The Centers for Disease Control and Prevention's 2022 Clinical Practice Guideline for Prescribing Opioids for Pain cautioned that inflexible opioid prescription duration limits may harm patients. ...Information about the relationship between initial opioid prescription duration and a subsequent refill could inform prescribing policies and practices to optimize patient outcomes. We assessed the association between initial opioid duration and an opioid refill prescription.
We conducted a retrospective cohort study of adults ≥19 years of age in 10 US health systems between 2013 and 2018 from outpatient care with a diagnosis for back pain without radiculopathy, back pain with radiculopathy, neck pain, joint pain, tendonitis/bursitis, mild musculoskeletal pain, severe musculoskeletal pain, urinary calculus, or headache. Generalized additive models were used to estimate the association between opioid days' supply and a refill prescription.
Overall, 220,797 patients were prescribed opioid analgesics upon an outpatient visit for pain. Nearly a quarter (23.5%) of the cohort received an opioid refill prescription during follow-up. The likelihood of a refill generally increased with initial duration for most pain diagnoses. About 1 to 3 fewer patients would receive a refill within 3 months for every 100 patients initially prescribed 3 vs. 7 days of opioids for most pain diagnoses. The lowest likelihood of refill was for a 1-day supply for all pain diagnoses, except for severe musculoskeletal pain (9 days' supply) and headache (3-4 days' supply).
Long-term prescription opioid use increased modestly with initial opioid prescription duration for most but not all pain diagnoses examined.
Background
In response to the opioid crisis in the United States, population-level prescribing of opioids has been decreasing; there are concerns, however, that dose reductions are related to ...potential adverse events.
Objective
Examine associations between opioid dose reductions and risk of 1-month potential adverse events (emergency department (ED) visits, opioid overdose, benzodiazepine prescription fill, all-cause mortality).
Design
This observational cohort study used electronic health record and claims data from eight United States health systems in a prescription opioid registry (Clinical Trials Network-0084). All opioid fills (excluding buprenorphine) between 1/1/2012 and 12/31/2018 were used to identify baseline periods with mean morphine milligram equivalents daily dose of ≥ 50 during six consecutive months.
Patients
We identified 60,040 non-cancer patients with ≥ one 2-month dose reduction period (600,234 unique dose reduction periods).
Main Measures
Analyses examined associations between dose reduction levels (1– < 15%, 15– < 30%, 30– < 100%, 100% over 2 months) and potential adverse events in the month following a dose reduction using logistic regression analysis, adjusting for patient characteristics.
Key Results
Overall, dose reduction periods involved mean reductions of 18.7%. Compared to reductions of 1– < 15%, dose reductions of 30– < 100% were associated with higher odds of ED visits (OR 1.14, 95% CI 1.10, 1.17), opioid overdose (OR 1.41, 95% CI 1.09–1.81), and all-cause mortality (OR 1.39, 95% CI 1.16–1.67), but lower odds of a benzodiazepine fill (OR 0.83, 95% CI 0.81–0.85). Dose reductions of 15– < 30%, compared to 1– < 15%, were associated with higher odds of ED visits (OR 1.08, 95% CI 1.05–1.11) and lower odds of a benzodiazepine fill (OR 0.93, 95% CI 0.92–0.95), but were not associated with opioid overdose and all-cause mortality.
Conclusions
Larger reductions for patients on opioid therapy may raise risk of potential adverse events in the month after reduction and should be carefully monitored.
Whereas only neurologists can "rule in" functional neurologic disorders (FNDs)-using physical signs and semiologic features-their role in follow-up care remains debated. We outlined the arguments for ...and against a neurologist's primary role in both assessing and managing FNDs. Favorable arguments include the following: (1) FND presents neurologically, and thus, only neurologists can ascertain the etiology of new neurologic deficits appearing on follow-up, and (2) neurologic encounters facilitate acceptance of diagnosis and enhance treatment engagement. Counter arguments include the following: (1) FND is a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition codified psychiatric disorder with largely psychiatric treatments, and (2) neurologists can reassess patients if new neurologic symptoms develop without playing a primary follow-up role. Although more research is needed to clarify optimal approaches, neurologic expertise could be leveraged for diagnostic and coordinating roles if the pool of neurologists, psychiatrists, psychotherapists, physical and occupational therapists, and other allied clinicians trained in the interdisciplinary care of FNDs is substantially increased.
Develop and implement a prescription opioid registry in 10 diverse health systems across the US and describe trends in prescribed opioids between 2012 and 2018.
Using electronic health record and ...claims data, we identified patients who had an outpatient fill for any prescription opioid, and/or an opioid use disorder diagnosis, between January 1, 2012 and December 31, 2018. The registry contains distributed files of prescription opioids, benzodiazepines and other select medications, opioid antagonists, clinical diagnoses, procedures, health services utilization, and health plan membership. Rates of outpatient opioid fills over the study period, standardized to health system demographic distributions, are described by age, gender, and race/ethnicity among members without cancer.
The registry includes 6 249 710 patients and over 40 million outpatient opioid fills. For the combined registry population, opioid fills declined from a high of 0.718 per member-year in 2013 to 0.478 in 2018, and morphine milligram equivalents (MMEs) per fill declined from 985 MMEs per fill in 2012 to 758 MMEs in 2018. MMEs per member declined from 692 MMEs per member in 2012 to 362 MMEs per member in 2018.
This study established a population-based opioid registry across 10 diverse health systems that can be used to address questions related to opioid use. Initial analyses showed large reductions in overall opioid use per member among the combined health systems. The registry will be used in future studies to answer a broad range of other critical public health issues relating to prescription opioid use.
Objectives
The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data ...quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research.
Methods
Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use.
Results
The NINDS Mito CDEs and supporting documents are publicly available on the NINDS CDE website (
https://commondataelements.ninds.nih.gov/
), organized into domain categories such as Participant/Subject Characteristics, Assessments, and Examinations.
Conclusion
We developed a comprehensive set of CDE recommendations, data definitions, case report forms (CRFs), and guidelines for use in Mito clinical research. The widespread use of CDEs is intended to enhance Mito clinical research endeavors, including natural history studies, clinical trial design, and data sharing. Ongoing international collaboration will facilitate regular review, updates and online publication of Mito CDEs, and support improved consistency of data collection and reporting.
Continuous glucose monitoring (CGM) parameters may identify individuals at risk for progression to overt type 1 diabetes. We aimed to determine whether CGM metrics provide additional insights into ...progression to clinical stage 3 type 1 diabetes.
One hundred five relatives of individuals in type 1 diabetes probands (median age 16.8 years; 89% non-Hispanic White; 43.8% female) from the TrialNet Pathway to Prevention study underwent 7-day CGM assessments and oral glucose tolerance tests (OGTTs) at 6-month intervals. The baseline data are reported here. Three groups were evaluated: individuals with 1) stage 2 type 1 diabetes (n = 42) with two or more diabetes-related autoantibodies and abnormal OGTT; 2) stage 1 type 1 diabetes (n = 53) with two or more diabetes-related autoantibodies and normal OGTT; and 3) negative test for all diabetes-related autoantibodies and normal OGTT (n = 10).
Multiple CGM metrics were associated with progression to stage 3 type 1 diabetes. Specifically, spending ≥5% time with glucose levels ≥140 mg/dL (P = 0.01), ≥8% time with glucose levels ≥140 mg/dL (P = 0.02), ≥5% time with glucose levels ≥160 mg/dL (P = 0.0001), and ≥8% time with glucose levels ≥160 mg/dL (P = 0.02) were all associated with progression to stage 3 disease. Stage 2 participants and those who progressed to stage 3 also exhibited higher mean daytime glucose values; spent more time with glucose values over 120, 140, and 160 mg/dL; and had greater variability.
CGM could aid in the identification of individuals, including those with a normal OGTT, who are likely to rapidly progress to stage 3 type 1 diabetes.
Regulation of translation initiation is well appropriate to adapt cell growth in response to stress and environmental changes. Many bacterial mRNAs adopt structures in their 5' untranslated regions ...that modulate the accessibility of the 30S ribosomal subunit. Structured mRNAs interact with the 30S in a two-step process where the docking of a folded mRNA precedes an accommodation step. Here, we used a combination of experimental approaches in vitro (kinetic of mRNA unfolding and binding experiments to analyze mRNA-protein or mRNA-ribosome complexes, toeprinting assays to follow the formation of ribosomal initiation complexes) and in vivo (genetic) to monitor the action of ribosomal protein S1 on the initiation of structured and regulated mRNAs. We demonstrate that r-protein S1 endows the 30S with an RNA chaperone activity that is essential for the docking and the unfolding of structured mRNAs, and for the correct positioning of the initiation codon inside the decoding channel. The first three OB-fold domains of S1 retain all its activities (mRNA and 30S binding, RNA melting activity) on the 30S subunit. S1 is not required for all mRNAs and acts differently on mRNAs according to the signals present at their 5' ends. This work shows that S1 confers to the ribosome dynamic properties to initiate translation of a large set of mRNAs with diverse structural features.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
In plants, autophagy has been assigned ‘pro‐death’ and ‘pro‐survival’ roles in controlling programmed cell death associated with microbial effector‐triggered immunity. The role of autophagy ...in basal immunity to virulent pathogens has not been addressed systematically, however. Using several autophagy‐deficient (atg) genotypes, we determined the function of autophagy in basal plant immunity. Arabidopsis mutants lacking ATG5, ATG10 and ATG18a develop spreading necrosis upon infection with the necrotrophic fungal pathogen, Alternaria brassicicola, which is accompanied by the production of reactive oxygen intermediates and by enhanced hyphal growth. Likewise, treatment with the fungal toxin fumonisin B1 causes spreading lesion formation in atg mutant genotypes. We suggest that autophagy constitutes a ‘pro‐survival’ mechanism that controls the containment of host tissue‐destructive microbial infections. In contrast, atg plants do not show spreading necrosis, but exhibit marked resistance against the virulent biotrophic phytopathogen, Pseudomonas syringae pv. tomato. Inducible defenses associated with basal plant immunity, such as callose production or mitogen‐activated protein kinase activation, were unaltered in atg genotypes. However, phytohormone analysis revealed that salicylic acid (SA) levels in non‐infected and bacteria‐infected atg plants were slightly higher than those in Col‐0 plants, and were accompanied by elevated SA‐dependent gene expression and camalexin production. This suggests that previously undetected moderate infection‐induced rises in SA result in measurably enhanced bacterial resistance, and that autophagy negatively controls SA‐dependent defenses and basal immunity to bacterial infection. We infer that the way in which autophagy contributes to plant immunity to different pathogens is mechanistically diverse, and thus resembles the complex role of this process in animal innate immunity.
Most natural history models for type 1 diabetes (T1D) propose that overt hyperglycemia results after a progressive loss of insulin-secreting β-cell mass and/or function. To experimentally address ...this concept, we prospectively determined morning blood glucose measurements every other day in multiple cohorts (total n = 660) of female NOD/ShiLtJ mice starting at 8 weeks of age until diabetes onset or 26 weeks of age. Consistent with this notion, a majority of mice that developed diabetes (354 of 489 72%) displayed a progressive increase in blood glucose with transient excursions >200 mg/dL, followed by acute and persistent hyperglycemia at diabetes onset. However, 135 of the 489 (28%) diabetic animals demonstrated normal glucose values followed by acute (i.e., sudden) hyperglycemia. Interestingly, diabetes onset occurred earlier in mice with acute versus progressive disease onset (15.37 ± 0.3207 vs. 17.44 ± 0.2073 weeks of age, P < 0.0001). Moreover, the pattern of onset (i.e., progressive vs. acute) dramatically influenced the ability to achieve reversal of T1D by immunotherapeutic intervention, with increased effectiveness observed in situations of a progressive deterioration in euglycemia. These studies highlight a novel natural history aspect in this animal model, one that may provide important guidance for the selection of subjects participating in human trials seeking disease reversal.
Cognitive behavioral therapy for chronic pain (CBT-CP) is an effective but underused treatment for high-impact chronic pain. Increased access to CBT-CP services for pain is of critical public health ...importance, particularly for rural and medically underserved populations who have limited access due to these services being concentrated in urban and high income areas. Making CBT-CP widely available and more affordable could reduce barriers to CBT-CP use.
As part of the National Institutes of Health Helping to End Addiction Long-term® (NIH HEAL) initiative, we designed and implemented a comparative effectiveness, 3-arm randomized control trial comparing remotely delivered telephonic/video and online CBT-CP-based services to usual care for patients with high-impact chronic pain. The RESOLVE trial is being conducted in 4 large integrated healthcare systems located in Minnesota, Georgia, Oregon, and Washington state and includes demographically diverse populations residing in urban and rural areas. The trial compares (1) an 8-session, one-on-one, professionally delivered telephonic/video CBT-CP program; and (2) a previously developed and tested 8-session online CBT-CP-based program (painTRAINER) to (3) usual care augmented by a written guide for chronic pain management. Participants are followed for 1 year post-allocation and are assessed at baseline, and 3, 6, and 12 months post-allocation. The primary outcome is minimal clinically important difference (MCID; ≥ 30% reduction) in pain severity (composite of pain intensity and pain-related interference) assessed by a modified 11-item version of the Brief Pain Inventory-Short Form at 3 months. Secondary outcomes include pain severity, pain intensity, and pain-related interference scores, quality of life measures, and patient global impression of change at 3, 6, and 12 months. Cost-effectiveness is assessed by incremental cost per additional patient with MCID in primary outcome and by cost per quality-adjusted life year achieved. Outcome assessment is blinded to group assignment.
This large-scale trial provides a unique opportunity to rigorously evaluate and compare the clinical and cost-effectiveness of 2 relatively low-cost and scalable modalities for providing CBT-CP-based treatments to persons with high-impact chronic pain, including those residing in rural and other medically underserved areas with limited access to these services.
ClinicalTrials.gov NCT04523714. This trial was registered on 24 August 2020.
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