Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
We ...analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling.
Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones.
Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. ...Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.
The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects.
EHR data were obtained from a health care system of more ...than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis.
The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses.
Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.
This thesis presents a real time software program written in MATLAB using off-the-self MEMS sensors from Shimmer-Research®. Parallel to the software development, a proof of concept was conducted ...using the produced program to quantify stride length, stride length variance and stride time for patients diagnosed with Parkinson's disease. Results from testing showed that the system measured the mean stride length error to 2.4% of stride length and a standard deviation of 13.7% of stride length. Results from testing further showed a stride time error of 2.70% of individual stride times with a standard deviation of 1.89%. The system shows promise as a pedagogical, gait analysis training tool for physiotherapists as well as in academic teaching. The system is flexible and data processing functions can be readily re-programmed with other or additional processing features while maintaining user feedback, storage and plotting functionalities implemented in the current version of the program.
Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal disease worldwide. Adhesion pili (or fimbriae), such as the CFA/I (colonization factor antigen I) organelles that enable ETEC to ...attach efficiently to the host intestinal tract epithelium, are critical virulence factors for initiation of infection. We characterized the intrinsic biomechanical properties and kinetics of individual CFA/I pili at the single-organelle level, demonstrating that weak external forces (7.5 pN) are sufficient to unwind the intact helical filament of this prototypical ETEC pilus and that it quickly regains its original structure when the force is removed. While the general relationship between exertion of force and an increase in the filament length for CFA/I pili associated with diarrheal disease is analogous to that of P pili and type 1 pili, associated with urinary tract and other infections, the biomechanical properties of these different pili differ in key quantitative details. Unique features of CFA/I pili, including the significantly lower force required for unwinding, the higher extension speed at which the pili enter a dynamic range of unwinding, and the appearance of sudden force drops during unwinding, can be attributed to morphological features of CFA/I pili including weak layer-to-layer interactions between subunits on adjacent turns of the helix and the approximately horizontal orientation of pilin subunits with respect to the filament axis. Our results indicate that ETEC CFA/I pili are flexible organelles optimized to withstand harsh motion without breaking, resulting in continued attachment to the intestinal epithelium by the pathogenic bacteria that express these pili.
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► CFA/I pili are flexible organelles optimized to withstand harsh motion without breaking. ► The force needed for pilus unwinding is a function of subunit–subunit interactions and the pitch of the subunits. ► ETEC- (enterotoxigenic E. coli) and UPEC (uropathogenic E. coli)-expressed helix-like pili show similar force–extension responses. ► CFA/I pili are easy to unwind but hard to linearize.
This study investigated the association between spinal alignment, mo-bility of the hips and the thoracic spine and low back pain in adolescent cross-country skiers. Cohort of 51 elite cross-country ...skiers from a cross-country skiing high school in Sweden participated in the study. Sagittal spinal alignment, active range of motion in flexion, extension and rotation of the thoracic spine as well as passive and active exten-sion of the hips were measured. The participants also completed a questionnaire regarding training, competition, skiing technique and oc-currence of low back pain. A simple linear regression was calculated to predict pain score based on thoraco-lumbar relation, with a significant (P<0.05) regression equation of y=-0.069x+2.280 (standard error of esti-mate, 0.034). Participants with greater lordosis than kyphosis were more likely to suffer from low back pain than subjects without this off-set. Thoracic mobility and passive or active hip extension showed no correlation with low back pain. Sagittal spinal alignment seems to be related with low back pain among young elite cross-country skiers. This study shows that range of motion of the thoracic spine and hips do not have an effect on the prevalence of low back pain in this population.
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