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Opioid use disorders (OUDs) pose a substantial global health burden, with methadone maintenance treatment (MMT) widely adopted as an intervention; however, MMT is associated with immunosuppression, metabolic disturbances, and dysbiosis of the gut microbiota. Despite the potential of acupuncture in reducing methadone dosages and opioid addiction, the underlying biological mechanisms remain unclear. Therefore, we aimed to integrate clinical trial data with multi-omics analysis, including single-cell sequencing, transcriptomics, metabolomics, and metagenomics, to evaluate the effects of acupuncture in patients undergoing MMT. We collected peripheral blood mononuclear cells, plasma, and fecal samples from 48 MMT participants in a randomized, placebo-controlled trial. Participants were divided into acupuncture ( n = 25) and sham-acupuncture ( n = 23) groups. After 8 weeks of intervention, 84% of patients in the acupuncture group achieved ≥20% reduction in methadone dosage, compared to 39% in the sham-acupuncture group ( P < 0.01). Our findings revealed that acupuncture may activate the defense response to viruses, with altered immune cell functions in classical monocytes correlating with clinical responses to reduced methadone doses. Acupuncture might ameliorate intestinal microbial disruptions caused by OUD by up-regulating Bilophila and modulating bile acid metabolism. Furthermore, acupuncture up-regulated galectin-9 (LGALS9)-mediated intercellular communication between classical monocytes and other immune subsets. To further validate the mechanistic link between bile acid metabolism and immune regulation, we conducted in vitro experiments using THP-1 monocytes treated with cholic acid. The results showed that bile acid exposure suppressed galectin-9 and IFN-γ expression, while low-dose bile acid (simulating acupuncture effects) partially reversed this effect. These findings support a bile acid–galectin–interferon axis that may be modulated by acupuncture in OUD. Collectively, our results provide clinical and mechanistic evidence supporting acupuncture as a potential adjunct therapy to mitigate the adverse effects of long-term opioid use.

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.

AbstractProhormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.