Patterns of Comorbidities and Prescribing and Dispensing of Non-steroidal Anti-inflammatory Drugs (NSAIDs) Among Patients with Osteoarthritis in the USA: Real-World Study.

BACKGROUND: Osteoarthritis (OA) is a major cause of chronic pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesics commonly used for musculoskeletal pain; however, NSAIDs can increase the risk of certain adverse events, such as gastrointestinal bleeding, edema, heart failure, and hypertension. OBJECTIVE: The objective of this study was to characterize existing comorbidities among patients with OA. For patients with OA with and without a coexisting medical condition of interest (CMCOI), we estimated the prevalence of prescribing and dispensing NSAIDs pre-OA and post-OA diagnosis. METHODS: Data from three large administrative claims databases were used to construct an OA retrospective cohort. Databases leveraged were IBM MarketScan Medicare Supplemental Database (MDCR), IBM MarketScan Commercial Database (CCAE), and Optum's de-identified Clinformatics® Data Mart Database (Optum CDM). The OA study population was defined to be those patients who had an OA diagnosis from an inpatient or outpatient visit with at least 365 days of prior observation time in the database during January 2000 through May 2021. Asthma, cardiovascular disorders, renal impairment, and gastrointestinal bleeding risks were the CMCOI of interest. Patients with OA were then classified as having or not having evidence of a CMCOI. For both groups, NSAID dispensing patterns pre-OA and post-OA diagnosis were identified. Descriptive analysis was performed within the Observational Health Data Sciences and Informatics framework. RESULTS: In each database, the proportion of the OA population with at least one CMCOI was nearly 50% or more (48.0% CCAE; 74.4% MDCR; 68.6% Optum CDM). Cardiovascular disease was the most commonly observed CMCOI in each database, and in two databases, nearly one in four patients with OA had two or more CMCOI (23.2% MDCR; 22.6% Optum CDM). Among the OA population with CMCOI, NSAID utilization post-OA diagnosis ranged from 33.0 to 46.2%. Following diagnosis of OA, an increase in the prescribing and dispensing of NSAIDs was observed in all databases, regardless of patient CMCOI presence. CONCLUSIONS: This study provides real-world evidence of the pattern of prescribing and dispensing of NSAIDs among patients with OA with and without CMCOI, which indicates that at least half of patients with OA in the USA have a coexisting condition. These conditions may increase the risk of side effects commonly associated with NSAIDs. Yet, at least 32% of these patients were prescribed and dispensed NSAIDs. These data support the importance of shared decision making between healthcare professionals and patients when considering NSAIDs for the treatment of OA in patients with NSAID-relevant coexisting medical conditions.

Establishing and Maintaining Trust: How the U.S. Preventive Services Task Force Uses Strategic Communications to Build Confidence in and Disseminate Its Evidence-Based Recommendations.

In an era of conflicting health guidance and misinformation, the need for evidence-based recommendations-and clear communication about them-is critical. This paper examines the ways in which strategic communications support for the United States Preventive Services Task Force (Task Force) helps to fulfill its mission to improve the health of all people nationwide through evidence-based preventive services recommendations. This paper describes communications challenges specific to the Task Force and how its strategic communications approach helps to address them. To exemplify the Task Force's process for developing recommendations and how it achieves impact, this paper provides two case examples, one that focuses on a topic that garnered a lot of public interest and one that focuses on the perception of "more care is better care." It also presents key principles in building and maintaining trust through focused communications that may assist others in effectively communicating and disseminating health information.

Zrsr2 Is Essential for the Embryonic Development and Splicing of Minor Introns in RNA and Protein Processing Genes in Zebrafish.

ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) is an essential splicing factor involved in 3' splice-site recognition as a component of both the major and minor spliceosomes that mediate the splicing of U2-type (major) and U12-type (minor) introns, respectively. Studies of ZRSR2-depleted cell lines and ZRSR2-mutated patient samples revealed its essential role in the U12-dependent minor spliceosome. However, the role of ZRSR2 during embryonic development is not clear, as its function is compensated for by Zrsr1 in mice. Here, we utilized the zebrafish model to investigate the role of zrsr2 during embryonic development. Using CRISPR/Cas9 technology, we generated a zrsr2-knockout zebrafish line, termed zrsr2hg129/hg129 (p.Trp167Argfs*9) and examined embryo development in the homozygous mutant embryos. zrsr2hg129/hg129 embryos displayed multiple developmental defects starting at 4 days post fertilization (dpf) and died after 8 dpf, suggesting that proper Zrsr2 function is required during embryonic development. The global transcriptome analysis of 3 dpf zrsr2hg129/hg129 embryos revealed that the loss of Zrsr2 results in the downregulation of essential metabolic pathways and the aberrant retention of minor introns in about one-third of all minor intron-containing genes in zebrafish. Overall, our study has demonstrated that the role of Zrsr2 as a component of the minor spliceosome is conserved and critical for proper embryonic development in zebrafish.

A predictive clinical model for moderate to severe intraventricular hemorrhage in very low birth weight infants.

IMPORTANCE: Intraventricular hemorrhage (IVH) occurs in 15-45% of all very low birth weight (VLBW) preterm infants. Despite improvements in the perinatal care, the incidence of IVH remains high. As more preterm infants survive, there will be a larger burden of neurodevelopmental abnormalities borne by former preterm infants. OBJECTIVE: The objective of this study was to develop a predictive clinical model of IVH risk within the first few hours of life in an effort to augment perinatal counseling and guide the timing of future targeted therapies aimed at preventing or slowing the progression of disease. DESIGN: This is a prospective observational cohort study of VLBW infants born in the NICU at John's Hopkins Children's Center from 2011 to 2019. The presence and severity of IVH was defined on standard head ultrasound screening (HUS) using the modified Papile classification. Clinical variables were identified as significant using absolute risk regression from a general linear model. The model predictors included clinically meaningful variables that were not collinear. SETTING: This study took place at the Johns Hopkins Children's Center Level IV NICU. PARTICIPANTS: The study sample included VLBW infants treated in the neonatal intensive care unit (NICU) at John's Hopkins Children's Center from 2011 to 2019. A total of 683 infants included in the study had no or grade I IVH, and 115 infants had grades II through IV IVH. Exclusion criteria included admission to the JHH NICU after 24 h of age, BW > 1500 g, and failure to consent. MAIN OUTCOME: The main outcome of this study was the presence of grades II-IV IVH on standard head ultrasound screening using the modified Papile classification [1]. RESULTS: A total of 798 VLBW infants were studied in this cohort and 14.4% had moderate to severe IVH. Fifty four percent of the cohort was black, 33% white, and half of the cohort was male. A higher gestational age, 5-min Apgar score, hematocrit, and platelet count were significantly associated with decreased incidence of IVH in a multi-predictor model (ROC 0.826). CONCLUSION AND RELEVANCE: In the face of continued lack of treatments for IVH, prevention is still a primary goal to avoid long-term developmental sequela. This model can be used for perinatal counseling and may provide important information during the narrow therapeutic window for targeted prevention therapies.

A systematic assessment of the epidemiologic literature regarding an association between acetaminophen exposure and cancer.

Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) reviewed the epidemiologic studies of acetaminophen and the data were judged to be "inadequate" to conclude that it is carcinogenic. In 2019 the California Office of Environmental Health Hazard Assessment initiated a review process on the carcinogenic hazard potential of acetaminophen. To inform this review process, the authors performed a comprehensive literature search and identified 136 epidemiologic studies, which for most cancer types suggest no alteration in risk associated with acetaminophen use. For 3 cancer types, renal cell, liver, and some forms of lymphohematopoietic, some studies suggest an increased risk; however, multiple factors unique to acetaminophen need to be considered to determine if these results are real and clinically meaningful. The objective of this publication is to analyze the results of these epidemiologic studies using a framework that accounts for the inherent challenge of evaluating acetaminophen, including, broad population-wide use in multiple disease states, challenges with exposure measurement, protopathic bias, channeling bias, and recall bias. When evaluated using this framework, the data do not support a causal association between acetaminophen use and cancer.

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients.

INTRODUCTION: Famotidine has been posited as a potential treatment for coronavirus disease 2019 (COVID-19). We compared the incidence of COVID-19 outcomes (i.e., death and death or intensive services use) among hospitalized famotidine users vs proton pump inhibitors (PPIs) users, hydroxychloroquine users, or famotidine nonusers separately. METHODS: We constructed a retrospective cohort study using data from COVID-19 Premier Hospital electronic health records. The study population was COVID-19 hospitalized patients aged 18 years or older. Famotidine, PPI, and hydroxychloroquine exposure groups were defined as patients dispensed any medication containing 1 of the 3 drugs on the day of admission. The famotidine nonuser group was derived from the same source population with no history of exposure to any drug with famotidine as an active ingredient before or on the day of admission. Time at risk was defined based on the intention-to-treat principle starting 1 day after admission to 30 days after admission. For each study comparison group, we fit a propensity score model through large-scale regularized logistic regression. The outcome was modeled using a survival model. RESULTS: We identified 2,193 users of PPI, 5,950 users of the hydroxychloroquine, 1,816 users of famotidine, and 26,820 nonfamotidine users. After propensity score stratification, the hazard ratios (HRs) for death were as follows: famotidine vs no famotidine HR 1.03 (0.89-1.18), vs PPIs: HR 1.14 (0.94-1.39), and vs hydroxychloroquine: 1.03 (0.85-1.24). Similar results were observed for the risk of death or intensive services use. DISCUSSION: We found no evidence of a reduced risk of COVID-19 outcomes among hospitalized COVID-19 patients who used famotidine compared with those who did not or compared with PPI or hydroxychloroquine users.

Quantifying bias in epidemiologic studies evaluating the association between acetaminophen use and cancer.

Many observational studies explore the association between acetaminophen and cancer, but known limitations such as vulnerability to channeling, protopathic bias, and uncontrolled confounding hamper the interpretability of results. To help understand the potential magnitude of bias, we identify key design choices in these observational studies and specify 10 study design variants that represent different combinations of these design choices. We evaluate these variants by applying them to 37 negative controls - outcome presumed not to be caused by acetaminophen - as well as 4 cancer outcomes in the Clinical Practice Research Datalink (CPRD) database. The estimated odds and hazards ratios for the negative controls show substantial bias in the evaluated design variants, with far fewer of the 95% confidence intervals containing 1 than the nominal 95% expected for negative controls. The effect-size estimates for the cancer outcomes are comparable to those observed for the negative controls. A comparison of exposed and unexposed reveals many differences at baseline for which most studies do not correct. We observe that the design choices made in many of the published observational studies can lead to substantial bias. Thus, caution in the interpretation of published studies of acetaminophen and cancer is recommended.

North American Yoga Practitioners' Lived Experiences of Mind-Body Connection: A Phenomenological Study.

The practice of yoga was born in India thousands of years ago and brought to North America gradually beginning in the 20th century. The traditional practice of yoga is spiritual in nature with an intention of purifying the mind and body, leading to an alleviation of suffering through connection with the Divine (i.e., liberation). Yoga has gained widespread popularity in North America, but whether North American yoga practice includes an intention on the purification of the mind-body, in contemporary practice often described as a mind-body connection, has yet to be explored. This research study investigated North American yoga practitioners' experiences of mind-body connection in their practices. Six yoga practitioners residing in North America were interviewed for this study. Interviews were audiorecorded and transcribed. Phenomenological analysis was conducted to produce the essence data, and thematic analysis was conducted to produce the contextual data. Phenomenological themes regarding the co-researchers' experiences of mind-body connection in their yoga practices were identified and grouped into four textural essences: (1) the experience of breath, (2) local or internal experiences, (3) an increased sense of awareness and mindfulness, and (4) transcendental and spiritual qualities. Four structural conditions that allow practitioners to experience mind-body connection during yoga practice were identified: (1) breath, (2) physical asana, (3) practitioner intentionality, and (4) environmental conditions. Findings of the current study suggest a capacity for North American yoga practitioners to experience mind-body connection that is essential to traditional yoga practice.

BE4max and AncBE4max Are Efficient in Germline Conversion of C:G to T:A Base Pairs in Zebrafish.

The ease of use and robustness of genome editing by CRISPR/Cas9 has led to successful use of gene knockout zebrafish for disease modeling. However, it still remains a challenge to precisely edit the zebrafish genome to create single-nucleotide substitutions, which account for ~60% of human disease-causing mutations. Recently developed base editing nucleases provide an excellent alternate to CRISPR/Cas9-mediated homology dependent repair for generation of zebrafish with point mutations. A new set of cytosine base editors, termed BE4max and AncBE4max, demonstrated improved base editing efficiency in mammalian cells but have not been evaluated in zebrafish. Therefore, we undertook this study to evaluate their efficiency in converting C:G to T:A base pairs in zebrafish by somatic and germline analysis using highly active sgRNAs to twist and ntl genes. Our data demonstrated that these improved BE4max set of plasmids provide desired base substitutions at similar efficiency and without any indels compared to the previously reported BE3 and Target-AID plasmids in zebrafish. Our data also showed that AncBE4max produces fewer incorrect and bystander edits, suggesting that it can be further improved by codon optimization of its components for use in zebrafish.

Channeling Bias in the Analysis of Risk of Myocardial Infarction, Stroke, Gastrointestinal Bleeding, and Acute Renal Failure with the Use of Paracetamol Compared with Ibuprofen.

INTRODUCTION: Observational studies estimating severe outcomes for paracetamol versus ibuprofen use have acknowledged the specific challenge of channeling bias. A previous study relying on negative controls suggested that using large-scale propensity score (LSPS) matching may mitigate bias better than models using limited lists of covariates. OBJECTIVE: The aim was to assess whether using LSPS matching would enable the evaluation of paracetamol, compared to ibuprofen, and increased risk of myocardial infarction, stroke, gastrointestinal (GI) bleeding, or acute renal failure. STUDY DESIGN AND SETTING: In a new-user cohort study, we used two propensity score model strategies for confounder controls. One replicated the approach of controlling for a hand-picked list. The second used LSPSs based on all available covariates for matching. Positive and negative controls assessed residual confounding and calibrated confidence intervals. The data source was the Clinical Practices Research Datalink (CPRD). RESULTS: A substantial proportion of negative controls were statistically significant after propensity score matching on the publication covariates, indicating considerable systematic error. LSPS adjustment was less biased, but residual error remained. The calibrated estimates resulted in very wide confidence intervals, indicating large uncertainty in effect estimates once residual error was incorporated. CONCLUSIONS: For paracetamol versus ibuprofen, when using LSPS methods in the CPRD, it is only possible to distinguish true effects if those effects are large (hazard ratio > 2). Due to their smaller hazard ratios, the outcomes under study cannot be differentiated from null effects (represented by negative controls) even if there were a true effect. Based on these data, we conclude that we are unable to determine whether paracetamol is associated with an increased risk of myocardial infarction, stroke, GI bleeding, and acute renal failure compared to ibuprofen, due to residual confounding.

Frequency of nonaspirin NSAID-relevant coexisting medical conditions in the primary-care setting: a retrospective database review.

BACKGROUND: Coexisting medical conditions and concomitant medications contribute to treatment challenges primary-care professionals (PCPs) face daily. The current study assessed the extent and distribution of nonaspirin NSAID-relevant coexisting medical conditions of interest (CMCOI) in patients visiting PCPs. METHODS: This retrospective database review analyzed data from three large health-care claim databases to identify the frequency of nonaspirin NSAID-relevant CMCOI among adults aged ≥18 years with a PCP visit in 2013. Claim databases employed were the Truven Health MarketScan® Commercial Claims and Encounters database, representative of the privately insured (PI) population; Truven Health MarketScan Multi-State Medicaid, representative of the Medicaid population (Medicaid); and Truven MarketScan Medicare Supplemental, representative of the Medicare population with employer-based supplemental Medicare insurance (Medicare-Supplement). Nonaspirin NSAID-relevant CMCOI, asthma, cardiovascular risk factors, gastrointestinal bleeding risk factors, and renal insufficiency were chosen based on US NSAID over-the-counter Drug Facts label warnings. Frequency of CMCOI was determined for those without and with a musculoskeletal diagnosis. RESULTS: In each database, ≥19% (19.0% PI, 29.9% Medicaid, 33.6% Medicare-Supplement) had a musculoskeletal diagnosis. A greater proportion of individuals with a musculoskeletal diagnosis had one or more CMCOI compared with those without a musculoskeletal diagnosis (61.3% vs 50.4% PI, 78.1% vs 66.8% Medicaid, 87.1% vs 82.3% Medicare-Supplement). The frequency of one or more CMCOI increased with age in each database. Across databases among CMCOI, cardiovascular risk factors were most common, followed by gastrointestinal bleeding risk factors, and proportions were higher among those with a musculoskeletal diagnosis. CONCLUSION: These data confirm the high frequency of nonaspirin NSAID-relevant CMCOI among patients presenting to PCPs for musculoskeletal diagnosis, as well as among older patients. These analyses reinforce the critical role health-care professionals can play in identifying patients with nonaspirin NSAID-relevant CMCOI, providing those patients with ongoing guidance on appropriate choice and use of over-the-counter analgesics, and educating patients about the impact aging, health status, concomitant conditions, and medicines have on selection of all medicines, including analgesics.

Five-year trends in acetaminophen use exceeding the recommended daily maximum dose.

Temporal patterns of acetaminophen use exceeding the recommended daily maximum dosage of 4 g over a 5-year period (4/1/2011-3/31/2016) were evaluated in an online 1-week diary study of 14 434 adult acetaminophen users who also reported acetaminophen use in the previous month. Specific medications taken were identified by list-based prompting; respondents were not required to know their medications contained acetaminophen. Details of use were recorded daily; total daily dosage was determined programmatically. Prevalence of >4 g use over time was modelled and tested for linear changes. The overall prevalence of >4 g use (6.3% of users and 3.7% of usage days) did not change over the 5 years: odds ratio (OR) persons, 1.02 (95% CI, 0.98-1.09); OR days, 0.98 (0.92-1.05). Deviations from label directions were largely unchanged, though concomitant use increased slightly. Thus, over a recent 5-year period, there was no evidence of change in how often acetaminophen use exceeded the labelled maximum daily dose.

Cost and effectiveness of prescribing emollient therapy for atopic eczema in UK primary care in children and adults: a large retrospective analysis of the Clinical Practice Research Datalink.

BACKGROUND: The Clinical Practice Research Datalink (CPRD) was used to evaluate the overall costs to the National Health Service, including healthcare utilisation, of prescribing emollients in UK primary care for dry skin and atopic eczema (DS&E). METHODS: Primary care patients in the UK were identified using the CPRD and their records were interrogated for the 2 years following first diagnosis of DS&E. Data from patients with (n = 45,218) and without emollient prescriptions (n = 9780) were evaluated. Multivariate regression models were used to compare healthcare utilisation and cost in the two matched groups (age, sex, diagnosis). Two sub-analyses of the Emollient group were performed between matched groups receiving (1) a colloidal oatmeal emollient (Aveeno-First) versus non-colloidal oatmeal emollients (Aveeno-Never) and (2) Aveeno prescribed first-line (Aveeno-First) versus prescribed Aveeno later (Aveeno-Subsequently). Logistic regression models calculated the odds of prescription with either potent / very potent topical corticosteroids (TCS) or skin-related antimicrobials. RESULTS: Costs per patient were £125.80 in Emollient (n = 7846) versus £128.13 in Non-Emollient (n = 7846) matched groups (p = 0.08). The Emollient group had fewer visits/patient (2.44 vs. 2.66; p < 0.0001) and lower mean per-visit costs (£104.15 vs. £113.25; p < 0.0001), compared with the Non-Emollient group. Non-Emollient patients had 18% greater odds of being prescribed TCS and 13% greater odds of being prescribed an antimicrobial than Emollient patients. In the Aveeno-First (n = 1943) versus Aveeno-Never (n = 1943) sub-analysis, costs per patient were lower in the Aveeno-First compared with the Aveeno-Never groups (£133.46 vs. £141.11; p = 0.0069). The Aveeno-Never group had ≥21% greater odds of being prescribed TCS or antimicrobial than the Aveeno-First group. In the Aveeno-First (n = 1357) versus Aveeno-Subsequently (n = 1357) sub-analysis, total costs were lower in the Aveeno-First group (£140.35 vs. £206.43; p < 0.001). Patients in the Aveeno-Subsequently group had 91% greater odds of being prescribed TCS and 75% greater odds of being prescribed an antimicrobial than the Aveeno-First group. CONCLUSIONS: Acknowledging limitations from unknown disease severity in the CRPD, the prescription of emollients to treat DS&E was associated with fewer primary care visits, reduced healthcare utilisation and reduced cost. Prescribing emollients, especially those containing colloidal oatmeal, was associated with fewer TCS and antimicrobial prescriptions. TRIAL REGISTRATION: The study is registered at http://isrctn.com/ISRCTN91126037 .

Exceeding the maximum daily dose of acetaminophen with use of different single-ingredient OTC formulations.

OBJECTIVES: To assess whether there are differences in the likelihood of exceeding the daily limit of 4 grams of acetaminophen when using different formulations (325 mg, 500 mg, 650 mg) of OTC single-ingredient (SI) acetaminophen medications. DESIGN AND SETTING: Multiyear observational study of acetaminophen use via daily online acetaminophen-usage diaries completed for 7 days. PARTICIPANTS: A total of 7579 U.S. adults from online research panels who used acetaminophen in the month preceding enrollment and used an OTC SI acetaminophen medication during the study. OUTCOME MEASURE: Exceeding the daily dose. RESULTS: On days when 325-mg or 500-mg OTC SI formulations were taken, users were not significantly more likely to exceed 4 grams than on days when OTC SI formulations were not used. On days when 650-mg extended-release (ER) formulations were taken, exceeding 4 grams was significantly more likely (8.9% of days vs. 4.4%; P < 0.0001; median on those days was 5.2 g) than on days with 325- or 500-mg OTC SI formulations. Users of 650-mg ER formulations were significantly less likely to know their dosing interval of 8 hours (33% vs. 49%; P < 0.0001) and more likely to redose too soon (26% vs. 10%; P < 0.0001) and to use other acetaminophen medications concomitantly (14% vs. 7%; P < 0.0001). These patterns were strongest among 650-mg ER products that did not include "8-Hour" in the product name. CONCLUSION: Usage of 500-mg OTC SI acetaminophen formulations does not contribute differently to exceeding dosage compared with other OTC SI acetaminophen formulations. Exceeding 4 grams is more likely when 650-mg ER formulations are used. Improved consumer information on the packages and counseling from pharmacists may help to reduce practices that contribute to exceeding the labeled daily limit of these medications.

Knowledge of dosing directions among current users of acetaminophen-containing medications.

OBJECTIVES: Users should know the active ingredients and dosing directions to optimize the safe use of acetaminophen-containing medications. The aim of this work was to examine knowledge of acetaminophen-containing medication directions among current users. DESIGN, SETTING, AND PARTICIPANTS: An Internet panel diary study (2012-2016) of 1-week usage of acetaminophen medications (over-the-counter [OTC] and prescription), recorded daily; 9629 participants. Users were asked about ingredients of medications taken; specific dosing instructions were asked for each OTC medication taken. Subjects were considered to be correct only if an accurate response was provided for all of the medications they used. OUTCOME MEASURES: Analyses examined prevalence of several aspects of knowledge and their relation to the corresponding deviations from directions. Knowledge that acetaminophen was an ingredient was compared between medication types. RESULTS: Two-thirds of 5161 participants who used only 1 acetaminophen medication knew the ingredient; the proportion was almost halved in 4468 users of 2 or more. Ingredient knowledge was highest for single-ingredient medications (74%); for combination medications it ranged from 39% (cough or cold) to 61% (sleep or other non-pain). About one-third knew the prohibition against concomitant use of multiple acetaminophen medications; 85% knew the maximum one-time OTC dose, but only 47% knew the minimum interval between doses. Correct knowledge was inversely associated with violating the relevant label directions; in particular, knowing the one-time dose decreased the odds of taking too much at one time fivefold. Knowing both the ingredient and the concomitant use prohibition decreased the odds of concomitant use by 50%. CONCLUSIONS: Knowledge of directions for safe use of acetaminophen-containing medications is poor, and its deficiency is associated with corresponding deviations from label instructions. This study demonstrates a need for education about safe use of acetaminophen-containing medications, particularly for combination products.

The Doubletime Homolog KIN-20 Mainly Regulates let-7 Independently of Its Effects on the Period Homolog LIN-42 in Caenorhabditis elegans.

The Caenorhabditis elegans (C. elegans) heterochronic pathway, which regulates developmental timing, is thought to be an ancestral form of the circadian clock in other organisms. An essential member of this clock is the Period protein whose homolog, lin-42, in C. elegans is an important heterochronic gene. LIN-42 functions as a transcriptional repressor of multiple genes including the conserved lin-4 and let-7 microRNAs. Like other Period proteins, levels of LIN-42 oscillate throughout development. In other organisms this cycling is controlled in part by phosphorylation. KIN-20 is the C. elegans homolog of the Drosophila Period protein kinase Doubletime. Worms containing a large deletion in kin-20 have a significantly smaller brood size and develop slower than wild type C. elegans Here we analyze the effect of kin-20 on lin-42 phenotypes and microRNA expression. We find that kin-20 RNAi enhances loss-of-function lin-42 mutant phenotypes and that kin-20 mutant worms express lower levels of LIN-42 We also show that kin-20 is important for post-transcriptional regulation of mature let-7 and lin-4 microRNA expression. In addition, the increased level of let-7 found in lin-42(n1089) mutant worms is not maintained after kin-20 RNAi treatment. Instead, let-7 is further repressed when levels of kin-20 and lin-42 are both decreased. Altogether these results suggest that though kin-20 regulates lin-42 and let-7 microRNA, it mainly affects let-7 microRNA expression independently of lin-42 These findings further our understanding of the mechanisms by which these conserved circadian rhythmic genes interact to ultimately regulate rhythmic processes, developmental timing and microRNA biogenesis in C. elegans.

Prevalence of exceeding maximum daily dose of paracetamol, and seasonal variations in cold-flu season.

AIMS: To estimate prevalence of excess intake of paracetamol and investigate seasonal variations therein. METHODS: Between 2011 and 2016, 14 481 US adults who used paracetamol in the preceding 30 days were sampled from national online panels and completed a detailed online daily diary of paracetamol medication use for 7 days. Respondents were not told that the study concerned paracetamol. Cold/flu season (CFS), identified using Google Trends data, was contrasted to off-season in symptoms, use of paracetamol medications, and consumption exceeding 4 g (the recommended daily maximum). RESULTS: Overall, 6.3% [95% confidence interval: 5.9-6.7%] of users exceeded 4 g on at least one day; 3.7% [3.5-3.8%] of usage days exceeded 4 g. Cold/flu symptoms were more likely to be experienced and treated with paracetamol in CFS than off-season. Paracetamol users were more likely to exceed 4 g during CFS (6.5% vs. 5.3%; odds ratio = 1.24, 1.04-1.48); days exceeding 4 g also increased (3.9% vs. 2.8%; odds ratio = 1.37, 1.11-1.69). This was not due to differences in characteristics of individuals using paracetamol in CFS, but primarily to increased use of over-the-counter combination medications designed to treat upper respiratory cold/flu symptoms (33.2% of usage days in CFS vs. 24.8% in off-season; odds ratio = 1.58, 1.46-1.72). When such medications were omitted, there was no statistically significant seasonal variation in exceeding 4 g. CONCLUSIONS: Paracetamol use and over-dosing increases in CFS, primarily due to increased use of over-the-counter combinations treating upper respiratory cold/flu symptoms. Pharmacists should warn users to follow labelled dosing directions, especially during CFS.

Exceeding the daily dosing limit of nonsteroidal anti-inflammatory drugs among ibuprofen users.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective and very commonly used, but also have side effects. We determined prevalence of NSAID dosing exceeding the daily limit (EDL) and identified related user characteristics and dosing patterns among current ibuprofen users. METHODS: Online 1-week diary study of 1326 ibuprofen users. NSAIDs were identified by list-based prompting; respondents were not required to know their medications were NSAIDs. Details of hourly use were recorded by respondents daily. Deviations from dosing directions were programmatically determined afterwards. An exit survey obtained information on demographics, medical history, physical and mental health status, attitudes regarding label reading and dosing behavior, and knowledge of product label instructions. RESULTS: Most diary users (90%) took over-the-counter ibuprofen during the week; 37% also took non-ibuprofen NSAIDs. Most did not recognize all products taken as NSAIDs. EDL occurred among 11% of users for ibuprofen, 4% of users for other NSAIDs, and on 9.1% of NSAID usage days. EDL was associated with deviations from detailed dosing directions, particularly exceeding the 1-time dose, which occurred more often with medications with 1-pill doses. Personal characteristics associated with EDL included male sex, ongoing pain, poor physical function, daily smoking, having the attitudes of "choosing my own dose" and not starting with the lowest dose, and poor knowledge of the recommended 1-time and 24-hour doses. CONCLUSIONS: The prevalence of EDL among NSAID users is nontrivial, and it is associated with potentially modifiable factors. Educating consumers about NSAIDs and their dosing directions could reduce excess dosing.

U.S. Preventive Services Task Force Methods to Communicate and Disseminate Clinical Preventive Services Recommendations.

The U.S. Preventive Services Task Force (USPSTF) issues evidence-based screening and prevention recommendations, and key to this task is dissemination and implementation of these recommendations. The Task Force has recommendations for more than 84 topics; each USPSTF Recommendation Statement includes a letter grade, a topline summary to guide clinician interpretation in practice, and a summary of gaps in evidence to help catalyze clinically relevant research. The USPSTF aims to update existing topics regularly and considers new topics to add each year. Clearly communicating and disseminating each recommendation is a critical task to ensure maximum benefit from use of the recommendations. The primary USPSTF audience is primary care clinicians. Over time, other audiences have become interested in the USPSTF and these entities have broad and diverse needs, necessitating a range of communication platforms and approaches. This includes engagement with and input from topic experts, primary care and federal partners, and the public to help shape the development of the recommendations. It also includes engagement of partners to disseminate USPSTF recommendations to help ensure that the primary care workforce remains up-to-date on USPSTF recommendations. This paper outlines the approaches used by the USPSTF to both solicit input (e.g., public comment periods), as well as to facilitate dissemination of its recommendations to help improve the health of all Americans (e.g., web-based and mobile application tools, journal publications, and annual reports to Congress).

Channeling in the Use of Nonprescription Paracetamol and Ibuprofen in an Electronic Medical Records Database: Evidence and Implications.

INTRODUCTION: Over-the-counter analgesics such as paracetamol and ibuprofen are among the most widely used, and having a good understanding of their safety profile is important to public health. Prior observational studies estimating the risks associated with paracetamol use acknowledge the inherent limitations of these studies. One threat to the validity of observational studies is channeling bias, i.e. the notion that patients are systematically exposed to one drug or the other, based on current and past comorbidities, in a manner that affects estimated relative risk. OBJECTIVES: The aim of this study was to examine whether evidence of channeling bias exists in observational studies that compare paracetamol with ibuprofen, and, if so, the extent to which confounding adjustment can mitigate this bias. STUDY DESIGN AND SETTING: In a cohort of 140,770 patients, we examined whether those who received any paracetamol (including concomitant users) were more likely to have prior diagnoses of gastrointestinal (GI) bleeding, myocardial infarction (MI), stroke, or renal disease than those who received ibuprofen alone. We compared propensity score distributions between drugs, and examined the degree to which channeling bias could be controlled using a combination of negative control disease outcome models and large-scale propensity score matching. Analyses were conducted using the Clinical Practice Research Datalink. RESULTS: The proportions of prior MI, GI bleeding, renal disease, and stroke were significantly higher in those prescribed any paracetamol versus ibuprofen alone, after adjusting for sex and age. We were not able to adequately remove selection bias using a selected set of covariates for propensity score adjustment; however, when we fit the propensity score model using a substantially larger number of covariates, evidence of residual bias was attenuated. CONCLUSIONS: Although using selected covariates for propensity score adjustment may not sufficiently reduce bias, large-scale propensity score matching offers a novel approach to consider to mitigate the effects of channeling bias.