Nanotechnology for Pain Management.

Introduction: In the context of the current opioid crisis, non-pharmacologic approaches to pain management have been considered important alternatives to the use of opioids or analgesics. Advancements in nano and quantum technology have led to the development of several nanotransporters, including nanoparticles, micelles, quantum dots, liposomes, nanofibers, and nano-scaffolds. These modes of nanotransporters have led to the development of new drug formulations. In pain medicine, new liposome formulations led to the development of DepoFoam™ introduced by Pacira Pharmaceutical, Inc. (Parsippany, NJ, USA). This formulation is the base of DepoDur™, which comprises a combination of liposomes and extended-release morphine, and Exparel™, which comprises a combination of liposomes and extended-release bupivacaine. In 2021, Heron Therapeutics (San Diego, CA, USA) created Zynrelef™, a mixture of bupivacaine and meloxicam. Advancements in nanotechnology have led to the development of devices/patches containing millions of nanocapacitors. Data suggest that these nanotechnology-based devices/patches reduce acute and chronic pain. Methods: Google and PubMed searches were conducted to identify studies, case reports, and reviews of medical nanotechnology applications with a special focus on acute and chronic pain. This search was based on the use of keywords like nanotechnology, nano and quantum technology, nanoparticles, micelles, quantum dots, liposomes, nanofibers, nano-scaffolds, acute and chronic pain, and analgesics. This review focuses on the role of nanotechnology in acute and chronic pain. Results: (1) Nanotechnology-based transporters. DepoDur™, administered epidurally in 15, 20, or 25 mg single doses, has been demonstrated to produce significant analgesia lasting up to 48 h. Exparel™ is infiltrated at the surgical site at the recommended dose of 106 mg for bunionectomy, 266 mg for hemorrhoidectomy, 133 mg for shoulder surgery, and 266 mg for total knee arthroplasty (TKA). Exparel™ is also approved for peripheral nerve blocks, including interscalene, sciatic at the popliteal fossa, and adductor canal blocks. The injection of Exparel™ is usually preceded by an injection of plain bupivacaine to initiate analgesia before bupivacaine is released in enough quantity from the depofoarm to be pharmacodynamically effective. Finally, Zynrelef™ is applied at the surgical site during closure. It was initially approved for open inguinal hernia, abdominal surgery requiring a small-to-medium incision, foot surgery, and TKA. (2) Nanotechnology-based devices/patches. Two studies support the use of nanocapacitor-based devices/patches for the management of acute and chronic pain. A randomized study conducted on patients undergoing unilateral primary total knee (TKA) and total hip arthroplasty (THA) provided insight into the potential value of nanocapacitor-based technology for the control of postoperative acute pain. The results were based on 2 studies, one observational and one randomized. The observational study was conducted in 128 patients experiencing chronic pain for at least one year. This study suggested that compared to baseline, the application of a nanocapacitor-based Kailo™ pain relief patch on the pain site for 30 days led to a time-dependent decrease in pain and analgesic use and an increase in well-being. The randomized study compared the effects of standard of care treatment to those of the same standard of care approach plus the use of two nanocapacitor-based device/patches (NeuroCuple™ device) placed in the recovery room and kept in place for three days. The study demonstrated that the use of the two NeuroCuple™ devices was associated with a 41% reduction in pain at rest and a 52% decrease in the number of opioid refills requested by patients over the first 30 days after discharge from the hospital. Discussion: For the management of pain, the use of nano-based technology has led to the development of nano transporters, especially focus on the use of liposome and nanocapacitors. The use of liposome led to the development of DepoDur™, bupivacaine Exparel™ and a mixture of bupivacaine and meloxicam (Zynrelef™) and more recently lidocaine liposome formulation. In these cases, the technology is used to prolong the duration of action of drugs included in the preparation. Another indication of nanotechnology is the development of nanocapacitor device or patches. Although, data obtained with the use of nanocapacitors are still limited, evidence suggests that the use of nanocapacitors devices/patches may be interesting for the treatment of both acute and chronic pain, since the studies conducted with the NeuroCuple™ device and the based Kailo™ pain relief patch were not placebo-controlled, it is clear that additional placebo studies are required to confirm these preliminary results. Therefore, the development of a placebo devices/patches is necessary. Conclusions: Increasing evidence supports the concept that nanotechnology may represent a valuable tool as a drug transporter including liposomes and as a nanocapacitor-based device/patch to reduce or even eliminate the use of opioids in surgical patients. However, more studies are required to confirm this concept, especially with the use of nanotechnology incorporated in devices/patches.

Opioid use disorder in pediatric populations: considerations for perioperative pain management and precision opioid analgesia.

INTRODUCTION: Opioids are commonly used for perioperative analgesia, yet children still suffer high rates of severe post-surgical pain and opioid-related adverse effects. Persistent and severe acute surgical pain greatly increases the child's chances of chronic surgical pain, long-term opioid use, and opioid use disorder. AREAS COVERED: Enhanced recovery after surgery (ERAS) protocols are often inadequate in treating a child's severe surgical pain. Research suggests that 'older' and longer-acting opioids such as methadone are providing better methods to treat acute post-surgical pain. Studies indicate that lower repetitive methadone doses can decrease the incidence of chronic persistent surgical pain (CPSP). Ongoing research explores genetic components influencing severe surgical pain, inadequate opioid analgesia, and opioid use disorder. This new genetic research coupled with better utilization of opioids in the perioperative setting provides hope in personalizing surgical pain management, reducing pain, opioid use, adverse effects, and helping the fight against the opioid pandemic. EXPERT OPINION: The opioid and analgesic pharmacogenomics approach can proactively 'tailor' a perioperative analgesic plan to each patient based on underlying polygenic risks. This transition from population-based knowledge of pain medicine to individual patient knowledge can transform acute pain medicine and greatly reduce the opioid epidemic's socioeconomic, personal, and psychological strains globally.

Gaining Insight into Teenagers' Experiences of Pain after Laparoscopic Surgeries: A Prospective Study.

There is an anecdotal impression that teenage patients report exaggerated postoperative pain scores that do not correlate with their actual level of pain. Nurse and parental perception of teenagers' pain can be complemented by knowledge of patient pain behavior, catastrophizing thoughts about pain, anxiety, and mood level. Two hundred and two patients completed the study-56.4% were female, 89.6% White, 5.4% Black, and 5% were of other races. Patient ages ranged from 11 to 17 years (mean = 13.8; SD = 1.9). The patient, the parent, and the nurse completed multiple questionnaires on day one after laparoscopic surgery to assess patient pain. Teenagers and parents (r = 0.56) have a high level of agreement, and teenagers and nurses (r = 0.47) have a moderate level of agreement on pain scores (p < 0.05). The correlation between patient APBQ (adolescent pain behavior questionnaire) and teenager VAS (visual analog scale) and between nurse APBQ and teenager VAS, while statistically significant (p < 0.05), is weaker (r range = 0.14-0.17). There is a moderate correlation between teenagers' pain scores and their psychological assessments of anxiety, catastrophic thoughts, and mood (r range = 0.26-0.39; p < 0.05). A multi-modal evaluation of postoperative pain can be more informative than only assessing self-reported pain scores.

Utilizing Peripheral Nerve Blocks for Pain Management in Pediatric Patients during Embolization and Sclerotherapy for Vascular Malformations.

Vascular anomalies are a diverse group of abnormal blood vessel developments that can occur at birth or shortly afterward. Embolization and sclerotherapy have been utilized as a treatment option for these malformations but may cause moderate-to-severe pain. This study aims to evaluate the utilization of peripheral nerve blocks in opioid consumption, pain scores, and length of stay. A retrospective chart review was conducted at the UPMC Children's Hospital of Pittsburgh for all patients who underwent embolization and sclerotherapy between 2011 and 2020. Patient data were collected to compare opioid consumption, pain scores, and length of stay. In total, 854 procedures were performed on 347 patients. The morphine milligram equivalent per kilogram mean difference between groups was 0.9 (0.86, 0.95) with a p-value of <0.001. The pain score mean ratio was -1.17 (-2.2, -0.1) with a p-value of 0.027. The length of stay had an incident rate ratio of 0.94 (0.4, 2) and a p-value of 0.875. By decreasing opioid consumption and postoperative pain scores, peripheral nerve blocks may have utility in patients undergoing embolization and sclerotherapy while not clinically increasing the length of stay for patients. Their use should be individualized and carefully discussed with the interventional radiologist.

Multicenter Population Pharmacokinetics of Fentanyl in Neonatal Surgical Patients Using Dried Blood Spot Specimen Collection Demonstrates Maturation of Elimination Clearance.

BACKGROUND: Fentanyl is widely used for analgesia and sedation in neonates, but pharmacokinetic (PK) analysis in this population has been limited by the relatively large sample volumes required for plasma-based assays. METHODS: In this multicenter observational study of fentanyl kinetics in neonates up to 42 weeks of postmenstrual age (PMA) who received fentanyl boluses and continuous infusions, dried blood spots were used for small-volume sampling. A population PK analysis was used to describe fentanyl disposition in term and preterm neonates. Covariates for the model parameters, including body weight, PMA, birth status (preterm or term), and presence of congenital cardiac disease, were assessed in a stepwise manner. RESULTS: Clearance was estimated to be greater than adult clearance of fentanyl and varied with weight. Covariate selection did not yield a significant relationship for age as a continuous or dichotomous variable (term or preterm, the latter defined as birth with PMA of <37 weeks) and clearance. CONCLUSIONS: A supra-allometric effect on clearance was determined during covariate analyses (exponential scaling factor for body weight >0.75), as has been described in population PK models that account for maturation of intrinsic clearance (here, predominantly hepatic microsomal activity) in addition to scaling for weight, both of which impact clearance in this age group.

Role of Intraoperative Neuromonitoring to Predict Postoperative Delirium in Cardiovascular Surgery.

OBJECTIVE: Postoperative delirium (POD) can occur in up to 50% of older patients undergoing cardiovascular surgery, resulting in hospitalization and significant morbidity and mortality. This study aimed to determine whether intraoperative neurophysiologic monitoring (IONM) modalities can be used to predict delirium in patients undergoing cardiovascular surgery. DESIGN: Adult patients undergoing cardiovascular surgery with IONM between 2019 and 2021 were reviewed retrospectively. Delirium was assessed multiple times using the Intensive Care Delirium Screening Checklist (ICDSC). Patients with an ICDSC score ≥4 were considered to have POD. Significant IONM changes were evaluated based on a visual review of electroencephalography (EEG) and somatosensory evoked potentials data and documentation of significant changes during surgery. SETTING: University of Pittsburgh Medical Center hospitals. PARTICIPANTS: Patients 18 years old and older undergoing cardiovascular surgery with IONM monitoring. MEASUREMENTS AND MAIN RESULTS: Of the 578 patients undergoing cardiovascular surgery with IONM, 126 had POD (21.8%). Significant IONM changes were noted in 134 patients, of whom 49 patients had delirium (36.6%). In contrast, 444 patients had no IONM changes during surgery, of whom 77 (17.3%) patients had POD. Upon multivariate analysis, IONM changes were associated with POD (odds ratio 2.12; 95% CI 1.31-3.44; p < 0.001). Additionally, baseline EEG abnormalities were associated with POD (p = 0.002). CONCLUSION: Significant IONM changes are associated with an increased risk of POD in patients undergoing cardiovascular surgery. These findings offer a basis for future research and analysis of EEG and somatosensory evoked potential monitoring to predict, detect, and prevent POD.

Role of the NeuroCuple™ Device for the Postoperative Pain Management of Patients Undergoing Unilateral Primary Total Knee and Hip Arthroplasty: A Pilot Prospective, Randomized, Open-Label Study.

BACKGROUND: The potential effectiveness of the non-pharmacological and nanotechnology-based NeuroCuple™ device in reducing postoperative surgical pain and opioid consumption remains unknown. METHODS: This randomized controlled open-label study was conducted in patients undergoing a primary unilateral total knee or total hip arthroplasty. In the recovery room, patients were randomized to receive either standard of care (control group) or standard of care plus two NeuroCuple™ devices. The outcome variables included pain and opioid consumption (oral morphine equivalent, OME in milligrams). RESULTS: A total of 69 patients were randomized to either the NeuroCuple™ group (n = 38) or the control group (n = 31). Use of the NeuroCuple™ devices was associated with a significant 34% reduction in pain at rest (means of area under the curve: 6.3 vs. 9.5; p = 0.018) during postoperative days 1-3. Opioid consumption was reduced by 9%. More importantly, use of the NeuroCuple™ devices reduced the number of patients requesting an opioid prescription following discharge from the hospital by 52% (26% vs. 55%, p = 0.016). CONCLUSIONS: Our data suggest that the NeuroCuple™ device may be an effective non-pharmacological alternative to opioids to manage postoperative pain following unilateral arthroplasty due to its ability to reduce postoperative opioid use.

Short-acting versus long-acting opioids for pediatric postoperative pain management.

INTRODUCTION: Opioids are potent analgesics commonly used to manage children's moderate to severe perioperative pain in children. A wide range of short and long-acting opioids are used to treat surgical pain and will be reviewed in this article. AREAS COVERED: Both short- and long-acting opioids contain unique therapeutic benefits and adverse effects; however, due to the side effect profile and safety concerns, lack of familiarity, and evidence with long-acting opioids to treat surgical pain, shorter-acting opioids have traditionally been used in children. Almost all opioids work by binding to the mu receptor. Methadone, a long-acting opioid, is an exception because it also has beneficial N-methyl-D-aspartate antagonist properties. Clinically methadone's properties could translate to improved analgesic outcomes, reduced risk of adverse events, less risk for acute hyperalgesia, tolerance and abuse potential, faster recovery, and reduced risk for chronic persistent surgical pain. This review article summarizes and compares the evidence of commonly used short and long-acting opioids for perioperative pain control in the pediatric population. EXPERT OPINION: Individualized methadone therapy using pharmacogenomics has the potential to transform opioid use in pain management by improving patient safety and analgesic outcomes, thereby addressing the gaps in current standardized ERAS protocols.

Development and Validation of a Machine Learning Model to Identify Patients Before Surgery at High Risk for Postoperative Adverse Events.

Importance: Identifying patients at high risk of adverse outcomes prior to surgery may allow for interventions associated with improved postoperative outcomes; however, few tools exist for automated prediction. Objective: To evaluate the accuracy of an automated machine-learning model in the identification of patients at high risk of adverse outcomes from surgery using only data in the electronic health record. Design, Setting, and Participants: This prognostic study was conducted among 1 477 561 patients undergoing surgery at 20 community and tertiary care hospitals in the University of Pittsburgh Medical Center (UPMC) health network. The study included 3 phases: (1) building and validating a model on a retrospective population, (2) testing model accuracy on a retrospective population, and (3) validating the model prospectively in clinical care. A gradient-boosted decision tree machine learning method was used for developing a preoperative surgical risk prediction tool. The Shapley additive explanations method was used for model interpretability and further validation. Accuracy was compared between the UPMC model and National Surgical Quality Improvement Program (NSQIP) surgical risk calculator for predicting mortality. Data were analyzed from September through December 2021. Exposure: Undergoing any type of surgical procedure. Main Outcomes and Measures: Postoperative mortality and major adverse cardiac and cerebrovascular events (MACCEs) at 30 days were evaluated. Results: Among 1 477 561 patients included in model development (806 148 females [54.5%; mean [SD] age, 56.8 [17.9] years), 1 016 966 patient encounters were used for training and 254 242 separate encounters were used for testing the model. After deployment in clinical use, another 206 353 patients were prospectively evaluated; an additional 902 patients were selected for comparing the accuracy of the UPMC model and NSQIP tool for predicting mortality. The area under the receiver operating characteristic curve (AUROC) for mortality was 0.972 (95% CI, 0.971-0.973) for the training set and 0.946 (95% CI, 0.943-0.948) for the test set. The AUROC for MACCE and mortality was 0.923 (95% CI, 0.922-0.924) on the training and 0.899 (95% CI, 0.896-0.902) on the test set. In prospective evaluation, the AUROC for mortality was 0.956 (95% CI, 0.953-0.959), sensitivity was 2148 of 2517 patients (85.3%), specificity was 186 286 of 203 836 patients (91.4%), and negative predictive value was 186 286 of 186 655 patients (99.8%). The model outperformed the NSQIP tool as measured by AUROC (0.945 [95% CI, 0.914-0.977] vs 0.897 [95% CI, 0.854-0.941], for a difference of 0.048), specificity (0.87 [95% CI, 0.83-0.89] vs 0.68 [95% CI, 0.65-0.69]), and accuracy (0.85 [95% CI, 0.82-0.87] vs 0.69 [95% CI, 0.66, 0.72]). Conclusions and Relevance: This study found that an automated machine learning model was accurate in identifying patients undergoing surgery who were at high risk of adverse outcomes using only preoperative variables within the electronic health record, with superior performance compared with the NSQIP calculator. These findings suggest that using this model to identify patients at increased risk of adverse outcomes prior to surgery may allow for individualized perioperative care, which may be associated with improved outcomes.

Isha yoga practices, vegan diet, and participation in Samyama meditation retreat: impact on the gut microbiome & metabolome - a non-randomized trial.

BACKGROUND: Growing evidence suggests a role for gut bacteria and their metabolites in host-signaling responses along the gut-brain axis which may impact mental health. Meditation is increasingly utilized to combat stress, anxiety, and depression symptoms. However, its impact on the microbiome remains unclear. This study observes the effects of preparation and participation in an advanced meditation program (Samyama) implemented with a vegan diet including 50% raw foods, on gut microbiome and metabolites profiles. METHODS: There were 288 subjects for this study. Stool samples were collected at 3-time points for meditators and household controls. Meditators prepared for 2 months for the Samyama, incorporating daily yoga and meditation practices with a vegan diet including 50% raw foods. Subjects were requested to submit stool samples for 3 time points - 2 months before Samyama (T1), right before Samyama (T2), and 3 months following Samyama (T3). 16 s rRNA sequencing was used to study participants' microbiome. Alpha and beta diversities along with short-chain fatty acid (SCFA) were assessed. Metabolomics were performed on a mass spectrometer coupled to a UHLPC system and analyzed by El-MAVEN software. RESULTS: Alpha diversity showed no significant differences between meditators and controls, while beta diversity showed significant changes (padj = 0.001) after Samyama in meditators' microbiota composition. After the preparation phase, changes in branched short-chain fatty acids, higher levels of iso-valerate (padj = 0.02) and iso-buytrate (padj = 0.019) were observed at T2 in meditators. Other metabolites were also observed to have changed in meditators at timepoint T2. CONCLUSION: This study examined the impact of an advanced meditation program combined with a vegan diet on the gut microbiome. There was an increase in beneficial bacteria even three months after the completion of the Samyama program. Further study is warranted to validate current observations and investigate the significance and mechanisms of action related to diet, meditation, and microbial composition and function, on psychological processes, including mood. TRIAL REGISTRATION: Registration number: NCT04366544 ; Registered on 29/04/2020.

Effects of oxycodone pharmacogenetics on postoperative analgesia and related clinical outcomes in children: a pilot prospective study.

Background: Variability in the pharmacokinetics and pharmacodynamics of oxycodone in children undergoing surgery could be due to genetic polymorphisms. Materials & methods: The authors studied the association between clinical outcomes and pharmacogenes in children undergoing major surgery. A total of 89 children (35 undergoing pectus excavatum repair and 54 undergoing spinal fusion) were recruited. Results: OPRM1 SNP rs6902403 showed an association with maximum pain score and total morphine equivalent dose (p < 0.05). Other polymorphisms in OPRM1 SNP, PXR, COMT and ABCB1 were also shown to be associated with average morphine equivalent dose, length of hospital stay and maximum surgical pain (p < 0.05). Conclusion: This study demonstrates novel associations between the above pharmacogenes and oxycodone's pharmacokinetics as well as postoperative outcomes in children. Clinical trial registration: NCT03495388 (ClinicalTrials.gov).

A Retrospective Study Comparing Outcomes of Paravertebral Clonidine Infusion for Pediatric Patients Undergoing Nuss Procedure.

INTRODUCTION: The continuous paravertebral blockade as part of the multimodal pain protocol is an effective regional technique to control pain after the Nuss procedure. We investigated the effectiveness of clonidine as an adjunct to paravertebral ropivacaine infusion. METHODS: We conducted a retrospective study of 63 patients who underwent Nuss procedures and received bilateral paravertebral catheters. Data on demographics, surgical, anesthesia, and block characteristics, numeric rating pain scores (NRS), opioids consumption, hospital length of stay, complications, and side effects from medication administration were collected in children who received paravertebral ropivacaine 0.2% infusion without (N = 45) and with clonidine (1 mcg/mL) (N = 18). RESULTS: The two groups had similar demographics, although the clonidine group had higher Haller indices (6.5 (4.8, 9.4) vs. 4.8 (4.1, 6.6), p = 0.013). The clonidine group required less morphine equivalent/kg on postoperative day 2 (median, interquartile range 0.24 (0.22, 0.31) vs. 0.47 (0.29, 0.61) p = 0.002). There was no difference in median NRS pain scores. Both groups had similar catheter infusion durations, hospital length of stay, and complication rates. CONCLUSION: A postoperative pain management plan that includes paravertebral analgesia, including clonidine as an adjunct, may be considered to minimize opioid administration for patients undergoing primary Nuss repair.

Placental volume in pregnant women with opioid use: prenatal MRI assessment.

OBJECTIVE: Opioid use in pregnant women is a growing public health concern and is shown to be associated with lower infant birth weights. Placental volume changes in prior studies correlated with various maternal and fetal conditions. We aimed to identify differences between placental volumes in pregnant women with opioid use, and control pregnant women without drug use. METHODS: We prospectively recruited 27 healthy pregnant women and 17 pregnant women with opioid use disorder who were on medication-assisted treatment (MAT). All women underwent placenta/fetal MRI at 27-39 weeks gestation on a 3 Tesla MR scanner. Placental volumes were measured in a blinded fashion using a previously validated technique. Multiple linear regression was used to identify associations of placental volume with multiple maternal and fetal clinical factors. The significance threshold was set at p < .05. RESULTS: Placental volume was significantly associated with gestational age at MRI (p < .0001), fetal sex (p = .027), MAT with smoking (p = .0008), MAT with polysubstance use (p = .01), and maternal BMI (p = .032). Placental volume was not associated with opioid MAT alone in our cohort. CONCLUSION: For pregnant women on medication-assisted treatment for opioid use disorder, there was no significant difference in placental volume compared to healthy pregnant women. However, concomitant smoking and polysubstance use in the setting of medication-assisted treatment may be detrimental to placental health. To our knowledge, this is the first study assessing placental volume in opioid use on prenatal MRI. These results support the benefit of medication-assisted treatment during pregnancy; however additional studies are needed to further elucidate the impact of opioid use on placental and fetal development and postnatal outcomes.

Implementation of CYP2D6-guided opioid therapy at Cincinnati Children's Hospital Medical Center.

PURPOSE: We describe the implementation of CYP2D6-focused pharmacogenetic testing to guide opioid prescribing in a quaternary care, nonprofit pediatric academic medical center. SUMMARY: Children are often prescribed oral opioids after surgeries, for cancer pain, and occasionally for chronic pain. In 2004, Cincinnati Children's Hospital Medical Center implemented pharmacogenetic testing for CYP2D6 metabolism phenotype to inform codeine prescribing. The test and reports were updated to align with changes over time in the testing platform, the interpretation of genotype to phenotype, the electronic health record, and Food and Drug Administration (FDA) guidance. The use of the test increased when a research project required testing and decreased as prescribing of oxycodone increased due to FDA warnings about codeine. Education about the opioid-focused pharmacogenetic test was provided to prescribers (eg, the pain and sickle cell teams) as well as patients and families. Education and electronic health record capability increased provider compliance with genotype-guided postsurgical prescribing of oxycodone, although there was a perceived lack of utility for oxycodone prescribing. CONCLUSION: The implementation of pharmacogenetic testing to inform opioid prescribing for children has evolved with accumulating evidence and guidelines, requiring changes in reporting of results and recommendations.

Placental cytochrome P450 methylomes in infants exposed to prenatal opioids: exploring the effects of neonatal opioid withdrawal syndrome on health horizons.

Background: Neonatal opioid withdrawal syndrome (NOWS), arises due to increased opioid use during pregnancy. Cytochrome P450 (CYP) enzymes play a pivotal role in metabolizing a wide range of substances in the human body, including opioids, other drugs, toxins, and endogenous compounds. The association between CYP gene methylation and opioid effects is unexplored and it could offer promising insights. Objective: To investigate the impact of prenatal opioid exposure on disrupted CYPs in infants and their anticipated long-term clinical implications. Study Design: DNA methylation levels of CYP genes were analyzed in a cohort of 96 placental tissues using Illumina Infinium MethylationEPIC (850 k) BeadChips. This involved three groups of placental tissues: 32 from mothers with infants exposed to opioids prenatally requiring pharmacologic treatment for NOWS, 32 from mothers with prenatally opioid-exposed infants not needing NOWS treatment, and 32 from unexposed control mothers. Results: The study identified 20 significantly differentially methylated CpG sites associated with 17 distinct CYP genes, with 14 CpGs showing reduced methylation across 14 genes (CYP19A1, CYP1A2, CYP4V2, CYP1B1, CYP24A1, CYP26B1, CYP26C1, CYP2C18, CYP2C9, CYP2U1, CYP39A1, CYP2R1, CYP4Z1, CYP2D7P1 and), while 8 exhibited hypermethylation (CYP51A1, CYP26B1, CYP2R1, CYP2U1, CYP4X1, CYP1A2, CYP2W1, and CYP4V2). Genes such as CYP1A2, CYP26B1, CYP2R1, CYP2U1, and CYP4V2 exhibited both increased and decreased methylation. These genes are crucial for metabolizing eicosanoids, fatty acids, drugs, and diverse substances. Conclusion: The study identified profound methylation changes in multiple CYP genes in the placental tissues relevant to NOWS. This suggests that disruption of DNA methylation patterns in CYP transcripts might play a role in NOWS and may serve as valuable biomarkers, suggesting a future pathway for personalized treatment. Further research is needed to confirm these findings and explore their potential for diagnosis and treatment.

Brain structural connectome in neonates with prenatal opioid exposure.

Introduction: Infants with prenatal opioid exposure (POE) are shown to be at risk for poor long-term neurobehavioral and cognitive outcomes. Early detection of brain developmental alterations on neuroimaging could help in understanding the effect of opioids on the developing brain. Recent studies have shown altered brain functional network connectivity through the application of graph theoretical modeling, in infants with POE. In this study, we assess global brain structural connectivity through diffusion tensor imaging (DTI) metrics and apply graph theoretical modeling to brain structural connectivity in infants with POE. Methods: In this prospective observational study in infants with POE and control infants, brain MRI including DTI was performed before completion of 3 months corrected postmenstrual age. Tractography was performed on the whole brain using a deterministic fiber tracking algorithm. Pairwise connectivity and network measure were calculated based on fiber count and fractional anisotropy (FA) values. Graph theoretical metrics were also derived. Results: There were 11 POE and 18 unexposed infants included in the analysis. Pairwise connectivity based on fiber count showed alterations in 32 connections. Pairwise connectivity based on FA values showed alterations in 24 connections. Connections between the right superior frontal gyrus and right paracentral lobule and between the right superior occipital gyrus and right fusiform gyrus were significantly different after adjusting for multiple comparisons between POE infants and unexposed controls. Additionally, alterations in graph theoretical network metrics were identified with fiber count and FA value derived tracts. Conclusion: Comparisons show significant differences in fiber count in two structural connections. The long-term clinical outcomes related to these findings may be assessed in longitudinal follow-up studies.

Online guided meditation training (Isha Kriya) improves self-reported symptoms of anxiety and depression within 2 weeks of practice-An observational study.

Introduction: Anxiety and depression have increased dramatically 2-3-fold with the COVID-19 pandemic. There is an urgent need for safe, cost-effective, and scalable approaches to alleviate this parallel mental health pandemic. Meditation has previously been shown to reduce stress, anxiety, and depression symptoms. Furthermore, online delivery of mind-body interventions will be impactful in addressing disparities in access to mental healthcare. In this observational pilot study, we investigate the impact of a digitally delivered guided meditation followed by daily practice on symptoms of anxiety and depression. Methods: Initially, 57 male and 202 female subjects enrolled in this study. Participants attended a webinar where they learned the Isha Kriya meditation practice. They were subsequently requested to perform the intervention daily for 6 weeks. Subjects were given scales to assess anxiety and depression at baseline, 2, 4, and 6 weeks following the training. The changes in the self-reported anxiety and depression scores were examined by the linear mixed effect models. Results: Participants completed survey responses for the following time points: baseline (n = 82), week 2 (n = 58), week 4 (n = 37), and week 6 (n = 28). During the 6 weeks of the study over 68% of subjects were compliant with their daily practice. When comparing baseline with week 2, the mean anxiety scores decreased from 25.4 to 16.8 (p < 0.01, d = 1.31). Similarly, mean depression scores decreased from 15 to 8.81 (p < 0.01, d = 0.9). The reduced scores for both anxiety and depression were maintained at weeks 4 and 6. Conclusion: This preliminary study assesses the effectiveness of online meditation training on self-reported symptoms of anxiety and depression. After 2 weeks of practice, those with baseline anxiety and depression showed significant improvement with a large effect size. The results from weeks 4 and 6 show sustained reduced anxiety and depression symptoms. These findings suggest that daily Isha Kriya practice could alleviate symptoms of these conditions. Future studies utilizing randomized control trials should be conducted to rigorously evaluate the benefits of this meditation practice on anxiety and depression. Trials registration: ClinicalTrials.gov, identifier: NCT05065476.

Advanced Meditation and Vegan Diet Increased Acylglycines and Reduced Lipids Associated with Improved Health: A Prospective Longitudinal Study.

Introduction: Samyama is an Isha Yoga 8-day residential meditation/yoga retreat combined with 60 days of preparation with vegan diet. We showed earlier Samyama retreat was associated with lower systemic inflammation and favorable lipid profiles along with other physical and mental health benefits. There is no mechanistic study on the impact of an advanced meditative process on multiple blood lipids and their implications on meditation-related improved physical and mental wellbeing. Methods: Sixty-four Samyama participants on vegan diet had blood sampled immediately before and immediately after the 8-day retreat for lipidomic analysis. The complex plasma lipidome was characterized using high-resolution mass spectrometric analysis and tandem mass spectrometry. Results: Pre- and post-Samyama blood samples of 64 Samyama participants were analyzed. Acylglycines (acetyl, propionyl, butyryl, and valeryl) were increased in the plasma post-Samyama compared with pre-Samyama (p < 0.001). Levels of glycerophosphocholines, glycerophosphoethanolamines, di-unsaturated ethanolamine plasmalogens, cholesterol esters, acylcarnitines, and acylgylcerines (triacylglycerols and diacylglycerols) decreased after the Samyama meditation. Plasma levels of glycerophosphoserines or glycerophosphoinositols were unchanged. Conclusion: An 8-day advanced meditation retreat resulted in increased acylglycines, an endocannabinoid-like fatty acid amide associated with increased cellular anandamide levels, anti-inflammation, analgesia, and vascular relaxation. Other serum lipid levels, including some that are associated with increased risk of atherosclerosis, were reduced following the Samyama program. ClinicalTrials.gov Registration: Identifier: NCT04366544.

Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure.

Background: Infants with prenatal opioid and substance exposure are at higher risk of poor neurobehavioral outcomes in later childhood. Early brain imaging in infancy has the potential to identify early brain developmental alterations that may help predict behavioral outcomes in these children. In this study, using resting-state functional MRI in early infancy, we aim to identify differences in global brain network connectivity in infants with prenatal opioid and substance exposure compared to healthy control infants. Methods and Materials: In this prospective study, we recruited 23 infants with prenatal opioid exposure and 29 healthy opioid naïve infants. All subjects underwent brain resting-state functional MRI before 3 months postmenstrual age. Covariate Assisted Principal (CAP) regression was performed to identify brain networks within which functional connectivity was associated with opioid exposure after adjusting for sex and gestational age. Associations of these significant networks with maternal comorbidities were also evaluated. Additionally, graph network metrics were assessed in these CAP networks. Results: There were four CAP network components that were significantly different between the opioid exposed and healthy control infants. Two of these four networks were associated with maternal psychological factors. Intra-network graph metrics, namely average flow coefficient, clustering coefficient and transitivity were also significantly different in opioid exposed infants compared to healthy controls. Conclusion: Prenatal opioid exposure is associated with alterations in global brain functional networks compared to non-opioid exposed infants, with intra-network alterations in graph network modeling. These network alterations were also associated with maternal comorbidity, especially mental health. Large-scale longitudinal studies can help in understanding the clinical implications of these early brain functional network alterations in infants with prenatal opioid exposure.