Citations

AbstractBackgroundWhile limited data suggest that the fecal microbiota in healthy people is stable over time, the intraindividual variability of the fecal microbiota in constipated patients is unknown.MethodsThis study evaluated the intraindividual reproducibility of fecal microbiota analyzed with 16S rRNA gene sequencing in two stool samples collected without and after a laxative, respectively, in 25 healthy people and 25 constipated women. Participants completed a food record for 3 d before the stool collection. Colonic transit was measured with scintigraphy.Key ResultsThe constipated patients were older (48±15 vs 39±10 y, P=.02) than healthy participants but had a similar BMI. The total daily caloric intake was less (P=.005) in constipated (1265±350 kcal) than healthy participants (1597±402 kcal). Fourteen patients but only two controls (P<.005), had delayed colonic transit. For most measures of alpha (eg, Observed OTU number, Shannon index) and beta diversity (eg, Bray‐Curtis dissimilarity, UniFrac, phyla level abundance), the ICCs between two stool samples were high, indicating moderate or strong agreement, and similar in healthy people and constipated patients. The ICC for the weighted UniFrac distance, which is weighted by abundance, was lower than its unweighted counterpart, indicating that the unweighted measure is more robust and reproducible.Conclusions and InferencesThe intraindividual reproducibility of fecal microbiota in constipated patients is high and comparable to healthy participants. For most purposes, evaluating the fecal microbiota in a single stool sample should generally suffice in adequately powered studies of healthy and constipated patients.

Background Atrial fibrillation ( AF ) has been associated with faster cognitive decline and increased dementia risk. Factors associated with dementia in patients with AF have been seldom studied. Methods and Results We studied 6432 individuals from the ARIC ‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). In 2011 to 2013, participants underwent a physical exam, echocardiography, detailed cognitive assessments, and a subset, brain magnetic resonance imaging. Dementia and mild cognitive impairment ( MCI ), as well as etiology of MCI /dementia, Alzheimer's disease–related or vascular, were adjudicated by an expert panel. AF was defined by study ECGs and past hospitalizations. We used logistic regression to estimate odds ratios and 95% CI of MCI /dementia by AF status and to assess cross‐sectional correlates of MCI /dementia in patients with AF . Among 6432 participants, 611 (9.5%) had prevalent AF . AF was associated with increased odds of dementia and MCI (odds ratio, 95% CI , 2.25, 1.64–3.10, and 1.28, 1.04–1.56, respectively). Prevalence of Alzheimer's disease–related MCI /dementia and vascular MCI /dementia were higher in participants with AF than without AF (odds ratio, 95% CI , 1.29, 1.04–1.61, and 1.50, 0.99–2.25, respectively). In multivariable analyses, older age, lower body mass index, diabetes mellitus, stroke, and APOE genotype were associated with dementia prevalence in participants with AF . In models evaluating MCI /dementia subtypes, diabetes mellitus was associated with Alzheimer's disease–related MCI /dementia, whereas male sex and stroke were risk factors for vascular MCI /dementia. Conclusions In a large, community‐based study, AF was associated with higher prevalence of MCI and dementia. Controlling cardiometabolic risk factors is a potential target for prevention of adverse cognitive outcomes in AF patients.

AimsDespite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens.Methods and resultsThe International Society of Urological Pathology (ISUP) established a reference image database through the input of experts in the field. Three panels were formed, one each for prostate, urinary bladder and renal pathology, consisting of 24 international experts. Each of the panel members uploaded microphotographs of cases into a non‐public database. The remaining 23 experts were asked to vote from a multiple‐choice menu. Prior to and while voting, panel members were unable to access the results of voting by the other experts. When a consensus level of at least two‐thirds or 16 votes was reached, cases were automatically transferred to the main database. Consensus was reached in a total of 287 cases across five projects on the grading of prostate, bladder and renal cancer and the classification of renal tumours and flat lesions of the bladder. The full database is available to all ISUP members at www.isupweb.org. Non‐members may access a selected number of cases.ConclusionsIt is anticipated that the database will assist pathologists in calibrating their grading, and will also promote consistency in the diagnosis of difficult cases.

Significance Deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and Aβ accumulation in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA) are pathological hallmarks of Alzheimer’s disease (AD). The clusterin ( CLU ) gene, which confers AD risk, is associated with amyloid deposition. Here we show that loss of CLU promotes cerebrovascular CAA, yet significantly reduces the amount of parenchymal plaques by altering perivascular drainage of Aβ in the APP/PS1 mouse model of AD. The absence of CLU in these mice is associated with a lower number of hemorrhages and a decrease in inflammation. These results suggest that CLU functions as a major Aβ chaperone to maintain Aβ solubility along interstitial fluid drainage pathways and prevent CAA formation.

BackgroundPresence of Q waves on the presenting electrocardiogram (ECG) in patients with ST‐segment elevation myocardial infarction (STEMI) has been associated with worse prognosis; however, whether the prognostic value of Q waves is influenced by baseline characteristics and/or rapidity of revascularization based on the guideline‐based metric of door‐to‐balloon time remains unknown.HypothesisWe hypothesized that Q waves in the presenting ECG will be predictive of long term mortality regardless of time to reperfusion.MethodsThe Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS‐AMI) trial enrolled 3602 patients with STEMI undergoing primary percutaneous coronary intervention. We stratified patients without prior history of myocardial infarction or coronary revascularization according to presence or absence of pathological Q waves on their presenting ECG. Associations between Q waves, death, and cardiovascular outcomes within 3 years were assessed using Cox proportional hazards regression.ResultsAmong 2723 patients with evaluable ECGs, 1084 (39.8%) had Q waves on their presenting ECG. Male sex and time from symptom onset to balloon inflation were independent predictors of presence of Q waves. Patients with Q waves had higher adjusted risks of all‐cause death (adjusted hazard ratio: 1.45, 95% confidence interval: 1.02‐2.05, P = 0.04) and cardiac death (adjusted hazard ratio: 1.72, 95% confidence interval: 1.08‐2.72, P = 0.02). The association between Q waves and cardiac death was consistent regardless of sex, diabetes status, target vessel, or door‐to‐balloon time (Pinteraction > 0.4 for all).ConclusionsPresence of Q waves on the presenting ECG in patients undergoing primary percutaneous coronary intervention due to STEMI is an independent predictor of mortality and adds prognostic value, regardless of sex or rapidity of revascularization.

Recent research shows that butyrylcholinesterase (BChE) is not simply a liver enzyme that detoxifies bioactive esters in food and medications. In fact, in pursuing other goals, we recently found that it has an equally important role in regulating the peptide hormone ghrelin and its impact on hunger, obesity, and emotions. Here, we present and examine means of manipulating brain BChE levels by viral gene transfer, either regionally or globally, to modulate ghrelin signaling for long-term therapeutic purposes and to set the stage for exploring the neurophysiological impact of such an intervention.

We report a 9-year-old Chinese girl with congenital thrombotic thrombocytopenic purpura found to be a compound heterozygote for 2 pathogenic variants in the ADAMTS13 gene, including a novel variation. The girl suffered from recurrent, life-threatening episodes of thrombocytopenia and hemolysis, and laboratory testing showed ADAMST13 enzyme activity of <5%. Sequencing of the ADAMTS13 gene revealed a previously reported missense variant, c.1787C>T (p.Ala596Val), and a novel duplication defined as c.1007_1025dup19 (p.Asp343Leufs*53); the duplication is predicted to result in a premature stop codon and protein truncation. We propose that this novel variant is partly responsible for the patient’s early-onset and severe phenotype.