: This description of primary care attributes in measurable terms provides an evaluation lexicon to assess initiatives to renew primary health care and serves as a guide for instrument selection.

Drug information resources used by nurse practitioners and collaborating physicians at the point of care in Nova Scotia, Canada: a survey and review of the literature.

BACKGROUND: Keeping current with drug therapy information is challenging for health care practitioners. Technologies are often implemented to facilitate access to current and credible drug information sources. In the Canadian province of Nova Scotia, legislation was passed in 2002 to allow nurse practitioners (NPs) to practice collaboratively with physician partners. The purpose of this study was to determine the current utilization patterns of information technologies by these groups of practitioners. METHODS: Nurse practitioners and their collaborating physician partners in Nova Scotia were sent a survey in February 2005 to determine the frequency of use, usefulness, accessibility, credibility, and current/timeliness of personal digital assistant (PDA), computer, and print drug information resources. Two surveys were developed (one for PDA users and one for computer users) and revised based on a literature search, stakeholder consultation, and pilot-testing results. A second distribution to nonresponders occurred two weeks following the first. Data were entered and analysed with SPSS. RESULTS: Twenty-seven (14 NPs and 13 physicians) of 36 (75%) recipients responded. 22% (6) returned personal digital assistant (PDA) surveys. Respondents reported print, health professionals, and online/electronic resources as the most to least preferred means to access drug information, respectively. 37% and 35% of respondents reported using "both print and electronic but print more than electronic" and "print only", respectively, to search monograph-related drug information queries whereas 4% reported using "PDA only". Analysis of respondent ratings for all resources in the categories print, health professionals and other, and online/electronic resources, indicated that the Compendium of Pharmaceuticals and Specialties and pharmacists ranked highly for frequency of use, usefulness, accessibility, credibility, and current/timeliness by both groups of practitioners. Respondents' preferences and resource ratings were consistent with self-reported methods for conducting drug information queries. Few differences existed between NP and physician rankings of resources. CONCLUSION: The use of computers and PDAs remains limited, which is also consistent with preferred and frequent use of print resources. Education for these practitioners regarding available electronic drug information resources may facilitate future computer and PDA use. Further research is needed to determine methods to increase computer and PDA use and whether these technologies affect prescribing and patient outcomes.

EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.

Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP+) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.