Decoding the κ Opioid Receptor (KOR): Advancements in Structural Understanding and Implications for Opioid Analgesic Development.

The opioid crisis in the United States is a significant public health issue, with a nearly threefold increase in opioid-related fatalities between 1999 and 2014. In response to this crisis, society has made numerous efforts to mitigate its impact. Recent advancements in understanding the structural intricacies of the κ opioid receptor (KOR) have improved our knowledge of how opioids interact with their receptors, triggering downstream signaling pathways that lead to pain relief. This review concentrates on the KOR, offering crucial structural insights into the binding mechanisms of both agonists and antagonists to the receptor. Through comparative analysis of the atomic details of the binding site, distinct interactions specific to agonists and antagonists have been identified. These insights not only enhance our understanding of ligand binding mechanisms but also shed light on potential pathways for developing new opioid analgesics with an improved risk-benefit profile.

Predicting long-term survival after de novo cardioverter-defibrillator implantation for primary prevention: A population based study.

Background: Implantable cardioverter-defibrillators (ICDs) reduce the risk of sudden cardiac death in patients with left ventricular dysfunction. While short-term mortality benefit of ICD insertion has been established in landmark randomized controlled trials, little is known about the long-term outcomes of patients with ICDs in clinical practice. In this paper, we describe the long-term survival of patients following de novo ICD implantation for primary prevention in clinical practice and determine the factors which help predict survival after ICD implant. Methods: Retrospective population-based study of all patients receiving a de novo ICD for primary prevention in Ontario, Canada from 2007 to 2011 using the Ontario ICD Database housed within ICES. Simple random selection was used to split the population into a derivation and internal validation cohort in a ratio of 2:1. Cox proportional hazards regression was used to determine predictors of interest and predict 10-year survival, model performance was assessed using calibration and validation. Results: In the derivation cohort (n = 3399), mean age was 65.3 years (standard deviation [SD] = 11.0), 664 patients were female (19.5 %) and 2344 patients (69.0 %) had ischemic cardiomyopathy. Ten year survival was 45.7 % (95 % confidence interval [CI] 44.0 %-47.4 %). The final prediction model included age, sex, disease factors (ischemic vs nonischemic cardiomyopathy, left ventricular ejection fraction) and patient factors (symptoms, comorbidities), and biomarkers at the time of ICD assessment. This model had good discrimination and calibration in derivation (0.79, 95 % CI 0.77, 0.81) and validation samples (0.78, 95 % CI 0.76, 0.79). Conclusions: A combination of demographic and clinical factors determined at baseline can be used to predict 10-year survival in patients with implantable cardioverter-defibrillators with good accuracy. Our findings help to identify individuals at risk of long-term mortality and may be useful in targeting future prevention strategies to enhance longevity in this high-risk population.

Decreasing ICU and Hospital Length of Stay through a Standardized Respiratory Therapist-driven Electronic Clinical Care Pathway for Status Asthmaticus.

Introduction: Status asthmaticus (SA) is a cause of many pediatric hospitalizations. This study sought to evaluate how a standardized asthma care pathway (ACP) in the electronic medical record impacted the length of stay (LOS). Methods: An interdisciplinary team internally validated a standardized respiratory score for patients admitted with SA to a 25-bed pediatric intensive care unit (PICU) at a tertiary children's hospital. The respiratory score determined weaning schedules for albuterol and steroid therapies. In addition, pharmacy and information technology staff developed an electronic ACP within our electronic medical record system using best practice alerts. These best practice alerts informed staff to initiate the pathway, wean/escalate treatment, transition to oral steroids, transfer level of care, and complete discharge education. The PICU, stepdown ICU (SD ICU), and acute care units implemented the clinical pathway. Pre- and postintervention metrics were assessed using process control charts and compared using Welch's t tests with a significance level of 0.05. Results: Nine hundred two consecutive patients were analyzed (598 preintervention, 304 postintervention). Order set utilization significantly increased from 68% to 97% (P < 0.001), PICU LOS decreased from 38.4 to 31.1 hours (P = 0.013), and stepdown ICU LOS decreased from 25.7 to 20.9 hours (P = 0.01). Hospital LOS decreased from 59.5 to 50.7 hours (P = 0.003), with cost savings of $1,215,088 for the patient cohort. Conclusions: Implementing a standardized respiratory therapist-driven ACP for children with SA led to significantly increased order set utilization and decreased ICU and hospital LOS. Leveraging information technology and standardized pathways may improve care quality, outcomes, and costs for other common diagnoses.

Real-world treatment patterns and clinical outcomes with first-line therapy in patients with locally advanced/metastatic urothelial carcinoma by cisplatin-eligibility.

INTRODUCTION: Patients with locally advanced/metastatic urothelial carcinoma (la/mUC) have a poor prognosis. With recent therapeutic advances, data on real-world treatment patterns and overall survival (OS) in patients with la/mUC treated with first-line therapy are limited, particularly when comparing patients who are cisplatin-ineligible versus cisplatin-eligible. METHODS: This was a retrospective observational study of real-world first-line treatment patterns and OS in patients with la/mUC stratified by cisplatin-eligibility and treatment. Data were from a nationwide electronic health record-derived de-identified database. Eligible patients were adults diagnosed with la/mUC from May 2016 to April 2021 and followed until death or end of data availability in January 2022. OS stratified by first-line treatment and cisplatin eligibility was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. RESULTS: Of 4,757 patients with la/mUC, 3,632 (76.4%) received first-line treatment, with 2,029 (55.9%) cisplatin-ineligible and 1,603 (44.1%) cisplatin-eligible. Patients who were cisplatin-ineligible were older (mean age, 74.9 vs. 68.8 years) and had lower CrCl (median, 46.4 vs. 87.0 ml/min). Only 43.8% of patients receiving first-line treatment (37.6% cisplatin-ineligible vs. 51.6% cisplatin-eligible) received second-line therapy. Median OS in all patients receiving first-line treatment was 10.8 (95% CI, 10.2-11.3) months and was shorter in patients who were cisplatin-ineligible than cisplatin-eligible (8.5 [95% CI, 7.8-9.0] vs. 14.4 [13.3-16.1]; hazard ratio [HR], 0.9 [0.7-1.1]). Cisplatin-based therapy was associated with longer OS (17.6 [15.1-20.4] months) than other first-line treatments (the shortest OS was with PD-1/L1 inhibitor monotherapy; 7.7 [6.8-8.8] months), including among patients who were classified as cisplatin-ineligible. CONCLUSIONS: Outcomes for patients with newly diagnosed la/mUC are poor, particularly for patients who are cisplatin-ineligible and/or do not receive cisplatin-based therapy. Many patients with la/mUC did not receive first-line treatment and among those who did, fewer than half received second-line therapy. These data highlight the need for more effective first-line therapies for all patients with la/mUC.

Methylnaltrexone for Opioid-Induced Dysmotility in Critically Ill Infants and Children: A Pilot Study.

OBJECTIVE: Critically ill pediatric patients commonly experience opioid-induced dysmotility. Methylnaltrexone, a subcutaneously administered, peripherally acting mu-opioid receptor antagonist, is a compelling adjunct to enteral laxatives in patients with opioid-induced dysmotility. Data for methylnaltrexone use in critically ill pediatric patients are limited. The purpose of this study was to determine the effectiveness and safety of methylnaltrexone for opioid-induced dysmotility in critically ill infants and children. METHODS: Patients younger than 18 years who received subcutaneous methylnaltrexone from January 1, 2013, through September 15, 2020, in the pediatric intensive care units at an academic institution were included in this retrospective analysis. Outcomes included incidence of bowel movement, enteral nutrition feeding volume, and adverse drug events. RESULTS: Twenty-four patients, median age 3.5 years (IQR, 0.58-11.1), received 72 methylnaltrexone doses. The median dose was 0.15 mg/kg (IQR, 0.15-0.15). Patients were receiving a mean ± SD of 7.5 ± 4.5 mg/kg/day of oral morphine milligram equivalents (MMEs) at methylnaltrexone administration and received opioids for median 13 days (IQR, 8.8-21) prior to methylnaltrexone administration. A bowel movement occurred within 4 hours following 43 (60%) administrations and within 24 hours following 58 (81%) administrations. Enteral nutrition volume increased by 81% (p = 0.002) following administration. Three patients had emesis and 2 received anti-nausea medication. No significant changes in sedation or pain scores were observed. Withdrawal scores and daily oral MMEs decreased following administration (p = 0.008 and p = 0.002, respectively). CONCLUSIONS: Methylnaltrexone may be an effective treatment for opioid-induced dysmotility in critically ill pediatric patients with low risk of adverse effects.

Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor.

The United States is experiencing the most profound and devastating opioid crisis in history, with the number of deaths involving opioids, including prescription and illegal opioids, continuing to climb over the past two decades. This severe public health issue is difficult to combat as opioids remain a crucial treatment for pain, and at the same time, they are also highly addictive. Opioids act on the opioid receptor, which in turn activates its downstream signaling pathway that eventually leads to an analgesic effect. Among the four types of opioid receptors, the µ subtype is primarily responsible for the analgesic cascade. This review describes available 3D structures of the µ opioid receptor in the protein data bank and provides structural insights for the binding of agonists and antagonists to the receptor. Comparative analysis on the atomic details of the binding site in these structures was conducted and distinct binding interactions for agonists, partial agonists, and antagonists were observed. The findings in this article deepen our understanding of the ligand binding activity and shed some light on the development of novel opioid analgesics which may improve the risk benefit balance of existing opioids.

Women and Alcohol: Limitations in the Cardiovascular Guidelines.

Patients and physicians rely on evidence-based guidelines to guide alcohol consumption recommendations, but significant discrepancies in alcohol consumption limits are found between different international societies. Current American Heart Association (AHA) preventive management guidelines on hypertension, transient ischemic attack, stroke, and stable ischemic heart disease recommend sex-specific daily alcohol consumption limits which are inconsistent from other international society recommendations. In this focused review of current American Heart Association guidelines and their sources, we evaluate the evidence behind sex-specific alcohol consumption cut-offs. We found insufficient experimental and epidemiologic evidence to conclude that women should have a reduced daily alcohol consumption limit as compared to men; further studies are required to determine whether sex-specific differences exist in alcohol metabolism and its related cardiovascular impact.

Disseminated Lyme disease and dilated cardiomyopathy: A systematic review.

Lyme carditis is a well-established manifestation of early disseminated Lyme infection, yet the relationship between late disseminated Lyme disease and the development of dilated cardiomyopathy (DCM) remains unclear. The present systematic review aims to summarize existing literature on the association between late disseminated Lyme disease and DCM. A systematic review was conducted in PubMed, Embase, CENTRAL, and MEDLINE databases, after which a total of 11 observational studies (n = 771) were ultimately included for final data extraction. Although most studies (7/11) identified evidence associating Borrelia-infection with DCM, further research is required to isolate late disseminated Borrelia infection as a causative agent of DCM.

ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

Treatment with opioids in patients with locally advanced or metastatic urothelial carcinoma and matched non-cancer controls.

BACKGROUND: Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive disease with a poor long-term survival. While patients frequently report pain, there are limited data on the patient experience with pain and pain medication use. This study used real-world data to quantify treatment with opioids, as a proxy for pain, in patients with la/mUC compared with matched non-cancer controls. METHODS: This was a retrospective claims analysis, using the IBM® MarketScan® databases, of adults diagnosed with urothelial carcinoma and initiating ≥1 la/mUC therapy between May 2016 and June 2019. Index date was date of first systemic therapy claim for la/mUC; baseline was the 6 months pre-index; follow-up was from index until disenrollment or study end. Proportion with treatment with opioids, number of opioid prescriptions, and daily morphine-equivalent dose (MEQ; in morphine milligram equivalents/day) in patients with la/mUC and matched non-cancer controls from the same databases were assessed. RESULTS: We identified 1293 patients with la/mUC and matched 1:3 with 3862 non-cancer controls. Mean (SD) follow-up was 1.26 (0.74) years in patients with la/mUC and 1.29 (0.72) years in controls. A greater proportion of patients with la/mUC, compared with controls, used opioids during both baseline (63.6% vs. 19.4%) and follow-up (61.4% vs. 27.9%). Among those who used opioids, mean monthly prescriptions (number of medications claims/patient/month) were 0.55 both in patients with la/mUC and controls during baseline, and 0.49 and 0.39, respectively, at follow-up. Daily MEQ among those who used opioids was 53.6 and 45.7 during baseline, and 74.7 and 40.8 at follow-up, in patients with la/mUC and controls, respectively. In patients with la/mUC, mean opioid prescriptions and daily MEQ increased during later lines of therapy. CONCLUSION: In patients with la/mUC, pain requiring opioids is common at diagnosis, worsens as the patient progresses, and is consistently higher than in matched controls. Improvement in disease control with more effective therapies may reduce cancer pain in this population.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Pacemaker Explantation in Patients With Lyme Carditis.

Early recognition of Lyme carditis is critical to preventing unnecessary pacemaker implantation for conduction abnormalities associated with this tick-born infection. Patients who do receive a pacemaker should be considered for device extraction after the completion of their antibiotic therapy if they recover normal atrioventricular node conduction. (Level of Difficulty: Intermediate.).

Prediction of Sudden Cardiac Arrest in the General Population: Review of Traditional and Emerging Risk Factors.

Sudden cardiac death (SCD) is the most common and devastating outcome of sudden cardiac arrest (SCA), defined as an abrupt and unexpected cessation of cardiovascular function leading to circulatory collapse. The incidence of SCD is relatively infrequent for individuals in the general population, in the range of 0.03%-0.10% per year. Yet, the absolute number of cases around the world is high because of the sheer size of the population at risk, making SCA/SCD a major global health issue. On the basis of conservative estimates, there are at least 2 million cases of SCA occurring worldwide on a yearly basis. As such, identification of risk factors associated with SCA in the general population is an important objective from a clinical and public health standpoint. This review will provide an in-depth discussion of established and emerging factors predictive of SCA/SCD in the general population beyond coronary artery disease and impaired left ventricular ejection fraction. Contemporary studies on the association of age, sex, race, socioeconomic status, and the emerging contribution of diabetes and obesity to SCD risk beyond their role as atherosclerotic risk factors are reviewed. In addition, the role of biomarkers, particularly electrocardiographic ones, on SCA/SCD risk prediction in the general population are discussed. Finally, the use of machine learning as a tool to facilitate SCA/SCD risk prediction is examined.

Long-term Outcomes in Treated Lyme Carditis.

Lyme disease is the most reported tick-borne illness in North America. Lyme carditis (LC) is an early-disseminated manifestation of Lyme disease, most commonly presenting as symptomatic high-degree atrioventricular block (AVB) which resolves with appropriate antibiotic therapy. However, long-term outcomes of treated LC have not previously been described. We present a series of 7 patients (median 28 years, 6 male) with serologically confirmed LC treated with a standard protocol developed at our center including antibiotics and pre-discharge stress test to assess AV node stability. At a mean follow-up of 20.8 months, all patients were asymptomatic, had resumed normal activities, and were free of conduction abnormalities. None required permanent pacing. Our study supports avoidance of permanent pacing for LC if conduction is stable at discharge.

Resolution of Coronavirus Disease 2019 Infection and Pulmonary Pathology With Nebulized DAS181: A Pilot Study.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 infections commonly lead to respiratory failure and potentially fatal systemic inflammation and organ failure. Nebulized DAS181, a host-directed biologics with sialidase activity, is an investigational drug with antiviral activities on parainfluenza and influenza under phase 3 and phase 2 development. The objective of this study (NCT04324489) is to investigate the safety and effects of nebulized DAS181 on hypoxic coronavirus disease 2019 patients. DESIGN: Single-center, prospective, open-label, compassionate use. SETTING: Renmin Hospital of Wuhan University, Department of Respiratory and Critical Care Medicine and Department of Infectious Diseases. SUBJECTS: Patients 18 to 70 years old who met Chinese criteria for severe coronavirus disease 2019 pneumonia and required supplemental oxygen but not on mechanical ventilator at screening. INTERVENTIONS: Nebulized DAS181 (4.5 mg) twice a day for 10 days. MEASUREMENTS AND MAIN RESULTS: Three male coronavirus disease 2019 hypoxic patients with bilateral lung involvement completed DAS181 treatment for 10 days. By day 14, all achieved return to room air (primary endpoint) and their nasopharyngeal swabs were negative for severe acute respiratory syndrome coronavirus 2. Clinical severity improved from severe coronavirus disease 2019 at baseline to moderate or mild disease by day 5, consistent with rapid reduction of inflammatory cytokines by days 2-3 and radiologic improvement by days 5-10. No DAS181-related adverse events were reported. CONCLUSIONS: Inhalation of DAS181 was well tolerated and potential clinical benefit of DAS181 on hypoxic coronavirus disease 2019 is the reduction of supplemental oxygen need. Efficacy and safety, including pharmacokinetics and viral studies of DAS181 in severe, hypoxic coronavirus disease 2019, should be examined by a double-blind, randomized controlled study.

Glycemic control in youth-onset type 2 diabetes correlates with weight loss.

OBJECTIVE: To identify risk factors for glycemic failure in youth with type 2 diabetes (T2D). METHODS: A retrospective review of HbA1c, anthropomorphic measures, medication records, and laboratory studies was performed using registry data from a dedicated pediatric T2D clinic. Latent profile analysis (LPA) was performed to model longitudinal trajectory of HbA1c over 5 years. RESULTS: The registry includes 229 youth with T2D, of whom 80% self-identify as Latinx. The odds ratio (OR) for uncontrolled diabetes 5 years after diagnosis correlated with diagnostic HbA1c, with OR of 2.41 if HbA1c at diagnosis >8.5% (sensitivity 68%, specificity 54%, P = .015). LPA modeling identified three HbA1c profiles: (a) mean HbA1c <8% throughout the 5 years, (b) persistent elevation of mean HbA1c >9%, and (c) mean HbA1c of 12% at diagnosis, rapid decline to 6.4% by 4 to 6 months, and increase to 11% by 18 months. Our analysis of medication regimen showed that, amongst patients treated with metformin, the addition of multiple daily injections (MDI) did not improve HbA1c compared to those on basal insulin. Finally, weight loss over the 1 year after diagnosis correlated with improvement in HbA1c in both subjects prescribed metformin monotherapy, as well as insulin-containing regimen. CONCLUSION: Youth with T2D exhibit distinct HbA1c profiles. Patients with diagnostic HbA1c >8.5% are at high risk for glycemic failure, irrespective of short-term improvement in HbA1c. Weight management has the potential to improve short-term HbA1c outcome in youth with T2D. Additional studies are needed to determine the role of medication adherence on glycemic control.

Simulation across representation: The interplay of schemas and simulation-based inference on different levels of abstraction.

Language comprehension of action verbs recruits embodied representations in the brain that are assumed to invoke a mental simulation (e.g., "grasping a peanut"). This extends to abstract concepts, as well ("grasping an idea"). We, therefore, argue that mental simulation works across levels of abstractness and involves higher-level schematic structures that subsume a generic structure of actions and events.

Does It work in Clinical Practice? A Comparison of Colonoscopy Cleansing Effectiveness in Clinical Practice Versus Efficacy from Selected Prospective Trials.

BACKGROUND: Adequate bowel preparation is essential for a high-quality colonoscopy. Many randomized controlled trials (RCTs) have investigated bowel preparation protocols, including split-dose and low-volume regimens. However, RCTs are conducted in an ideal, controlled setting, and translation of trial results to clinical practice is challenging. In this study, we compared the quality of bowel preparations of real-world patients from clinical practice with those enrolled in several prospective trials. METHODS: Bowel preparation quality, defined by the Ottawa Bowel Preparation Scale (OBPS), from four RCTs and one prospective trial were compared with two observational diary studies. Bowel preparations were polyethylene glycol preparation (PEG) or sodium picosulfate plus magnesium citrate (P/MC) taken via traditional or split-dose timing regimen. Age, sex, average number of bowel movements per day, comorbidities, colonoscopy indication and colonoscopy completion rates were also collected. RESULTS: Patients enrolled in prospective trials had a better OBPS by one point when compared with those in observational clinical practice studies (P<0.049), after controlling for age, sex, colonoscopy indication and type of bowel preparation used. We also found that each 10-year increase in age was associated with a 0.2 point increase in OBPS (P=0.008), and men were associated with a 0.5 increase in OBPS when compared with women P=0.014). CONCLUSION: Patients from clinical practice have higher OBPS than prospective trial patients. Increased age and male sex were also associated with increased OBPS. We believe increased patient motivation and education around bowel preparation regimen plays an important role in the success of bowel preparations.

Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T.

Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.