Citations

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Abstract Background and aims Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE. Methods A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. Results The TRI-SCORE was low (≤3) in 32%, intermediate (4–5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively). Conclusions Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.

In this article, we present a flexible model for microbiome count data. We consider a quasi‐likelihood framework, in which we do not make any assumptions on the distribution of the microbiome count except that its variance is an unknown but smooth function of the mean. By comparing our model to the negative binomial generalized linear model (GLM) and Poisson GLM in simulation studies, we show that our flexible quasi‐likelihood method yields valid inferential results. Using a real microbiome study, we demonstrate the utility of our method by examining the relationship between adenomas and microbiota. We also provide an R package “fql” for the application of our method.

Abstract In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline. We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites. We identified metabolites associated with higher or lower risk of HF incidence, the associations that were not confounded by the other metabolites, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. We revealed the underlying relationships of the findings. For example, asparagine directly influenced glycine, and both were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids which are not synthesized in the human body and come directly from the diet. Metabolites may play a critical role in linking genetic background and lifestyle factors to HF progression. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates a mechanistic understanding of HF progression.

Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

OBJECTIVE Compared with laminectomy with posterior cervical fusion (PCF), cervical laminoplasty (CL) may result in different outcomes for those operated on for cervical spondylotic myelopathy (CSM). The aim of this study was to compare 24-month patient-reported outcomes (PROs) for laminoplasty versus PCF by using the Quality Outcomes Database (QOD) CSM data set. METHODS This was a retrospective study using an augmented data set from the prospectively collected QOD Registry Cervical Module. Patients undergoing laminoplasty or PCF for CSM were included. Using the nearest-neighbor method, the authors performed 1:1 propensity matching based on age, operated levels, and baseline modified Japanese Orthopaedic Association (mJOA) and visual analog scale (VAS) neck pain scores. The 24-month PROs, i.e., mJOA, Neck Disability Index (NDI), VAS neck pain, VAS arm pain, EQ-5D, EQ-VAS, and North American Spine Society (NASS) satisfaction scores, were compared. Only cases in the subaxial cervical region were included; those that crossed the cervicothoracic junction were excluded. RESULTS From the 1141 patients included in the QOD CSM data set who underwent anterior or posterior surgery for cervical myelopathy, 946 (82.9%) had 24 months of follow-up. Of these, 43 patients who underwent laminoplasty and 191 who underwent PCF met the inclusion criteria. After matching, the groups were similar for baseline characteristics, including operative levels (CL group: 4.0 ± 0.9 vs PCF group: 4.2 ± 1.1, p = 0.337) and baseline PROs (p > 0.05), except for a higher percentage involved in activities outside the home in the CL group (95.3% vs 81.4%, p = 0.044). The 24-month follow-up for the matched cohorts was similar (CL group: 88.4% vs PCF group: 83.7%, p = 0.534). Patients undergoing laminoplasty had significantly lower estimated blood loss (99.3 ± 91.7 mL vs 186.7 ± 142.7 mL, p = 0.003), decreased length of stay (3.0 ± 1.6 days vs 4.5 ± 3.3 days, p = 0.012), and a higher rate of routine discharge (88.4% vs 62.8%, p = 0.006). The CL cohort also demonstrated a higher rate of return to activities (47.2% vs 21.2%, p = 0.023) after 3 months. Laminoplasty was associated with a larger improvement in 24-month NDI score (−19.6 ± 18.9 vs −9.1 ± 21.9, p = 0.031). Otherwise, there were no 3- or 24-month differences in mJOA, mean NDI, VAS neck pain, VAS arm pain, EQ-5D, EQ-VAS, and distribution of NASS satisfaction scores (p > 0.05) between the cohorts. CONCLUSIONS Compared with PCF, laminoplasty was associated with decreased blood loss, decreased length of hospitalization, and higher rates of home discharge. At 3 months, laminoplasty was associated with a higher rate of return to baseline activities. At 24 months, laminoplasty was associated with greater improvements in neck disability. Otherwise, laminoplasty and PCF shared similar outcomes for functional status, pain, quality of life, and satisfaction. Laminoplasty and PCF achieved similar neck pain scores, suggesting that moderate preoperative neck pain may not necessarily be a contraindication for laminoplasty.