Discovery and validation of dominantly inherited Alzheimer\u27s disease mutations in populations from Latin America

BACKGROUND: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. METHODS: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. RESULTS: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. CONCLUSIONS: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD

Relationship between distal radius fracture malunion and arm-related disability: A prospective population-based cohort study with 1-year follow-up

<p>Abstract</p> <p>Background</p> <p>Distal radius fracture is a common injury and may result in substantial dysfunction and pain. The purpose was to investigate the relationship between distal radius fracture malunion and arm-related disability.</p> <p>Methods</p> <p>The prospective population-based cohort study included 143 consecutive patients above 18 years with an acute distal radius fracture treated with closed reduction and either cast (55 patients) or external and/or percutaneous pin fixation (88 patients). The patients were evaluated with the disabilities of the arm, shoulder and hand (DASH) questionnaire at baseline (concerning disabilities before fracture) and one year after fracture. The 1-year follow-up included the SF-12 health status questionnaire and clinical and radiographic examinations. Patients were classified into three hypothesized severity categories based on fracture malunion; no malunion, malunion involving either dorsal tilt (>10 degrees) or ulnar variance (≥1 mm), and combined malunion involving both dorsal tilt and ulnar variance. Multivariate regression analyses were performed to determine the relationship between the 1-year DASH score and malunion and the relative risk (RR) of obtaining DASH score ≥15 and the number needed to harm (NNH) were calculated.</p> <p>Results</p> <p>The mean DASH score at one year after fracture was significantly higher by a minimum of 10 points with each malunion severity category. The RR for persistent disability was 2.5 if the fracture healed with malunion involving either dorsal tilt or ulnar variance and 3.7 if the fracture healed with combined malunion. The NNH was 2.5 (95% CI 1.8-5.4). Malunion had a statistically significant relationship with worse SF-12 score (physical health) and grip strength.</p> <p>Conclusion</p> <p>Malunion after distal radius fracture was associated with higher arm-related disability regardless of age.</p

Developing a Statewide Childhood Body Mass Index Surveillance Program

Background Several states have implemented childhood obesity surveillance programs supported by legislation. Representatives from Idaho wished to develop a model for childhood obesity surveillance without the support of state legislation, and subsequently report predictors of overweight and obesity in the state. Methods A coalition comprised of the Idaho State Department of Education and 4 universities identified a randomized cluster sample of schools. After obtaining school administrator consent, measurement teams traveled to each school to measure height and weight of students. Sex and race/ethnicity data were also collected. Results The collaboration between the universities resulted in a sample of 6735 students from 48 schools and 36 communities. Overall, 29.2% of the youth in the sample were classified as overweight or obese, ranging from 24.0% for grade 1 to 33.8% for grade 5. The prevalence of overweight and obesity across schools was highly variable (31.2 ± 7.58%). Hierarchical logistic regression indicated that sex, age, race/ethnicity, socioeconomic status, and region were all significant predictors of overweight and obesity, whereas school was not. Conclusions This coalition enabled the state of Idaho to successfully estimate the prevalence of overweight and obesity on a representative sample of children from all regions of the state, and subsequently identify populations at greatest risk

Attentional Focus and Feedback Frequency Among First Graders in Physical Education

Purpose: External attentional focused instructions and feedback have shown to enhance motor performance among adults, adolescents, and older children. This study examined type and frequency of instructions and feedback among younger children performing an overhand throw. Method: First graders (N = 65) were provided external or internal focused instructions at high- or low-frequency rates resulting in four experimental groups (External-High, External-Low, Internal-High, and Internal-Low). Results: Internal focused groups performed significantly better than external focused groups during retention–transfer, and children who received feedback that is more frequent performed better. External-Low performed better than External-High at the end of acquisition and retention–transfer, whereas Internal-High performed better than Internal-Low throughout acquisition. Conclusion: Data support previous research indicating children need more feedback when learning a motor skill but did not support prior studies regarding attentional focus. More work is needed to understand how and why young children respond differently to attentional focused instructions and feedback

Three Levels of Learning in Simulations: Participating, Debriefing, and Journal Writing

Simulations and games provide three levels of learning: through participating, debriefing and writing. While taking part in the simulation; the participant experiences different types off acts, emotions, relationships, strategies, and feelings. The participant learns to handle various social situations and experience the excitement of discovery. During the debriefing discussions, the student harnesses the vast information and makes sense out of these experiences by sharing his ideas and listening to other's impressions. The debriefer facilitates the discussion by using the four Es of debriefing: events, emotions, empathy, and explanations. The assumption of oral debriefing is that all participants learn the same things at the same time and in the same manner. Journal writing significantly extends the analytical learning process by requiring each participant to organize the material and debrief on an individual basis. The richness of the journal develops frm the writer weaving his own personal thread through his experiences, through other's encounters, and through theoretical concepts. The writing provides a record of each student's learning experience.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69040/2/10.1177_1046878192232005.pd