The impact of physical activity modification on the well-being of a cohort of children with an inherited arrhythmia or cardiomyopathy.

BACKGROUND: We evaluated a cohort of 35 children diagnosed with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy with regard to physical and psychosocial well-being. MATERIAL AND METHODS: Patients wore an accelerometer to record their time involved in moderate- to vigorous-intensity physical activity and completed the Pediatric Quality of Life Inventory and the Pediatric Cardiac Quality of Life Inventory. Parents were also asked to describe if their child had changed their physical activity because of their diagnosis and how difficult and upsetting it was for the child to adapt to the physical activity recommendations. RESULTS: Patients were involved in less moderate- to vigorous-intensity physical activity per day (35 min/day versus 55 min/day) and had lower Pediatric Quality of Life Inventory total health scores (79 versus 84) compared to normative data. Overall, 51% of the cohort modified their physical activity in some way because of their diagnosis and changing physical activity was associated with lower Pediatric Quality of Life Inventory and Pediatric Cardiac Quality of Life Inventory scores. CONCLUSION: Our cohort was involved in less moderate- to vigorous-intensity physical activity and had lower Pediatric Quality of Life Inventory total health scores compared to normative paediatric data. Modifying one's physical activity was associated with worse health-related quality of life scores, highlighting a vulnerable sub-group of children. These findings are useful for families and healthcare professionals caring for children who are adjusting to a new cardiac diagnosis of an inherited arrhythmia or cardiomyopathy.

Physical activity restriction for children and adolescents diagnosed with an inherited arrhythmia or cardiomyopathy and its impact on body mass index.

BACKGROUND: Historically, individuals diagnosed with an inherited arrhythmia or cardiomyopathy have been advised to avoid participating in competitive sports. Consequently, these individuals may be more susceptible to weight gain and obesity. METHODS: A retrospective longitudinal chart review was performed for a population of children with a genetic or clinical diagnosis of the long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy. We recorded the physical activity recommendation, postdiagnosis sports participation, and body mass index (BMI) over time. RESULTS: A total of 109 charts were reviewed. Some level of physical activity restriction was documented for the majority of phenotype-positive children (80%) but was less common for phenotype-negative children (37%) (P < 0.001). Overall, 38% ( n = 41) of the study population were reportedly participating in a moderate or high dynamic sports following their diagnosis. Nonetheless, the BMI did not differ over time based on physical activity restriction or sports participation, and the proportion of overweight and obese children at follow-up was consistent with that seen in the Canadian pediatric population. CONCLUSION: Physical activity restriction was recommended for the majority of phenotype-positive children with an inherited arrhythmia or cardiomyopathy. However, many children continue to participate in competitive sports. Children prescribed physical activity restriction appear to face similar concerns relating to obesity as other Canadian children. This study highlights the need to further assess the effectiveness of physical activity recommendations and its impact on the cardiovascular health.

Uptake of Predictive Genetic Testing and Cardiac Evaluation for Children at Risk for an Inherited Arrhythmia or Cardiomyopathy.

Predictive genetic testing in minors should be considered when clinical intervention is available. Children who carry a pathogenic variant for an inherited arrhythmia or cardiomyopathy require regular cardiac screening and may be prescribed medication and/or be told to modify their physical activity. Medical genetics and pediatric cardiology charts were reviewed to identify factors associated with uptake of genetic testing and cardiac evaluation for children at risk for long QT syndrome, hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. The data collected included genetic diagnosis, clinical symptoms in the carrier parent, number of children under 18 years of age, age of children, family history of sudden cardiac arrest/death, uptake of cardiac evaluation and if evaluated, phenotype for each child. We identified 97 at risk children from 58 families found to carry a pathogenic variant for one of these conditions. Sixty six percent of the families pursued genetic testing and 73% underwent cardiac screening when it was recommended. Declining predictive genetic testing was significantly associated with genetic specialist recommendation (p < 0.001) and having an asymptomatic carrier father (p = 0.006). Cardiac evaluation was significantly associated with uptake of genetic testing (p = 0.007). This study provides a greater understanding of factors associated with uptake of genetic testing and cardiac evaluation in children at risk of an inherited arrhythmia or cardiomyopathy. It also identifies a need to educate families about the importance of cardiac evaluation even in the absence of genetic testing.

Exercise and ß-blocker therapy recommendations for inherited arrhythmogenic conditions.

BACKGROUND: Management of individuals with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy may involve exercise restriction and/or ß-blocker therapy. OBJECTIVE: This study assessed the practices of a group of paediatric electrophysiologists regarding the management of genotype-positive/phenotype-positive and genotype-positive/phenotype-negative individuals with these conditions. METHOD: An online survey was circulated to members of the Pediatric and Congenital Electrophysiology Society in May, 2014. The survey included questions addressing the respondents' approach regarding exercise recommendations and prescription of ß-blocker therapy. RESULTS: A total of 45 cardiologists completed the survey. The majority of respondents restricted symptomatic patients from competitive sports; however, only approximately half restricted phenotype-negative mutation carriers from this level of activity. Recommendations were less consistent regarding other types of activities. A trend was identified regarding physician physical activity and exercise recommendations for phenotype-negative mutation carriers. Less-active physicians were more likely to restrict exercise. ß-blocker therapy was discussed by the majority of respondents for symptomatic patients and a significant number of asymptomatic patients. CONCLUSION: Exercise restriction for patients with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy varies based on several factors including phenotype, type of exercise, guidelines referred to, and physicians' own level of activity.

Protocol for a Prospective, Observational Cost-effectiveness Analysis of Returning Secondary Findings of Genome Sequencing for Unexplained Suspected Genetic Conditions.

PURPOSE: Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets. Secondary finding testing is actively debated because some consider it opportunistic screening for future health risks that may not manifest. Given the economic implications of secondary finding testing and follow-up and its unproven clinical utility, the objective is to assess the incremental cost-effectiveness of secondary finding ascertainment per case detected and per unit of improved clinical utility in families of children with unexplained suspected genetic conditions undergoing clinical GWS. METHODS: Those undergoing trio genome or exome sequencing are eligible for the study. Positive secondary finding index cases will be matched to negative controls (1:2) based on age group, primary result(s) type, and clinical indication. During the 2-year study, 71 cases and 142 matched controls are expected. Health service use will be collected in patients and 1 adult family member every 6 months. The per-child and per-dyad total cost will be determined by multiplying use of each resource by a corresponding unit price and summing all cost items. Costs will be estimated from the public and societal payer perspectives. The mean cost per child and per dyad for secondary finding-positive and secondary finding-negative groups will be compared statistically. If important demographic differences are observed between groups, ordinary least-squares regression, log transformation, or other nonparametric technique will be used to compare adjusted mean costs. The ratio of the difference in mean cost to the secondary finding yield will be used to estimate incremental cost-effectiveness. In secondary analyses, effectiveness will be estimated using the number of clinical management changes due to secondary findings or the Clinician-Reported Genetic Testing Utility Index (C-GUIDE) score, a validated measure of clinical utility. Sensitivity analysis will be undertaken to assess the robustness of the findings to variation in key parameters. IMPLICATIONS: This study generates key evidence to inform clinical practice and funding allocation related to secondary finding testing. The inclusion of family members and a new measure of clinical utility represent important advancements in economic evaluation in genomics.

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

Global variation in copy number in the human genome.

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.

Defining the role of laboratory genetic counselor.

An increasing number of genetic counselors are moving into non-clinical roles, where their primary duties do not involve direct patient contact. According to the National Society of Genetic Counselors Professional Status Survey in 2010, 23% of counselors working in non-clinical roles identified laboratory or genetic testing as their primary area of work. Using a survey, we identified 43 genetic counselors who work predominately in laboratory settings. The two primary tasks performed by participants, include acting as a customer liaison (95%) and calling out test results (88%). Nineteen participants (44.2%) also reported spending a considerable amount of time signing reports. The most prevalent areas of job satisfaction were support from laboratory directors (76.8%), autonomy (76.7%), interactions with clinicians (69.7%) and interaction with other genetics counselors (67.5%). This is the first study specifically looking at the roles of laboratory genetic counselors, which is an expanding area of genetic counseling.

Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario.

BACKGROUND: Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada. METHODS: The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected). INTERPRETATION: Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.

Objective: Infectious illness, including lower respiratory tract infection (LRTI), is a leading cause of childhood morbidity and infant mortality in Inuit children in Nunavut Canada. The carnitine palmitoyltransferase 1A (CPT1A) p.P479L variant is common in arctic Indigenous populations of Alaska, Canada, and Greenland. CPT1A is a fatty acid oxidation enzyme expressed in the liver, immunocytes and other tissues, and is needed to use fats for energy during fasting. Previous association of the variant with early childhood infectious illness and infant death has been challenged because of sample size and limited adjustment for confounders. We evaluated whether the p.P479L variant is associated with infectious illness in Inuit children of Nunavut, Canada. Methods: We conducted a retrospective clinical chart review of 2,225 Inuit children (0-5 years) for infectious illness (including otitis media, gastroenteritis, and hospital admission for LRTI), prenatal, perinatal, and socioeconomic indicators, subsequently linking to CPT1A genotype. Multivariable logistic regression adjusted for birth characteristics, breastfeeding, maternal smoking, food insecurity, and socioeconomic indicators. Results: Overall, 27% of children were hospitalized for LRTI, 86% had otitis media and 50% had gastroenteritis. The p.P479L allele frequency was 0.82. In multivariable analysis, p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46-5.64), otitis media (aOR:1.83, 95%CI:1.05-3.21), and gastroenteritis (aOR:1.74, 95%CI:1.09-2.77), compared to non-carriers. Conclusion: Children homozygous for the p.P479L variant were more likely to experience infectious illness than non-carriers, including hospitalization for respiratory tract infections. Given the role of CPT1A in immunocytes, our findings indicate that more study is needed to determine if there is a role of the variant in immune response. Continued Inuit involvement is essential when considering next steps.

Homocysteine is not associated with global motor or cognitive measures in nondemented older Parkinson's disease patients.

Levodopa (L-dopa) treatment of Parkinson's disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B-vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B-vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B-vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12.

Severe expressive-language delay related to duplication of the Williams-Beuren locus.

The Williams-Beuren syndrome (WBS) locus, at 7q11.23, is prone to recurrent chromosomal rearrangements, including the microdeletion that causes WBS, a multisystem condition with characteristic cardiovascular, cognitive, and behavioral features. It is hypothesized that reciprocal duplications of the WBS interval should also occur, and here we present such a case description. The most striking phenotype was a severe delay in expressive speech, in contrast to the normal articulation and fluent expressive language observed in persons with WBS. Our results suggest that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities.

Involvement of ApoE E4 and H63D in sporadic Alzheimer's disease in a folate-supplemented Ontario population.

Dysregulation of iron homeostasis is implicated in Alzheimer's disease (AD). In this pilot study, common variants of the apolipoprotein E (APOE) and HFE genes resulting in the iron overload disorder of hereditary hemochromatosis (C282Y, H63D and S65C) were evaluated as factors in sporadic AD in an Ontario sample in which folic acid fortification has been mandatory since 1998. Laboratory studies also were done to search for genetic effects on blood markers of iron status, red cell folates and serum B12. Participants included 58 healthy volunteers (25 males, 33 females) and 54 patients with probable AD (20 males, 34 females). Statistical analyses were interpreted at the 95% confidence level. Contingency table and odds ratio analyses supported the hypothesis that in females of the given age range, E4 significantly predisposed to AD in the presence but not absence of H63D. In males, E4 significantly predisposed to AD in the absence of H63D, and H63D in the absence of E4 appeared protective against AD. Among E4+ AD patients, H63D was associated with significant lowering of red cell folate concentration, possibly as the result of excessive oxidative stress. However, folate levels in the lowest population quartile did not affect the risk of AD. A model is presented to explain the experimental findings.

Phenotype-genotype characterization of alpha-thalassemia mental retardation syndrome due to isolated monosomy of 16p13.3.

An 8-year-old Caucasian girl presented with mild dysmorphic features and intellectual disability (ID) affecting multiple spheres. Dysmorphisms included a high forehead with up-slanting palpebral fissures, prominent nasal root and bridge, flattened maxilla, high-arched palate, and anterior frenulum. Structural brain anomalies included reduced periventricular white matter volume and thin corpus callosum. The presence of HbH bodies and her clinical presentation raised suspicion for autosomal alpha-thalassemia mental retardation syndrome (ATR-16). Whole-genome array analysis at 1 Mb resolution was performed, which revealed a sub-microscopic loss of 16p involving clones RP11-344L6 at 0.1 Mb, RP1-121I4 at 0.2 Mb and RP11-334D3 at 1 Mb. FISH confirmed deletion (del) of the terminal clone (RP1-121I4) on 16pter, which was de novo in origin. The more proximal clone RP11-334D3 (at 1 Mb) showed diminished FISH signal intensity on one of the homologues, suggesting that one breakpoint occurred within this clone. Quantitative PCR (qPCR) confirmed a de novo deletion encompassing SOX8 (at 0.97 Mb). ATR-16 is characterized by ID with mild, nonspecific dysmorphic features, and is associated with terminal del16p (MIM No. 141750). Cases of isolated monosomy for 16p are rarely described; such descriptions help to delineate the syndrome in the absence of confounding karyotypic anomalies. We describe detailed molecular cytogenetic and clinical findings relating to a subject with ATR-16.

Report of an international survey of molecular genetic testing laboratories.

OBJECTIVE: To collect data on the practices of molecular genetic testing (MGT) laboratories for the development of national and international policies for quality assurance (QA). METHODS: A web-based survey of MGT laboratory directors (n = 827; response rate 63%) in 18 countries on 3 continents. QA and reporting indices were developed and calculated for each responding laboratory. RESULTS: Laboratory setting varied among and within countries, as did qualifications of the directors. Respondents in every country indicated that their laboratory receives specimens from outside their national borders (64%, n = 529). Pair-wise comparisons of the QA index revealed a significant association with the director having formal training in molecular genetics (p < 0.005), affiliation with a genetics unit (p = 0.003), accreditation of the laboratory (p < 0.005) and participation in proficiency testing (p < 0.005). Research labs had a lower mean report score compared to all other settings (p < 0.05) as did laboratories accessioning <150 samples per year. CONCLUSION: MGT is provided under widely varying conditions and regulatory frameworks. The data provided here may be a useful guide for policy action at both governmental and professional levels.

Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease.

Congenital heart disease (CHD), comprising structural or functional abnormalities present at birth, is the most common birth defect in humans. Reduced expression of connexin40 (Cx40) has been found in association with atrial fibrillation, and deletion of Cx40 in a mouse model causes various structural heart abnormalities in 18% of heterozygotes. We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (GJA5) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans. Dosage of Cx40 flanking genes (ACPL1 and Cx50 gene, GJA8) was determined by real-time PCR for all apparent positive cases. In total, 3 cases were found to carry deletions on chromosome 1q21.1 spanning ACPL1, Cx40, and Cx50 genes. Absence of heterozygosity was observed in all 3 index cases over a 1.5- to 3-Mb region. Samples from the parents of two cases were obtained, and microsatellites across 1q21.1 were genotyped. One of the apparently unaffected parents was found to carry this deletion. All 3 index cases presented with obstruction of the aortic arch as the common structural cardiac malformation, and had no consistent dysmorphic features. Genotyping of 520 unrelated normal controls for this deletion was negative. We hypothesize that this 1q21.1 multigene deletion is associated with a range of cardiac defects, with anomalies of the aortic arch being a particular feature.

A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots.

Individuals with a germ-line mutation in one of the DNA mismatch repair (MMR) genes are at significant risk for colorectal cancer and other tumors. Three families have previously been reported with individuals homozygous for mutations in the MMR gene MLH1 that are predicted to compromise MMR. These individuals develop hematological malignancies and/or neurofibromatosis type 1 at an early age. Here, in an individual, we demonstrate that a homozygous novel mutation in the MMR gene MSH2 is associated with leukemia and multiple café-au-lait spots, a feature of neurofibromatosis type 1. Because the hematological malignancies observed in the individuals homozygous for the loss of MMR are reflective of the lymphomas seen in mice lacking MMR, the mice may provide a useful model for human neoplasia.

Heteroduplex-based genotyping with microchip electrophoresis and dHPLC.

This work compares the methods of mutation detection via denaturing high-performance liquid chromatography (dHPLC) and a microchip-based heteroduplex analysis (HA) method. The mutations analyzed were 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 with, as additional examples, 188del11 and 5396 + 1G --> A in BRCA1. Our HA method is based upon the use of a replaceable, highly denaturing sieving matrix that has dynamic coating capabilities, rendering our method relatively insensitive to contamination. We have found significant advantages in the microchip analysis in terms of reagent consumption, ease of use, versatility, simplicity of the protocol, the lack of constraints upon sample preparation or content, and the lack of parameters that need be adjusted. Although HA methods have a lower sensitivity than that of dHPLC, the electropherograms of the present HA method appear to provide more information and may allow mutations within the same amplicon to be distinguished. Although the dHPLC method has a remarkably high sensitivity, with this sensitivity there come constraints that may prevent it, in its present form, from being used in some applications, particularly those involving higher levels of integration. The advantages of the present HA method, along with recent developments in microchip-based single-nucleotide polymorphism (SNP) detection and high-throughput arrays, suggest that microchip-based systems could provide compact and integrated platforms capable of large-scale genotyping or mutational screening.

Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke.

Risk factors for dementia development are not well-defined. We evaluated several factors alone and in combination in a unique cohort of Caucasian volunteers over an approximately 6-year observation window using a nested case/control design. Factors included: apolipoprotein E (ApoE) gene variants (the E4 allele is the strongest confirmed genetic predisposing factor for Alzheimer's disease), the hemochromatosis-HFE gene mutations (H63D and C282Y), diabetes, and stroke. At study entry, subjects were ≥65 years of age (M ± SD = 73.0 ± 4.9), had an MMSE score ≥24, and no evidence of cerebrovascular disease or current depression. Genotyping was completed on 163 available DNA samples from three different groups at the study end: those who still had normal cognitive function; those who had developed dementia; and those with Mild Cognitive Impairment (MCI). Analyses were interpreted at the 95% confidence level without Bonferroni corrections. In the subgroup with dementia, all cases of diabetes were type 2 and present at study entry, whereas all strokes occurred during the study. The results highlight apparently synergistic interactions between genetic and medical risk factors for dementia development, gender differences in risk factors, and involvement of HFE mutations. Having E4 (i.e., either of E3/4 or E4/4), C282Y, H63D, diabetes, or stroke alone did not attain significance. Significant predisposing factors with post-hoc power ≥80% were: E4 homozygosity (E4/4)males+females, odds ratio (OR) = 56.0); E4+diabetes (males+females, OR = 13.7; E4+H63D+diabetes (females, OR = 52.0); E4+stroke (males, OR = 46.5). The importance of preventing diabetes and stroke to ward off dementia and the possible role of iron dysmetabolism in dementia are discussed.

Discrepant HIV results resolved by human DNA testing.

A high-risk patient was informed of a positive HIV antibody/antigen test. However, follow-up samples taken 2-3 months later for HIV RNA and anti-HIV antibodies were negative. Human DNA testing confirmed that all samples were from this patient, excluding a sample mix-up. Laboratory investigations revealed a likely splash-over contamination event.