Top Three Healthcare Trends in Orthopaedics Affecting Musculoskeletal Care in the Elderly.

Several trends toward patient-centered multi-care models employing translational research strategies are currently emerging in orthopaedics. These align seamlessly with epigenetics discussions in pain, a clinical approach to pain management that prioritizes tailoring healthcare to individual needs, preferences, and circumstances. Recognizing the unique genetic and epigenetic factors influencing pain perception, healthcare providers can integrate personalized insights into their patient-centered approach, offering more targeted and effective pain management strategies tailored to each individual's experience. Custom 3D-printing technologies may also become increasingly relevant to more effectively and reliably treat painful degenerative structural abnormalities. They are expected to go hand-in-hand with the precision medicine redefinition of musculoskeletal care. More effective analysis of surgeons' clinical decision-making and patients' perception of high-value orthopaedic care is needed. Shared Decision Making (SDM) is critical to identifying the best solution for each patient and improving stakeholders' understanding of factors influencing the diverse prioritizing values of surgical or non-surgical treatments by payers, systems, and other providers. Identifying high-value orthopaedic surgeries via effective SDM in orthopedic surgery requires more than just presenting patients with information. The Rasch analysis of patient expectations can provide this nuanced approach that involves understanding patient values, addressing misconceptions, and aligning surgical recommendations with patient-specific goals. Optimizing orthopaedic treatment within the patient-centered framework can drive innovation in reimbursement policies that support the field more broadly. Research on separating high-value from low-value orthopaedic procedures may likely impact healthcare decision- makers' resource allocation.

Hemiplegic Migraines Exacerbated using an Injectable GLP-1 Agonist for Weight Loss.

The widespread adoption of Glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity and diabetes has raised concerns about their potential adverse effects, including the induction of depression and suicide ideation. We report on a male patient in his early 50s with a complex medical history, including adult Attention-Deficit/Hyperactive Disorder, narcolepsy with cataplexy, and major depressive disorder in remission, who experienced exacerbated hemiplegic migraines after initiating treatment with an injectable GLP-1 agonist (Saxenda) for weight loss. Despite a previous history of experiencing hemiplegic migraines once or twice a year, the patient reported daily occurrences of migraines, many of which were hemiplegic, during the 60 days of GLP-1 agonist treatment. The migraines abated only upon discontinuation of the medication. This case underscores the need to carefully consider patient history and potential genetic predispositions when prescribing GLP-1 agonists, highlighting the complex interactions between these medications, existing comorbidities, and the dopaminergic and calcitonin gene-related peptide pathways. Our findings suggest that GLP-1 agonists, while beneficial for some, may pose significant risks for patients with specific genetic backgrounds or neurological conditions, calling for personalized approaches to treatment and increased awareness of potential adverse effects.

A historical perspective on clonidine as an alpha-2A receptor agonist in the treatment of addictive behaviors: Focus on opioid dependence.

Clonidine operates through agonism at the alpha-2A receptor, a specific subtype of the alpha-2-adrenergic receptor located predominantly in the prefrontal cortex. By inhibiting the release of norepinephrine, which is responsible for withdrawal symptoms, clonidine effectively addresses withdrawal-related conditions such as anxiety, hypertension, and tachycardia. The groundbreaking work by Gold et al. demonstrated clonidine's ability to counteract the effects of locus coeruleus stimulation, reshaping the understanding of opioid withdrawal within the field. In the 1980s, the efficacy of clonidine in facilitating the transition to long-acting injectable naltrexone was confirmed for individuals motivated to overcome opioid use disorders (OUDs), including physicians and executives. Despite challenges with compliance, naltrexone offers sustained blockade of opioid receptors, reducing the risk of overdose, intoxication, and relapse in motivated patients in recovery. The development of clonidine and naltrexone as treatment modalities for OUDs, and potentially other addictions, including behavioral ones, underscores the potential for translating neurobiological advancements from preclinical models (bench) to clinical practice (bedside), ushering in innovative approaches to addiction treatment.

Dopamine Dysregulation in Reward and Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments.

Potential Link Between Exercise and N-Methyl-D-Aspartate Glutamate Receptors in Alcohol Use Disorder: Implications for Therapeutic Strategies.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

Exercise Influences the Brain's Metabolic Response to Chronic Cocaine Exposure in Male Rats.

Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors.

Summary Document Research on RDS Anti-addiction Modeling: Annotated Bibliography.

Annotated bibliography of genetic addiction risk severity (GARS) publications, pro-dopamine regulation in nutraceuticals (KB220 nutraceutical variants), and policy documents. Further research is required to encourage the field to consider "Reward Deficiency Syndrome (RDS) Anti-addiction Modeling" which involves early risk identification by means of genetic assessment similar to GARS, followed by induction of dopamine homeostasis by means of genetically guided pro-dopamine regulation similar to KB220. These results suggest that genetically based treatments may be a missing piece in the treatment of substance use disorder (SUD).

Addressing cortex dysregulation in youth through brain health check coaching and prophylactic brain development.

The Carter Center has estimated that the addiction crisis in the United States (US), if continues to worsen at the same rate, may cost the country approximately 16 trillion dollars by 2030. In recent years, the well-being of youth has been compromised by not only the coronavirus disease 2019 pandemic but also the alarming global opioid crisis, particularly in the US. Each year, deadly opioid drugs claim hundreds of thousands of lives, contributing to an ever-rising death toll. In addition, maternal usage of opioids and other drugs during pregnancy could compromise the neurodevelopment of children. A high rate of DNA polymorphic antecedents compounds the occurrence of epigenetic insults involving methylation of specific essential genes related to normal brain function. These genetic antecedent insults affect healthy DNA and mRNA transcription, leading to a loss of proteins required for normal brain development and function in youth. Myelination in the frontal cortex, a process known to extend until the late 20s, delays the development of proficient executive function and decision-making abilities. Understanding this delay in brain development, along with the presence of potential high-risk antecedent polymorphic variants or alleles and generational epigenetics, provides a clear rationale for embracing the Brain Research Commission's suggestion to mimic fitness programs with an adaptable brain health check (BHC). Implementing the BHC within the educational systems in the US and other countries could serve as an effective initiative for proactive therapies aimed at reducing juvenile mental health problems and eventually criminal activities, addiction, and other behaviors associated with reward deficiency syndrome.

Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy.

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review.

Methylphenidate (MP) is a psychostimulant commonly prescribed for individuals with attention deficit hyperactivity disorder (ADHD) but it is also taken with and without a prescription for performance enhancement. Prior research has characterized the effects of MP on behavior, cognition, and neurochemistry. This exploratory review covers the uses of MP and examined the effects of MP on gene expression in the brain following exposure. Overall, MP causes a wide-spread potentiation of genes, in a region-specific manner; consequently, inducing neuronal alterations, such as synaptic plasticity and transmission, resulting in observed behaviors and affects. Monoamine neurotransmitters and post-synaptic density protein genes generally had a potentiating effect in gene expression after exposure to MP.

The Role of Estrogen Signaling and Exercise in Drug Abuse: A Review.

BACKGROUND: Discovering how sex differences impact the efficacy of exercise regimens used for treating drug addiction is becoming increasingly important. Estrogen is a hormone believed to explain a large portion of sex differences observed during drug addiction, and why certain exercise regimens are not equally effective between sexes in treatment. Addiction is currently a global hindrance to millions, many of whom are suffering under the influence of their brain's intrinsic reward system coupled with external environmental factors. Substance abuse disorders in the U.S. alone cost billions of dollars annually. REVIEW SUMMARY: Studies involving the manipulation of estrogen levels in female rodents, primarily via ovariectomy, highlight its impact regarding drug addiction. More specifically, female rodents with higher estrogen levels during the estrus phase increase cocaine consumption, whereas those in the non-estrus phase (low estrogen levels) decrease cocaine consumption. If estrogen is reintroduced, self-administration increases once again. Exercise has been proven to decrease relapse tendency, but its effect on estrogen levels is not fully understood. CONCLUSIONS: Such findings and results discussed in this review suggest that estrogen influences the susceptibility of females to relapse. Therefore, to improve drug-abuse-related treatment, exercise regimens for females should be generated based on key sex differences with respect to males.

Neurogenetics and Epigenetics of Loneliness.

Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.

Exercise Modifies the Brain Metabolic Response to Chronic Cocaine Exposure Inhibiting the Stria Terminalis.

It is well known that exercise promotes health and wellness, both mentally and physiologically. It has been shown to play a protective role in many diseases, including cardiovascular, neurological, and psychiatric diseases. The present study examined the effects of aerobic exercise on brain glucose metabolic activity in response to chronic cocaine exposure in female Lewis rats. Rats were divided into exercise and sedentary groups. Exercised rats underwent treadmill running for six weeks and were compared to the sedentary rats. Using positron emission tomography (PET) and [18F]-Fluorodeoxyglucose (FDG), metabolic changes in distinct brain regions were observed when comparing cocaine-exposed exercised rats to cocaine-exposed sedentary rats. This included activation of the secondary visual cortex and inhibition in the cerebellum, stria terminalis, thalamus, caudate putamen, and primary somatosensory cortex. The functional network of this brain circuit is involved in sensory processing, fear and stress responses, reward/addiction, and movement. These results show that chronic exercise can alter the brain metabolic response to cocaine treatment in regions associated with emotion, behavior, and the brain reward cascade. This supports previous findings of the potential for aerobic exercise to alter the brain's response to drugs of abuse, providing targets for future investigation. These results can provide insights into the fields of exercise neuroscience, psychiatry, and addiction research.

Genetic Correlates as a Predictor of Bariatric Surgery Outcomes after 1 Year.

This study analyzed genetic risk assessments in patients undergoing bariatric surgery to serve as a predictive factor for weight loss parameters 1 year after the operation. Thirty (30) patients were assessed for Genetic Addiction Risk Severity (GARS), which analyzes neurogenetic polymorphisms involved in addiction and reward deficiency. Genetic and psychosocial data collected before the operation were correlated with weight loss data, including changes in weight, body mass index (BMI), and percent of expected weight loss (%EWL). Results examined correlations between individual gene risk alleles, 1-year body weight data, and psychosocial trait scores. Spearman's correlations revealed that the OPRM1 (rs1799971) gene polymorphism had significant negative correlation with 1-year weight (rs = -0.4477, p < 0.01) and BMI (rs = -0.4477, p < 0.05). In addition, the DRD2 risk allele (rs1800497) was correlated negatively with BMI at 1 year (rs = -0.4927, p < 0.05), indicating that one risk allele copy was associated with lower BMI. However, this allele was positively correlated with both ∆Weight (rs = 0.4077, p < 0.05) and %EWL (rs = 0.5521, p < 0.05) at 1 year post-surgery. Moreover, the overall GARS score was correlated with %EWL (rs = 0.4236, p < 0.05), ∆Weight (rs = 0.3971, p < 0.05) and ∆BMI (rs = 0.3778, p < 0.05). Lastly, Food Cravings Questionnaire (FCQ) scores were negatively correlated with %EWL (rs = -0.4320, p < 0.05) and ∆Weight at 1 year post-surgery (rs = -0.4294, p < 0.05). This suggests that individuals with a higher genetic addiction risk are more responsive to weight loss treatment, especially in the case of the DRD2 polymorphism. These results should translate clinically to improve positivity and attitude related to weight management by those individuals born with the risk alleles (rs1800497; rs1799971).

EPIC Spinal Procedure with Sound Wave Technology Induces Biomechanical Alignment Putatively Influencing Pain Response.

Spinal biomechanical alignment is now able to be altered through the use of unique sound wave technology. This methodological commentary will correlate recent studies demonstrating the ability of sound waves to carry mass, how the EPIC technique spinal procedure uses a sound wave impulse to create measurable changes in spinal alignment, and the clinical safety and efficacy of this approach. The EPIC technique is a direct genealogical descendant of the technique originally developed by the founding family of chiropractic. With sound wave therapies currently being used to break up kidney stones, called lithotripsy, in physical therapy for the treatment of soft tissue injuries, in the treatment of prostate cancer, and in the treatment of Alzheimer's disease, it is possible that the use of sound wave therapies may enter into the realm of altering joint biomechanics. Through a neurovascular examination, the EPIC technique spinal procedure can ascertain the presence of craniocervical subluxation, followed by acquiring multi-dimensional radiographic images for structural analysis. Currently using digital radiographic analysis, the EPIC technique acquires an epigenetic profile of structural asymmetries as well as a multi-directional biomechanical malposition profile of the spine, combining both profiles to ascertain the exact degrees for realignment. EPIC clinics have successfully utilized EPIC on over 20,000 cases. Comparison of pre-treatment biomechanical lateral displacement of the C1 vertebra around the Z-axis measured on digital radiographs, and post-treatment biomechanical lateral displacement of the C1 vertebra measured on digital radiographs immediately following the procedure, demonstrated an average 52% reduction in lateral biomechanical displacement around the Z-axis in a select group of over 2,000 cases. While more research is required, we are encouraged by these preliminary results. WC 265.