High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial.

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30-600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.

Transmodulation of Dopaminergic Signaling to Mitigate Hypodopminergia and Pharmaceutical Opioid-Induced Hyperalgesia.

Neuroscientists and psychiatrists working in the areas of "pain and addiction" are asked in this perspective article to reconsider the current use of dopaminergic blockade (like chronic opioid agonist therapy), and instead to consider induction of dopamine homeostasis by putative pro-dopamine regulation. Pro-dopamine regulation could help pharmaceutical opioid analgesic agents to mitigate hypodopaminergia-induced hyperalgesia by inducing transmodulation of dopaminergic signaling. An optimistic view is that early predisposition to diagnosis based on genetic testing, (pharmacogenetic/pharmacogenomic monitoring), combined with appropriate urine drug screening, and treatment with pro-dopamine regulators, could conceivably reduce stress, craving, and relapse, enhance well-being and attenuate unwanted hyperalgesia. These concepts require intensive investigation. However, based on the rationale provided herein, there is a good chance that combining opioid analgesics with genetically directed pro-dopamine-regulation using KB220 (supported by 43 clinical studies). This may become a front-line technology with the potential to overcome, in part, the current heightened rates of chronic opioid-induced hyperalgesia and concomitant Reward Deficiency Syndrome (RDS) behaviors. Current research does support the hypothesis that low or hypodopaminergic function in the brain may predispose individuals to low pain tolerance or hyperalgesia.

Pediatric Sports-Related Injuries.

At any time there are millions of athletes ages 6 to 18 years participating in sports-related activities and the number is increasing. Unfortunately, the number of overuse injuries is also on the rise. This increase is most likely associated with single-sport specialization before the onset of puberty. As physicians and health care providers, we must educate these young athletes, their parents, and coaches to ensure safety. Short breaks are recommended and everyone involved should understand the athlete should not train more than 5 days per week and must take off 2 to 4 months per year consecutively depending on the specific sport and position on the team. To understand the complexity of these overuse injuries, it is important to have knowledge of the unique characteristics of the immature musculoskeletal system, periods of rapid growth, and the function of the growth plate, which is often involved in these injuries.

Driving a Liquid Crystal Phase Transition Using a Photochromic Hydrazone.

The dynamic manipulation of the properties of soft matter can lead to adaptive functional materials that can be used in advanced applications. Here we report on a new chiral dopant, built on an isosorbide scaffold attached to two bistable hydrazone-based light switches that can be used to control the self-assembly, and hence photophysical properties, of nematic liquid crystals (LCs). The bistability of the switch allows kinetic trapping of various helical assemblies as a function of the photostationary states, resulting in the reflection of different wavelengths of light. Surprisingly, doping 5CB with the chiral switch, followed by irradiation with blue light, triggers an isothermal phase change from the helical cholesteric phase to the untwisted lamellar smectic A* phase. This transition was used to modulate the transparency of a LC film, resulting in a light-gated optical window.

Promoting Precision Addiction Management (PAM) to Combat the Global Opioid Crisis.

It is universally agreed that dopamine is a major neurotransmitter in terms of reward dependence, however, there remains controversy regarding how to modulate its role clinically to treat and prevent relapse for both substance and non-substance-related addictive behaviors. It is also agreed by most that there is a need to provide early genetic identification possibly through a novel researched technology referred to Genetic Addiction Risk Score(GARS).™ The existing FDA-approved medications promote blocking dopamine, however, we argue that a more prudent paradigm shift should be biphasic-short-term blockade and long-term upregulation, enhancing functional connectivity of brain reward. It is critical to understand that the real phenotype is not any specific drug or non -drug addictive behavior, but instead is Reward Deficiency Syndrome (RDS). Thus the true phenotype of all addictive behaviors is indeed RDS. Finally, we are suggesting that one way to combat the current out of control Opioid /Alcohol crisis worldwide is to seriously reconsider treating RDS by simply supplying powerful narcotic agents (e.g. Buprenorphine). This type of treatment will only keep people addicted. A more reasonable solution involving genetic testing, urine drug screens using Comprehensive Analysis of Reported Drugs (CARD) and dopamine homeostasis we call " Precision Addiction Management" ™ seems parsonomiuos.

New molecular switch architectures.

In this paper we elaborate on recently developed molecular switch architectures and how these new systems can help with the realization of new functions and advancement of artificial molecular machines. Progress in chemically and photoinduced switches and motors is summarized and contextualized such that the reader may gain an appreciation for the novel tools that have come about in the past decade. Many of these systems offer distinct advantages over commonly employed switches, including improved fidelity, addressability, and robustness. Thus, this paper serves as a jumping-off point for researchers seeking new switching motifs for specific applications, or ones that address the limitations of presently available systems.

Reversible exacerbation of obstructive sleep apnea by α1-adrenergic blockade with tamsulosin: A case report.

Obstructive sleep apnea (OSA) is characterized by repeated involuntary closure of the pharyngeal airspace during sleep. Normal activity of the genioglossus (GG) muscle is important in maintaining airway patency, and inhibition of GG activity can contribute to airway closure. Neurons in the hypoglossal motor nucleus (HMN) regulate GG activity. Adrenergic tone is an important regulator of HMN neuronal excitability. In laboratory models α1-adrenergic antagonists inhibit HMN neurons and GG activity, suggesting that α1-adrenergic antagonism might adversely affect patients with OSA. To date there has been no report of such a case. CASE SUMMARY: The patient was a 67-year old man with a 27-month history of obstructive sleep apnea. Diagnostic polysomnography demonstrated a baseline apnea-hypopnea index (AHI) of 21.3 and a trough oxygen saturation of 84%. Treatment with continuous positive airway pressure (CPAP) was initiated. The AHI in year 1 averaged 1.0 ± 0.1 (mean ± SD) and 0.8 ± 0.1 in year 2. Other medical conditions included hypertension controlled with losartan and benign prostatic hypertrophy not well controlled by finasteride monotherapy. The α1-adrenergic receptor antagonist tamsulosin 0.4 mg daily was added. Shortly after initiation of tamsulosin, subjective sleep quality deteriorated. Significant surges in obstructive events, apneic episodes, and AHI were also recorded, and nocturnal airway pressure was frequently sustained at the CPAP device maximum of 20 cm H2O. Tamsulosin was discontinued. CPAP parameters and sleep quality returned to the pre-tamsulosin baselines within 10 days. These findings suggest that α1-adrenergic blockade with tamsulosin may exacerbate sleep-disordered breathing in susceptible patients.

Liquid crystal self-assembly of random-sequence DNA oligomers.

In biological systems and nanoscale assemblies, the self-association of DNA is typically studied and applied in the context of the evolved or directed design of base sequences that give complementary pairing, duplex formation, and specific structural motifs. Here we consider the collective behavior of DNA solutions in the distinctly different regime where DNA base sequences are chosen at random or with varying degrees of randomness. We show that in solutions of completely random sequences, corresponding to a remarkably large number of different molecules, e.g., approximately 10(12) for random 20-mers, complementary still emerges and, for a narrow range of oligomer lengths, produces a subtle hierarchical sequence of structured self-assembly and organization into liquid crystal (LC) phases. This ordering follows from the kinetic arrest of oligomer association into long-lived partially paired double helices, followed by reversible association of these pairs into linear aggregates that in turn condense into LC domains.

An approach to shorten time to infarct artery patency in patients with ST-segment elevation myocardial infarction.

We developed a regional strategy to decrease the time to percutaneous coronary intervention (PCI) for patients with acute ST-segment elevation myocardial infarction (STEMI). Protocols were created for paramedics and referring hospitals to identify and directly triage all patients with STEMI to a single PCI center. Time to PCI reperfusion and in-hospital mortality were assessed in 233 consecutive patients with STEMI. Ninety-minute initial hospital door-to-patent infarct artery was achieved in 58.3% of paramedic-diagnosed and directly triaged patients compared with 37.5% of "walk-ins" to the PCI hospital and with only 5.2% of those transferred from another hospital emergency department (ED; p <0.001). Overall in-hospital mortality was 2.1%, 0% in paramedic identified patients, and 0% in those walk-ins to the PCI hospital ED compared with 4.3% for those transferred from a referring hospital ED (p = 0.007). Paramedic diagnosis of STEMI and direct triage to a prealerted interventional hospital for primary PCI was associated with a high percentage of patients achieving <90-minute infarct artery patency. Substantial delays remained for those who presented initially to a non-PCI hospital ED despite the expedited protocol. In conclusion, this observational study suggests that wider use of paramedic electrocardiographic STEMI diagnosis and direct triage to a prealerted PCI hospital catheterization team may help improve outcomes of patients with STEMI.