The gut microbiome has important effects on human health, yet its importance in human ageing remains unclear. In the present study, we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age. We leverage three independent cohorts comprising over 9,000 individuals and find that compositional uniqueness is strongly associated with microbially produced amino acid derivatives circulating in the bloodstream. In older age (over ~80 years), healthy individuals show continued microbial drift towards a unique compositional state, whereas this drift is absent in less healthy individuals. The identified microbiome pattern of healthy ageing is characterized by a depletion of core genera found across most humans, primarily Bacteroides. Retaining a high Bacteroides dominance into older age, or having a low gut microbiome uniqueness measure, predicts decreased survival in a 4-year follow-up. Our analysis identifies increasing compositional uniqueness of the gut microbiome as a component of healthy ageing, which is characterized by distinct microbial metabolic outputs in the blood.

Background Currently available biomarkers of Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD. Objective Investigate miRNAs in CSF obtained from living donors as biomarkers for AD. Methods We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated. Results We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80–0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84. Conclusions CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification.

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the gene, a -794CATT microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.

We previously discovered microRNAs (miRNAs) in cerebrospinal fluid (CSF) that differentiate Alzheimer’s disease (AD) patients from Controls. Here we examined the performance of 37 candidate AD miRNA biomarkers in a new and independent cohort of CSF from 47 AD patients and 71 Controls on custom TaqMan® arrays. We employed a consensus ranking approach to provide an overall priority score for each miRNA, then used multimarker models to assess the relative contributions of the top-ranking miRNAs to differentiate AD from Controls. We assessed classification performance of the top-ranking miRNAs when combined with apolipoprotein E4 (APOE4) genotype status or CSF amyloid-β42 (Aβ42):total tau (T-tau) measures. We also assessed whether miRNAs that ranked higher as AD markers correlate with Mini-Mental State Examination (MMSE) scores. We show that of 37 miRNAs brought forth from the discovery study, 26 miRNAs remained viable as candidate biomarkers for AD in the validation study. We found that combinations of 6–7 miRNAs work better to identify AD than subsets of fewer miRNAs. Of 26 miRNAs that contribute most to the multimarker models, 14 have higher potential than the others to predict AD. Addition of these 14 miRNAs to APOE4 status or CSF Aβ42:T-tau measures significantly improved classification performance for AD. We further show that individual miRNAs that ranked higher as AD markers correlate more strongly with changes in MMSE scores. Our studies validate that a set of CSF miRNAs serve as biomarkers for AD, and support their advancement toward development as biomarkers in the clinical setting.

Patients and clinicians want to know who is protected from SARS-CoV-2 infection. This update is part of a living systematic review to understand the potential value of antibody testing as a correlate of protection against infection. Because the previous review found that seroconversion was a near-universal consequence of recent infection in immunocompetent patients, this review examines the risk for reinfection in adults after SARS-CoV-2 infection, whether diagnosed by polymerase chain reaction test, antibody test, or a combination of both.

Background: Measurements of maternal fat mass (FM) are important for studies of maternal and fetal health. Common methods of estimating FM have not been previously compared in pregnancy with measurements using more complete body composition models. Objectives: The goal of this pilot study was to compare multiple methods that estimate FM, including 2-, 3-and 4-compartment models in pregnant women at term, and to determine how these measures compare with FM by dual-energy X-ray absorptiometry (DXA) 2 wk postpartum. Design: Forty-one healthy pregnant women with prepregnancy body mass index (in kg/m 2 ) 19 to 46 underwent skinfold thickness (SFT), bioelectrical impedance analysis (BIA), body density (D b ) via air displacement plethysmography (ADP), and deuterium dilution of total body water (TBW) with and without adjustments for gestational age using van Raaij (VRJ) equations at 37-38 wk of gestation and 2 wk postpartum to derive 8 estimates of maternal FM. Deming regression analysis and Bland-Altman plots were used to compare methods of FM assessment. Results: Systematic differences in FM estimates were found. Methods for FM estimates from lowest to highest were 4-compartment, DXA, TBW (VRJ) , 3-compartment, D b(VRJ) , BIA, air displacement plethysmography body density, and SFT ranging from a mean 6 SD of 29.5 6 13.2 kg via 4-compartment to 39.1 6 11.7 kg via SFT. Compared with postpartum DXA values, Deming regressions revealed no substantial departures from trend lines in maternal FM in late pregnancy for any of the methods. The 4-compartment method showed substantial negative (underestimating) constant bias, and the air displacement plethysmography body density and SFT methods showed positive (overestimating) constant bias. ADP via D b(VRJ) and 3-compartment methods had the highest precision; BIA had the lowest. Conclusions: ADP that uses gestational age-specific equations may provide a reasonable and practical measurement of maternal FM across a spectrum of body weights in late pregnancy. SFT would be acceptable for use in larger studies. This trial was registered at clinicaltrials.gov as NCT02586714.

Background:Osteochondral allograft (OCA) transplantation has become a standard therapy for cartilage restoration in young patients.Purpose:To determine the efficacy of fresh OCA transplantation for focal cartilage lesions in patients aged ≥40 years compared with a group of patients aged ≤39 years.Study Design:Cohort study; Level of evidence, 3.Methods:A database was used to identify patients who underwent fresh OCA transplantation in the knee in a single-surgeon practice over a 10-year period and who completed baseline patient-reported outcome (PRO) questionnaires, including the International Knee Documentation Committee (IKDC); Knee injury and Osteoarthritis Outcome Score (KOOS) subscales of Pain, Symptoms, Activities of Daily Living, Quality of Life (QOL), and Sports & Recreation; and Veterans RAND 12-Item Health Survey (VR-12). Patients who completed the same PRO measures at a minimum 12-month follow-up were categorized into 2 groups based on age at surgery and were observed longitudinally. Mixed-model regression was used to predict longitudinal growth curves for each PRO score while controlling for confounding patient and surgical variables.Results:The study group consisted of 38 patients with a mean age of 52.32 years (range, 40-69 years) and mean final follow-up of 44.47 ± 24.32 months. The control group consisted of 42 patients with a mean age of 27.19 years (range, 15-39 years) and mean final follow-up of 33.75 ± 19.53 months. A statistically significant improvement from baseline to final follow-up was seen for the IKDC score and all 5 KOOS subscores in both the study and the control groups (P < .01 in 10 of 12 comparisons and P < .05 for the other 2 comparisons). Maximum improvements were seen in the KOOS QOL and Sports & Recreation subscores for both groups. There was no statistically significant difference between groups in the change from baseline to final follow-up or in differences at any time point in model-based longitudinal projections for any PRO score through 5 years.Conclusion:There was a significant improvement of outcomes for both groups, with no statistically significant difference between groups over longitudinal follow-up. The efficacy of fresh OCA transplantation in adults aged ≥40 years with a focal chondral lesion and without osteoarthritis is similar to that of younger adults, and benefits are greatest for the KOOS QOL and Sports & Recreation subscales, which reflect functional outcomes.

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