Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected "target" chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.

Three hundred forty-two subjects underwent 428 research lumbar punctures for studies of cerebrospinal fluid (CSF) biomarkers. Subjects were 67 Alzheimer disease or mild cognitive impairment (AD/MCI) patients and 275 cognitively normal adults aged 21 to 88. Lumbar puncture was performed in the lateral decubitus or sitting position using the Sprotte 24 g atraumatic spinal needle. Up to 34 ml of cerebrospinal fluid were collected. Anxiety and pain experienced during lumbar puncture were rated on a visual analog scale. The frequency of any adverse event (11.7%), clinically significant adverse events (3.97%), and typical post-lumbar puncture headache (PLPHA) (0.93%) was low. Risk of post-lumbar puncture headache was unrelated to age, gender, position during lumbar puncture, ml of cerebrospinal fluid collected, or minutes of recumbent rest following lumbar puncture. The frequency of post-lumbar puncture headache was lower in AD/MCI (P = 0.03) than any other subject group. Anxiety and pain ratings were low. Younger subjects reported more anxiety than old (P = 0.001) and AD/MCI subjects (P = 0.008) and more pain than older normal subjects (P = 0.013). Pain ratings for women were higher than those for men (P = 0.006). Using the Sprotte 24 g spinal needle, research lumbar puncture can be performed with a very low rate of clinically significant adverse events and with good acceptability in cognitively impaired persons and cognitively normal adults of all ages.

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Lewy-related pathology (LRP) is a common pathologic finding at autopsy in dementia patients. Recently criteria for categorizing types of LRP in dementia patients were published, though these criteria have yet to be systematically applied to large dementia samples. We examined a large (n = 208) referral-based autopsy sample for LRP, and applied the published criteria for LRP categorization to these cases. We found almost half (49%) of LRP positive cases from this sample were not classifiable. However, modifying the published criteria by reducing the number of regions requiring examination, allowing more variability in LRP severity scores within specific brain regions, and adding an amygdala predominant category permitted classification of 97% of LRP positive cases from the referral-based sample. Application of the modified criteria to an unrelated community-based autopsy sample (n = 226) allowed classification of 96% of LRP positive cases. Modest modifications in the published criteria permit a significantly greater number of dementia cases with LRP to be classified. In addition, this modification allows for more limited sampling of brain regions for classification of LRP. We propose that these modified criteria for the categorization of LRP be utilized in patients with a history of dementia.

BACKGROUND CONTEXT There have been no full-scale trials of the optimal number of visits for the care of any condition with spinal manipulation. PURPOSE To identify the dose-response relationship between visits to a chiropractor for spinal manipulation and chronic low back pain (cLBP) outcomes; to determine the efficacy of manipulation by comparison to a light-massage control. STUDY DESIGN/SETTING Practice-based randomized controlled trial. PATIENT SAMPLE Four hundred participants with cLBP. OUTCOME MEASURES The primary cLBP outcomes were the100-point Modified Von Korff pain intensity and functional disability scales evaluated at the 12 and 24-week primary endpoints. Secondary outcomes included days with pain and functional disability, pain unpleasantness, global perceived improvement, medication use, and general health status. METHODS One hundred participants with cLBP were randomized to each of four dose levels of care: 0, 6, 12, or 18 sessions of spinal manipulation from a chiropractor. Participants were treated three times per week for six weeks. At sessions when manipulation was not assigned, they received a focused light massage control. Covariate-adjusted linear dose effects and comparisons to the no-manipulation control group were evaluated at 6, 12, 18, 24, 39, and 52 weeks. RESULTS For the primary outcomes, mean pain and disability improvement in the manipulation groups was 20 points by 12 weeks and sustainable to 52 weeks. Linear dose-response effects were small, reaching about two points per six manipulation sessions at 12 and 52 weeks for both variables (P < .025). At 12 weeks, the greatest differences from the no-manipulation control were found for 12 sessions (8.6 pain and 7.6 disability points, P < .025); at 24 weeks, differences were negligible. At 52 weeks, the greatest group differences were seen for 18 visits (5.9 pain and 8.8 disability points, P < .025). CONCLUSIONS The number of spinal manipulation visits had modest effects on cLBP outcomes above those of 18 hands-on visits to a chiropractor. Overall, 12 visits yielded the most favorable results, but was not well distinguished from other dose levels.