Citations

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

Artificial intelligence (AI) is rapidly moving from an experimental phase to an implementation phase in many fields, including medicine. The combination of improved availability of large datasets, increasing computing power, and advances in learning algorithms has created major performance breakthroughs in the development of AI applications. In the last 5 years, AI techniques known as deep learning have delivered rapidly improving performance in image recognition, caption generation, and speech recognition. Radiology, in particular, is a prime candidate for early adoption of these techniques. It is anticipated that the implementation of AI in radiology over the next decade will significantly improve the quality, value, and depth of radiology's contribution to patient care and population health, and will revolutionize radiologists' workflows. The Canadian Association of Radiologists (CAR) is the national voice of radiology committed to promoting the highest standards in patient-centered imaging, lifelong learning, and research. The CAR has created an AI working group with the mandate to discuss and deliberate on practice, policy, and patient care issues related to the introduction and implementation of AI in imaging. This white paper provides recommendations for the CAR derived from deliberations between members of the AI working group. This white paper on AI in radiology will inform CAR members and policymakers on key terminology, educational needs of members, research and development, partnerships, potential clinical applications, implementation, structure and governance, role of radiologists, and potential impact of AI on radiology in Canada.

Background: Brain imaging measurements can provide evidence of possible preclinical Alzheimer’s disease (AD). Their ability to predict individual imminent clinical conversion remains unclear. Objective: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairment (aMCI) within 2 years. Methods: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8±0.8 years (progressors); 20 participants matched for sex, age, education, and APOE allele dose remained cognitively unimpaired for at least 4 years (nonprogressors). A complementary control group not matched for APOE allele dose included 35 nonprogressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures. Results: Compared to non-progressors and regardless of APOE-matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual’s imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE-matched cohorts). Conclusion: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline.

Background: Trapeziectomy with ligament reconstruction tendon interposition (LRTI) or suspensionplasty is an effective treatment in older patients with end-stage thumb basilar arthritis. However, the survivability of this procedure is unknown in younger patients who may impart more stress on their thumbs. Methods: A retrospective review was performed on all patients who underwent trapeziectomy and LRTI or suspensionplasty at 55 years of age or younger from 1992 to 2008. Objective clinical outcome measures included preoperative to postoperative changes in thumb range of motion, grip and pinch strength, a study-specific thumb function score, and the Buck-Gramcko subjective outcome score. Progressive metacarpal subsidence was evaluated on radiographs. Survivorship free from revision surgery was calculated with a Kaplan-Meier analysis. Results: A total of 57 wrists underwent trapeziectomy and LRTI (n = 18) or suspensionplasty (n = 39). The mean patient age at the time of surgery was 49.6 years (range: 38-55 years). Mean clinical and radiographic follow-up were 10.2 and 6.4 years, respectively. Overall, there were significant improvements in pain and grip strength despite progressive and metacarpal subsidence. Survivorship was 100% and 86% free from revision surgery at 10 and 15 years, respectively (n = 2 failures). Conclusions: Trapeziectomy and LRTI or suspensionplasty in patients less than or equal to 55 years of age can result in considerable improvements in pain and grip strength with a 10-year survivorship free from revision.

AbstractEpidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Background: Palliative care is associated with improved survival and quality of life, but its use among patients with colorectal cancer varies nationwide and the determinants of those variations are not clear. Objective: To determine the factors associated with palliative care use among patients who died of colorectal cancer. Methods: Deceased patients treated for colorectal cancer (2004-2013) were identified within the National Cancer Database. Multivariable logistic regression was used to evaluate patient and institutional characteristics associated with palliative care use. Patients were classified based on their length of survival (<6 months, 6-24 months, and 24+ months) to provide timing context. Results: A total of 287 923 patients were analyzed. Overall, 4.3% of the patients received palliative care. Patients who received palliative care were more likely to be younger, recently diagnosed, treated at academic hospitals, and have stage IV disease. Patients living in Mountain and Pacific regions had higher odds of palliative care receipt than those in the East Coast. Patients without insurance had higher odds of palliative care if they survived <24 months. Insurance coverage through Medicaid was associated with increased palliative care use among patients who survived 6 to 24 months. Patients who survived <6 months and lived >9 miles from the institution received more palliative care. Conclusion: Palliative care use among patients with colorectal cancer is associated with a younger age, a more recent year of diagnosis, insurance status, academic hospitals, and living in Mountain and Pacific regions.

BackgroundAppropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision‐making.ObjectivesThe American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology.MethodsThe RAND/UCLA appropriateness methodology, which combines evidence‐based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology.ResultsWith the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered “usually appropriate,” 52 (25%) “rarely appropriate” and 43 (20%) “uncertain appropriateness.”LimitationsThe methodology requires a focus on appropriateness without comparison between tests and irrespective of cost.ConclusionsThe ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness—AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed “uncertain appropriateness” and where consensus was not reached may benefit from further research.