Pronounced Declines in Meperidine in the US: Is the End Imminent?

Background: Once a widely used analgesic in the United States (US), meperidine offered an alternative opioid to other opioids as a pain reliever and was widely assumed to be safer with acute pancreatitis. However, within the last two decades meperidine, has gone from a frequently used drug to being used only when patients exhibit atypical reactions to opioids (e.g., morphine and hydromorphone), to being taken off the World Health Organization List of Essential Medications and receiving strong recommendations for overall avoidance. The aim of this study was to identify changes in meperidine distribution in the US, and regional disparities as reported to the Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (DEA ARCOS) and Medicaid. Methods: Data related to meperidine distribution was obtained through ARCOS (2001−2021) and Medicaid public use files (2016−2021). Heat maps were used to visualize regional disparities in distribution by state. States outside a 95% confidence interval were statistically significant. Results: Meperidine distribution between 2001 and 2021 decreased by 97.4% (R = −0.97, p < 0.0001). There was a 34-fold state-level difference in meperidine distribution between Arkansas (16.8 mg/10 persons) and Connecticut (0.5 mg/10 persons) in 2020. Meperidine distribution in 2020 was elevated in Arkansas, Mississippi, and Alabama. In 2021, meperidine distribution was highest in Arkansas (16.7 mg/10 persons) and lowest in Connecticut (0.8 mg/10 persons). Total prescriptions of meperidine as reported by Medicaid decreased by 73.8% (R = −0.67, p = 0.045) between 2016 and 2021. Conclusion: We observed a decrease in the overall distribution of meperidine in the past two decades, with a similar recent decline in prescribing it to Medicaid enrollees. The shortage of some parenteral formulations is an important contributor to these declines, however, the most likely explanation for this global decline in use is related to an increased recognition of safety concerns related to important drug interactions and a neurotoxic metabolite. This data may reflect plans to phase out the use of this opioid, especially in the many situations where safer and more preferred opioids are available.

Declines and pronounced regional disparities in meperidine use in the United States.

There have been increasing concerns about adverse effects and drug interactions with meperidine. The goal of this study was to characterize meperidine use in the United States. Meperidine distribution data were obtained from the Drug Enforcement Administration's Automated of Reports and Consolidated Orders System. The Medicare Part D Prescriber Public Use File was utilized to capture overall trends in national prescriptions in this observational report. Nationally, meperidine distribution decreased by 94.6% from 2001 to 2019. In 2019, Arkansas, Alabama, Oklahoma, and Mississippi saw significantly greater distribution when compared with the US state average of 9.27 mg per 10 persons (SD = 6.82). Meperidine distribution showed an 18-fold difference between the highest state (Arkansas = 36.8 mg) and lowest state (Minnesota = 2.1 mg). Five of the six states with the lowest distribution were in the Northeast. Meperidine distribution per state was correlated with the prevalence of adult obesity (r(48) = +0.48, p < .001). Family medicine and internal medicine physicians accounted for 28.9% and 20.5%, respectively, of meperidine total daily supply (TDS) in 2017. Interventional pain management (5.66) and pain management (3.48) physicians accounted for the longest TDS per provider. The use of meperidine declined over the last two decades. Meperidine varied by geographic region with south-central states, and those with more obesity, showing greater distribution. Primary care doctors continue to account for the majority of meperidine daily supply. Increasing knowledge of meperidine's undesirable adverse effects like seizures and serious drug-drug interactions is likely responsible for these pronounced reductions.

Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1.

Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in establishing a telomere length set point remains elusive. Here, we characterize the contribution of the shorter isoform of TPP1 (TPP1S) and the amino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length control. We demonstrate that cells deficient for TPP1S (TPP1S knockout [KO]), as well as the complete TPP1 KO cell lines, undergo telomere shortening. However, TPP1S KO cells are able to stabilize short telomeres, while TPP1 KO cells die. We compare these phenotypes with those of TPP1L104A/L104A mutant cells, which have short and stable telomeres similar to the TPP1S KO. In contrast to TPP1S KO cells, TPP1L104A/L104A cells respond to increased telomerase levels and maintain protected telomeres. However, TPP1L104A/L104A shows altered sensitivity to expression changes of shelterin proteins suggesting the mutation causes a defect in telomere length feedback regulation. Together this highlights TPP1L104A/L104A as the first shelterin mutant engineered at the endogenous locus of human stem cells with an altered telomere length set point.

Dimerization quality control ensures neuronal development and survival.

Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains.

Cancer-associated TERT promoter mutations abrogate telomerase silencing.

Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells.

Smoking history predicts for increased risk of second primary lung cancer: a comprehensive analysis.

BACKGROUND: Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). METHODS: All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. RESULTS: A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P = .031]), corresponding to an 8% increased risk per 10 pack-year exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P = .069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. CONCLUSIONS: SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival.

Body mass index, dose to organs at risk during vaginal brachytherapy, and the role of three-dimensional CT-based treatment planning.

PURPOSE: To assess the effect of body mass index (BMI) on dose to organs at risk (OARs) during high-dose-rate vaginal brachytherapy and evaluate the role of three-dimensional dose evaluation during treatment planning. METHODS AND MATERIALS: Three-dimensional dosimetric data for rectum, bladder, sigmoid colon, and small bowel for 125 high-dose-rate vaginal brachytherapy fractions were analyzed. Dose-volume histograms were generated for D0.1 cc and D2 cc of each OAR. Contributing factors including the use of urinary catheter and cylinder size were also recorded. As different dose fractionations were used, the OAR doses were tabulated as a percent dose prescribed to 0.5cm. All patients were treated to 4cm of the vaginal length. RESULTS: Median BMI in this cohort was 31.7kg/m(2). The BMI values had a weak inverse correlation with D0.1 cc to sigmoid colon (rs=-0.18, p=0.047) and D0.1 cc to bladder (rs=-0.19, p=0.038). There was a strong inverse correlation of D2 cc and increasing BMI (rs=-0.64, p=0.003). The median D2 cc was 25.1% for BMI higher than 31 and 61.9% for BMI of 31 or lower. For D0.1 cc, there was also a strong inverse correlation with increasing BMI (rs=-0.57, p<0.001). Median D1 cc was 33.5% for BMI >31 and 84.4% for BMI ≤ 31. On multivariate analysis higher BMI remained a significant predictor of lower small bowel D2 cc (p<0.001) and D0.1 cc (p<0.001). CONCLUSIONS: Women with a lower BMI receive higher doses to the bladder and small bowel compared with those with a higher BMI. Three-dimensional dose evaluation should be considered in patients with low BMI, particularly when combined with external beam radiation.

Burden of allergic rhinitis: allergies in America, Latin America, and Asia-Pacific adult surveys.

Allergic rhinitis (AR; also nasal allergies or "hay fever") is a chronic upper airway inflammatory disease that affects ∼60 million adults and children in the United States. The duration and severity of AR symptoms contribute to a substantial burden on patients' quality of life (QoL), sleep, work productivity, and activity. This study was designed to examine symptoms, QoL, productivity, comorbidities, disease management, and pharmacologic treatment of AR in United States and ex-U.S. sufferers. Allergies in America was a comprehensive telephone-based survey of 2500 adults with AR. These data are compared and contrasted with findings from the Pediatric Allergies in America, Allergies in Latin America, and Allergies in Asia-Pacific telephone surveys. The prevalence of physician-diagnosed AR was 14% in U.S. adults, 7% in Latin America adults, and 9% in Asia-Pacific adults. Nasal congestion is the most common and bothersome symptom for adults. Approximately two-thirds of adults rely on medication to relieve intolerable AR symptoms. Incomplete relief, slow onset, <24-hour relief, and reduced efficacy with sustained use were commonly reported with AR medications, including intranasal corticosteroids. One in seven U.S. adults reported achieving little to no relief with AR medications. Bothersome adverse effects of AR medications included drowsiness, a drying feeling, medication dripping down the throat, and bad taste. Perception of inadequate efficacy was the leading cause of medication discontinuation or change and contributed to treatment dissatisfaction. These findings support the assertion that AR burden has been substantially underestimated and identify several important challenges to successful management of AR.

Nasal allergies in the Asian-Pacific population: results from the Allergies in Asia-Pacific Survey.

BACKGROUND: The Allergies in Asia-Pacific Survey describes the symptoms, impact, and treatment of allergic rhinitis (AR) across Australia, China, Hong Kong, Malaysia, Singapore, Taiwan, Vietnam, and the Philippines. The Allergies in Asia-Pacific Survey was undertaken to further clarify the prevalence of physician-diagnosed nasal allergies (NAs), impact on quality-of-life (QOL), existing treatment paradigms and gaps, and NA medications currently used in treatment. METHODS: Thirty-three thousand three hundred seventy-eight households were screened for individuals, ≥ 4 years old, with a physician diagnosis of AR or NA and either symptoms or treatment in the past 12 months. Standardized questionnaires were used to make comparisons across regions. A total of 1043 adults and 192 children were included in the survey. RESULTS: Nine percent of participants were diagnosed with AR with two of three responding that their NAs were seasonal in nature. Nasal congestion was the most common and bothersome symptom of AR. Most participants reported that AR impacted their QOL with nearly one-half citing impairments in school/work performance/productivity. Sleep disturbances, secondary to AR, were also shown to be appreciable. Two-thirds of patients took medication for their AR. Less than one-quarter of survey respondents reported taking an intranasal corticosteroid and the satisfaction rate was similar to that of over-the-counter medications. The most common reasons cited for dissatisfaction were related to inadequate efficacy and bothersome side effects. CONCLUSION: AR appears to be extremely common across Asia-Pacific nations. Many individuals with AR suffer from symptoms that reduce QOL and treatment gaps exist with current therapies. Through identification of disease impact and highlighting treatment gaps, clinicians may better understand and treat AR, leading to improvements in overall patient satisfaction and QOL.

Nasal allergies in the Asian-Pacific population: Results from the Allergies in Asia-Pacific Survey.

BACKGROUND: The Allergies in Asia-Pacific Survey describes the symptoms, impact, and treatment of allergic rhinitis (AR) across Australia, China, Hong Kong, Malaysia, Singapore, Taiwan, Vietnam, and the Philippines. The Allergies in Asia-Pacific Survey was undertaken to further clarify the prevalence of physician-diagnosed nasal allergies (NAs), impact on quality-of-life (QOL), existing treatment paradigms and gaps, and NA medications currently used in treatment. METHODS: Thirty-three thousand three hundred seventy-eight households were screened for individuals, ≥4 years old, with a physician diagnosis of AR or NA and either symptoms or treatment in the past 12 months. Standardized questionnaires were used to make comparisons across regions. A total of 1043 adults and 192 children were included in the survey. RESULTS: Nine percent of participants were diagnosed with AR with two of three responding that their NAs were seasonal in nature. Nasal congestion was the most common and bothersome symptom of AR. Most participants reported that AR impacted their QOL with nearly one-half citing impairments in school/work performance/productivity. Sleep disturbances, secondary to AR, were also shown to be appreciable. Two-thirds of patients took medication for their AR. Less than one-quarter of survey respondents reported taking an intranasal corticosteroid and the satisfaction rate was similar to that of over-the-counter medications. The most common reasons cited for dissatisfaction were related to inadequate efficacy and bothersome side effects. CONCLUSION: AR appears to be extremely common across Asia-Pacific nations. Many individuals with AR suffer from symptoms that reduce QOL and treatment gaps exist with current therapies. Through identification of disease impact and highlighting treatment gaps, clinicians may better understand and treat AR, leading to improvements in overall patient satisfaction and QOL.

The role of radiation therapy in uterine-confined endometrial carcinoma.

The treatment of endometrial cancer begins with surgery, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal lavage, and a consideration for lymph node evaluation. Selection of adjuvant therapy is based on an approximation of the risk of recurrence with features such as stage, tumor histology, lymphovascular space invasion, and patient age. The role of adjuvant radiation therapy in patients with intermediate risk of recurrence is a matter of ongoing controversy. Several randomized trials indicate that adjuvant radiation therapy improves loco-regional control. However, the ideal form of radiation therapy in these patients continues to be under debate.

Nasal allergies in the Latin American population: results from the Allergies in Latin America survey.

Allergies in Latin America is the first cross-national survey that describes the symptoms, impact, and treatment of nasal allergies (NAs) in individuals >or=4 years old in Latin America (LA). In total, 22,012 households across the Latin American countries of Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, and Venezuela were screened for children, adolescents, and adults with a diagnosis of NA and either symptoms or treatment in the past 12 months. A total of 1088 adults and 457 children and adolescents were included and the sample was probability based to ensure valid statistical inference to the population. Approximately 7% of the LA population was diagnosed with NAs with two of three respondents stating that their allergies were seasonal or intermittent in nature. A general practice physician or otolaryngologist diagnosed the majority of individuals surveyed. Nasal congestion was the most common and bothersome symptom of NAs. Sufferers indicated that their symptoms affected productivity and sleep and had a negative impact on quality of life. Two-thirds of patients reported taking some type of medication for their NAs, with a roughly equal percentage of patients reporting taking over-the-counter versus prescription medications. Changing medications was most commonly done in those reporting inadequate efficacy. The most common reasons cited for dissatisfaction with current medications were related to inadequate effectiveness, effectiveness wearing off with chronic use, failure to provide 24-hour relief, and bothersome side effects (e.g., unpleasant taste and retrograde drainage into the esophagus). Findings from this cross-national survey on NAs have confirmed a high prevalence of physician-diagnosed NAs and a considerable negative impact on daily quality of life and work productivity as well as substantial disease management challenges in LA. Through identification of disease impact on the LA population and further defining treatment gaps, clinicians in LA may better understand and treat NAs, thus leading to improvements in overall patient satisfaction and quality of life.

Implications of the growing use of wireless telephones for health care opinion polls.

OBJECTIVE: To assess the effect of wireless telephone substitution in a survey of health care reform opinions. DATA SOURCE: Survey of New Jersey adults conducted by landline and wireless telephones from June 1 to July 9, 2007. STUDY DESIGN: Eighty-one survey measures are compared by wireless status. Logistic regression is used to confirm landline-wireless gaps in support for coverage reforms, controlling for population differences. Weights adjust for selection probability, complex sample design, and demographic distributions. PRINCIPAL FINDINGS: Significant differences by wireless status were found in many survey measures. Wireless users were significantly more likely to favor coverage reforms. Higher support for government-sponsored universal coverage, income-related state coverage subsidies, and an individual mandate remain after adjustment for demographic variables. CONCLUSIONS: Opinion polls excluding wireless users are likely to understate support for coverage reforms.

Burden of allergic rhinitis: results from the Pediatric Allergies in America survey.

Allergic rhinitis (AR), a chronic inflammatory disease of the upper airway, is one of the most common chronic diseases in the United States and is estimated to affect up to 60 million people. Pediatric Allergies in America is the largest and most comprehensive survey to date of pediatric patients and parents of patients with allergy, as well as health care providers (HCPs), regarding AR in children and its treatment. The goals of the survey were to determine the prevalence of AR in the US pediatric population and to collect information on what effect the condition has on patients in terms of symptom burden, quality of life, productivity, disease management, and pharmacologic treatment. This national survey screened 35,757 households to identify 500 children with HCP-diagnosed nasal allergies and 504 children without nasal allergies who were between the ages of 4 and 17 years. Parents of young children, as well as children 10 to 17 years of age, were questioned about the condition and its treatment. In parallel, 501 HCPs were interviewed. This survey has captured previously unavailable data on the prevalence of nasal allergies and their most common and most bothersome symptoms, on the effect of nasal allergies on the quality of life of children, and on medication use, including both over-the-counter and prescription medications, and has identified factors affecting satisfaction with treatment. The Pediatric Allergies in America survey also identifies distinct areas for improvement in the management of AR in children. In fact, based on the results of this survey, it appears that HCPs overestimate patients' and parents' satisfaction with disease management and the benefit of medications used for the treatment of nasal allergies in children. Findings from this national survey have identified important challenges to the management of AR, suggesting that its burden on children in the United States has been significantly underestimated.

Patient and healthcare-provider perspectives on the burden of allergic rhinitis.

Allergic rhinitis (AR) is a chronic inflammatory disease characterized by nasal itching, sneezing, rhinorrhea, and nasal obstruction. Although the incidence of AR has been increasing, the reported prevalence of AR differs among surveys. Allergies in America was a comprehensive national survey that included 2500 adults diagnosed with AR and 400 healthcare practitioners who treat AR. Participants were interviewed about the burden of AR and comorbid conditions and the effect of AR on productivity and quality of life. Approximately 43% of nasal allergy sufferers reported that their nasal allergies were seasonal, and 56% indicated that their allergies were persistent throughout the year. Seasonal allergies were worse during the spring and fall, as reported by 56 and 45% of sufferers, respectively. Nasal congestion was ranked as the most common symptom experienced by patients daily or on most days during the worst month for nasal allergies. Patients and healthcare providers indicated that nasal congestion was the most bothersome symptom of AR. Asthma was diagnosed in 20% of patients with AR. Nasal allergy sufferers and healthcare providers indicated that nasal allergies affected productivity, led to missed workdays, and had a negative effect on patient quality of life. Patients and healthcare professionals report that symptoms of AR are bothersome. Effective treatment options for nasal symptoms of AR may decrease the burden of illness and improve patient productivity and quality of life.

The health status and quality of life of adults with X-linked agammaglobulinemia.

Forty-one adults (mean age 33) with a definitive diagnosis of X-linked agammaglobulinemia (XLA) completed a questionnaire concerning current and past medical problems and quality of life. Thirty-six of the 41 were working full time or were full time students; 18 had not missed any work or school due to infection in the previous year. Their quality of life was equivalent to that of the general US male population. Thirteen of the 41 reported that they had chronic lung disease, and 33 indicated that they had one or more episodes of sinusitis in the preceding year. Arthritis, diarrhea and skin infections were common but not debilitating. The 41 study subjects were more likely to have a prior family history of XLA, and they were more likely to have milder mutations in Btk, the gene responsible for XLA. These results indicate that most adults with XLA are moderately healthy and lead productive lives.

RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome.

RNA polymerase (pol) III synthesizes essential small RNAs, including tRNA and 5S rRNA. Wild-type p53 can repress pol III transcription both in vitro and in vivo. Many tumours carry substitutions in p53 which have selective effects on its functions. We identify tumour-derived mutations that compromise the ability of p53 to regulate pol III transcription. Furthermore, substitution R175H, the most common mutation in cancers, converts p53 from a repressor to an activator of pol III. Oncoproteins neutralize p53 in some tumours; we show that human papillomavirus E6 and cellular hdm2 can both release pol III from repression by p53. These data suggest that the restraining influence of p53 on pol III will be lost in many tumours. In addition to these features of sporadic cancers, some individuals inherit mutant forms of p53 and consequently suffer from Li-Fraumeni syndrome, showing genetic predisposition to certain malignancies. We find that pol III transcriptional activity is often highly elevated in primary fibroblasts from Li-Fraumeni patients, especially if the germline p53 mutation is followed by loss of the remaining allele. Our data suggest that p53 status can have a profound effect upon pol III transcription and hence on the biosynthetic capacity of cells.