medRxiv : the preprint server for health sciences最新文献

We aimed to identify plasma cell-free transcripts (cfRNA) associated with Parkinson's disease (PD) that also have a high predictive value to differentiate PD from healthy controls. Leveraging two independent populations from two different movement disorder centers we identified 2,188 differentially expressed cfRNAs after meta-analysis. The identified transcripts were enriched in PD relevant pathways, such as PD (p=9.26×10^-4), ubiquitin-mediated proteolysis (p=7.41×10^-5) and endocytosis (p=4.21×10^-6). Utilizing in-house and publicly available brain, whole blood, and acellular plasma transcriptomic and proteomic PD datasets, we found significant overlap across dysregulated biological species in the different tissues and the different biological layers. We developed three predictive models containing increasing number of transcripts that can distinguish PD from healthy control with an area under the ROC Curve (AUC) ≥0.85. Finally, we showed that several of the predictive transcripts significantly correlate with symptom severity measured by UPDRS-III. Overall, we have demonstrated that cfRNA contains pathological signatures and has the potential to be utilized as biomarker to aid in PD diagnostics and monitoring.

SARS-CoV-2 vaccine-acquired immunity provides robust cross-variant recognition, while infection-acquired immunity can be heterogenous, with disease severity often modulating post-recovery responses. We assessed antibody waning dynamics between infection- and vaccination-acquired immunity across variants of concern (VOC). mRNA vaccination induced potent, cross-VOC Spike recognition and functional responses, but waned more rapidly for Omicron Spike. Hospitalized individuals developed more durable functional responses with lower peaks compared to mRNA vaccination, while outpatients exhibited slower decay than inactivated vaccine recipients. Humoral decay for the receptor binding domain tracked with neutralizing antibody titers, while S2-directed responses tracked with antibody-dependent myeloid cellular phagocytosis. Boosting the recovered patients with mRNA or inactivated vaccines expanded humoral breadth, durability, and restored functional responses, eliminating the severity- and platform-associated decay differences. Therefore, post-recovery hybrid immunization compensates for this distinction and broadens humoral breadth, highlighting the value of boosting immunity in previously infected individuals.

Objective: Multiple studies have attempted to generate visual field (VF) mean deviation (MD) estimates using cross-sectional optical coherence tomography (OCT) data. However, whether such models offer any value in detecting longitudinal VF progression is unclear. We address this by developing a machine learning (ML) model to convert OCT data to MD and assessing its ability to detect longitudinal worsening.

Design: Retrospective, longitudinal study.

Participants: A model dataset of 70,575 paired OCT/VFs to train an ML model converting OCT to VF-MD. A separate progression dataset of 4,044 eyes with ≥ 5 paired OCT/VFs to assess the ability of OCT-derived MD to detect worsening. Progression dataset eyes had two additional unpaired VFs (≥ 7 total) to establish a "ground truth" rate of progression defined by MD slope.

Methods: We trained an ML model using paired VF/OCT data to estimate MD measurements for each OCT scan (OCT-MD). We used this ML model to generate longitudinal OCT-MD estimates for progression dataset eyes. We calculated MD slopes after substituting/supplementing VF-MD with OCT-MD and measured the ability to detect progression. We labeled true progressors using a ground truth MD slope <0.5 dB/year calculated from ≥ 7 VF-MD measurements. We compared the area under the curve (AUC) of MD slopes calculated using both VF-MD (with <7 measurements) and OCT-MD. Because we found OCT-MD substitution had a statistically inferior AUC to VF-MD, we simulated the effect of reducing OCT-MD mean absolute error (MAE) on the ability to detect worsening.

Main outcome measures: AUC.

Results: OCT-MD estimates had an MAE of 1.62 dB. AUC of MD slopes with partial OCT-MD substitution was significantly worse than the VF-MD slope. Supplementing VF-MD with OCT-MD also did not improve AUC, regardless of MAE. OCT-MD estimates needed an MAE ≤ 1.00 dB before AUC was statistically similar to VF-MD alone.

Conclusion: ML models converting OCT data to VF-MD with error levels lower than published in prior work (MAE: 1.62 dB) were inferior to VF-MD data for detecting trend-based VF progression. Models converting OCT data to VF-MD must achieve better prediction errors (MAE ≤ 1 dB) to be clinically valuable at detecting VF worsening.

Background: Tuberculosis (TB) cases and deaths in the United States fluctuated substantially during the COVID-19 pandemic. We analyzed multiple data sources to understand the factors contributing to these changes and estimated future TB trends.

Methods: We identified four mechanisms potentially contributing to observed TB trends during 2020-2023: immigration, respiratory contact rates, rates of accurate diagnosis and treatment initiation, and mortality rates for persons with TB disease. We employed a Bayesian approach to synthesize evidence on how these mechanisms changed during the pandemic and how they might have combined to produce observed 2020-2023 TB data, using a transmission-dynamic model to link mechanisms to TB outcomes. We also simulated a no-pandemic counterfactual scenario that assumed mechanisms followed pre-pandemic trends. We estimated TB outcomes associated with the pandemic until 2035 to capture lagged effects. We evaluated additional scenarios to estimate the individual effect of each mechanism.

Results: Over the 2020-2035 study period, we estimate an additional 2,784 (95% uncertainty interval: 2,164-3,461) TB cases and 1,138 (1,076-1,201) TB deaths in the United States associated with changes occurring during the COVID-19 pandemic. The four mechanisms had offsetting effects - decreases in TB diagnosis rates and increases in TB mortality rates led to more TB deaths, while reductions in contact rates reduced TB deaths. Immigration changes initially reduced TB deaths, but increased deaths over time.

Discussion: While the direct impacts of the COVID-19 pandemic occurred between 2020-2023, these changes may continue to influence TB incidence and mortality in future years.

Background: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.

Methods: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.

Results: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.

Conclusions: This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring.

Trial registration: ClinicalTrials.gov NCT04607408.

Funding: National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).

Fibrotic-like abnormalities are present in 60% of a single-center, longitudinal, multi-ethnic cohort 3-years after severe COVID-19. They are independently associated with male sex, low BMI, shorter telomere length, increased severity of illness, and mechanical ventilation; Black race and asthma are protective. Participants with fibrotic-like abnormalities are more likely to have reduced diffusion capacity and 6-minute walk distance. Fibrotic-like abnormalities persist but modestly improve over time. Transbronchial biopsies show small airways histopathology, consistent with high prevalence of air trapping in expiration, and infrequent interstitial thickening. This study highlights the need for continued monitoring of patients with persistent fibrosis after severe COVID-19.

Background: Currently, no biomarkers are available to identify resistance to androgen-deprivation therapies (ADT) in men with hormone-naive prostate cancer. Since 5-hydroxymethylcytosines (5hmC) in gene body are associated with gene activation, in this study, we evaluated whether 5hmC signatures in cell-free DNA (cfDNA) predicts early resistance to ADT.

Results: We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at three time points including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). To quantify 5hmC abundance across the genome, we used selective chemical labeling sequencing and mapped sequence reads to individual genes. Differential methylation analysis in baseline samples identified significant 5hmC difference in 1,642 of 23,433 genes between patients with and without progression (false discovery rate, FDR<0.1). Patients with disease progression showed significant 5hmC enrichments in multiple hallmark gene sets with androgen responses as top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients featuring a significant 5hmC hypermethylation in the gene sets involving AR , FOXA1 and GRHL2 . To quantify overall activities of these gene sets, we developed a gene set activity scoring algorithm and observed significant association of high activity scores with poor progression-free survival (P<0.05). Longitudinal analysis showed that the high activity scores were significantly reduced after 3-months of initiating ADT (P<0.0001) but returned to higher levels when the disease was progressed (P<0.05).

Conclusions: This study demonstrates that 5hmC-based activity scores from gene sets involved in AR , FOXA1 and GRHL2 may be used as biomarkers to determine early treatment resistance, monitor disease progression, and potentially identify patients who would benefit from upfront treatment intensification.

Background: Paralytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management.

Methods: To investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (n_{cases/controls}=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (n_{cases/controls}=517/182,423) using GWAS data from the FinnGen project.

Results: Based on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally.

Conclusions: Our study's findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.

Background: Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved.

Methods: We prospectively enrolled 284 unrelated MVP probands, of whom 178 (63%) had bi-leaflet MVP and 106 had PostMVP (37%). Familial screening within PostMVP patients allowed the identification of 20 families with inherited forms of PostMVP for whom whole genome sequencing was carried out in probands. Functional in vivo and in vitro investigations were performed in zebrafishand in Hek293T cells.

Results: In the 20 families with inherited form of PostMVP, 38.8% of relatives had a MVP/prodromal form, mainly of the posterior leaflet, with transmission consistent with an autosomal dominant mode of inheritance. Compared with control relatives, PostMVP family patients have clear posterior leaflet dystrophy on echocardiography. Patients with PostMVP present a burden of rare genetic variants in ARHGAP24. ARHGAP24 encodes the filamin A binding RhoGTPase-activating protein FilGAP and its silencing in zebrafish leads to atrioventricular regurgitation. In vitro functional studies showed that variants of FilGAP, found in PostMVP families, are loss-of-function variants impairing cellular adhesion and mechano-transduction capacities.

Conclusions: PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP.

Clinical perspective: Isolated posterior mitral valve prolapse (PostMVP), often called fibro-elastic deficiency MVP, is at least in some patients, a specific inherited phenotypic traitPostMVP has both genetic and functional pathophysiological origins Genetic variants in the ARHGAP24 gene, which encodes for the FilGAP protein, cause progressive Post MVP in familial cases, and impair cell adhesion and mechano-transduction capacities.