Prescription Bias Research Articles

Beyond the descriptive-prescriptive cline: Encoding language ideology in in Hobson-Jobson, a Victorian dictionary of Indian English.

This paper considers the presence of language ideology in dictionaries through both prescriptive bias and descriptive procedures. To that purpose, it examines the example provided by Hobson-Jobson, a dictionary of Indian English first published in England in 1886, and it investigates how this work encodes imperialistic language ideology. Two major tenets of Victorian language ideology are considered in particular – standard British English superiority and the global status of English – and shown to be overtly or covertly reflected in both the paratexts (title, preface, introductory remarks) and lexicographic text (word list, definitions and translated illustrative quotations). Ideological stance is thus identified in both prescriptive and descriptive procedures, and Hobson-Jobson is thus shown to be a good example of how the ideological bias in dictionaries extends beyond the descriptive-prescriptive cline.

Use of Aerosolized Prostacyclins in Critically Ill Patients and Association With Clinical Outcomes.

To compare the effects of inhaled epoprostenol and inhaled iloprost in critically ill patients with refractory hypoxia. We performed a retrospective cohort analysis of patients admitted to the ICUs at the University of Oklahoma Health Sciences Center between 2015 and 2018. Adult patients who received aerosolized epoprostenol or iloprost for more than 4 hours were included in the analysis. The primary endpoint measured was to compare the change in Pao2/Fio2 ratio between patients treated with iloprost compared with epoprostenol. Secondary outcomes measured were 90-day in-hospital mortality and improvement in vasopressor requirements. A total of 126 patients were included in the study, 95 of whom received iloprost (75%) and 31 patients (25%) received epoprostenol. There were significant improvements in Pao2/Fio2 ratio in both the iloprost and epoprostenol group. Patients in the epoprostenol group appeared to have a higher 90-day mortality compared with the iloprost group. However, our study was not powered to detect a mortality difference and this finding likely represents a sicker population in the epoprostenol group and prescription bias. The use of iloprost was associated with higher vasopressor requirements in the first 12 hours of administration, an association was not observed in the epoprostenol group. In this retrospective cohort analysis, use of both pulmonary vasodilators was associated with similar improvement in gas exchange. The mortality difference observed likely represents difference in severity of illness. Further studies are needed to corroborate these findings.

Minimal Risk of Drug-Induced Liver Injury With Molnupiravir and Ritonavir-Boosted Nirmatrelvir

Minimal Risk of Drug-Induced Liver Injury With Molnupiravir and Ritonavir-Boosted Nirmatrelvir

Evaluation of long-term TNFi effectiveness after a first switch in early axial spondyloarthritis considering time-varying prescription bias: an inverse-probability weighting analysis of the DESIR cohort

ObjectiveTo evaluate long-term effectiveness of tumour necrosis factor inhibitor (TNFi) after a first switch, and their associated factors in an early axial spondyloarthritis (axSpA) population, considering time-varying prescription bias.MethodsObservational prospective...

Tocilizumab or glucocorticoids treatment for patients with SARS-CoV-2 pneumonia: An observational study

ObjectiveTo estimate the effect of tocilizumab or glucocorticoids in preventing death and intubation in patients hospitalized with SARS-CoV-2 pneumonia. MethodsThis was a retrospective cohort study enrolling all consecutive patients hospitalized at Reggio Emilia AUSL between February the 11th and April 14th 2020 for severe COVID-19 and treated with tocilizumab or glucocorticoids (at least 80 mg/day of methylprednisolone or equivalent for at least 3 days).The primary outcome was death within 30 days from the start of the considered therapies. The secondary outcome was a composite outcome of death and/or intubation. All patients have been followed-up until May 19th 2020, with a follow-up of at least 30 days for every patient.To reduce confounding due to potential non-comparability of the two groups, those receiving tocilizumab and those receiving glucocorticoids, a propensity score was calculated as the inverse probability weighting of receiving treatment conditional on the baseline covariates. Results and conclusionTherapy with tocilizumab alone was associated with a reduction of deaths (OR 0.49, 95% CI 0.21-1.17) and of the composite outcome death/intubation (OR 0.35, 95% CI 0.13-0.90) compared to glucocorticoids alone. Nevertheless, this result should be cautiously interpreted due to a potential prescription bias.

Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders.

Simple SummaryLow-dose aspirin has a preventive effect against multiple malignancies, including hepatocellular carcinoma. Whether aspirin could also ameliorate the prognosis of patients who already developed advanced cancer remains an elusive question. In the case of hepatocellular carcinoma, randomized clinical trials are difficult to design and observational studies suffer from multiple biases. We tried to address these problems performing a large-scale observational study, which allowed multiple corrections to reduce the main known biases. We found that among patients who received sorafenib as an antineoplastic treatment, patients who concurrently received aspirin had better outcomes than non-aspirin users. Once the confounders were properly addressed, this advantage was confirmed, albeit at the cost an increased rate of minor bleeding events. Even if we are aware that confirmatory randomized clinical trials are difficult to organize, our results warrant further investigation, as aspirin might be a low-cost, effective and safe additional treatment for selected patients with advanced hepatocellular carcinoma.Case–control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child–Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543–0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted.

Editors' Note: Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality

Dr. Xu et al. compared cognitive trajectories and the occurrence of severe dementia or death in 11,652 patients started on cholinesterase inhibitors (ChEIs) vs 5,826 untreated patients with Alzheimer dementia (AD) in the Swedish Dementia Registry. During an average of 5 years of follow-up, they found that ChEIs were associated with modest but persistent cognitive benefits with lower mortality. Galantamine was the only ChEI that was associated with a significantly lower risk of developing severe dementia. In response, Dr. Kuschpel noted that there were important baseline differences between patients who were and were not treated with ChEIs, with associated difficulties matching the 2 groups for analyses. Dr. Kuschpel also highlighted the importance of considering the stage and severity of comorbidities about survival estimates and is skeptical of the sizeable mortality reduction with ChEIs seen in the study, given the lack of precedence, the absence of a plausible molecular mechanism, and potential confounding by prescription bias. Concerns are raised about potential discrepancies in numbers between the abstract and the results section about observed differences in Mini-Mental State Examination (MMSE) scores. Responding to these comments, the authors argue that although there were significant baseline differences between the 2 groups, they were able to achieve a well-matched cohort, although they acknowledge the possibility of residual and unknown confounders, especially in the absence of data on comorbidity severity. They cite the previous work by their group observing reductions in myocardial infarction, stroke, and mortality with ChEI use, as well as a lower 2-year mortality with galantamine seen in a prior randomized-controlled trial. They note that previous trials of ChEIs have had considerably shorter follow-up durations. In summary, this exchange highlights the uncertain causal association between ChEI use and lower mortality in patients with AD, and the challenges of convincingly demonstrating such an association with observational data. Robust validation of this association would have important implications for the care of patients with AD. Dr. Xu et al. compared cognitive trajectories and the occurrence of severe dementia or death in 11,652 patients started on cholinesterase inhibitors (ChEIs) vs 5,826 untreated patients with Alzheimer dementia (AD) in the Swedish Dementia Registry. During an average of 5 years of follow-up, they found that ChEIs were associated with modest but persistent cognitive benefits with lower mortality. Galantamine was the only ChEI that was associated with a significantly lower risk of developing severe dementia. In response, Dr. Kuschpel noted that there were important baseline differences between patients who were and were not treated with ChEIs, with associated difficulties matching the 2 groups for analyses. Dr. Kuschpel also highlighted the importance of considering the stage and severity of comorbidities about survival estimates and is skeptical of the sizeable mortality reduction with ChEIs seen in the study, given the lack of precedence, the absence of a plausible molecular mechanism, and potential confounding by prescription bias. Concerns are raised about potential discrepancies in numbers between the abstract and the results section about observed differences in Mini-Mental State Examination (MMSE) scores. Responding to these comments, the authors argue that although there were significant baseline differences between the 2 groups, they were able to achieve a well-matched cohort, although they acknowledge the possibility of residual and unknown confounders, especially in the absence of data on comorbidity severity. They cite the previous work by their group observing reductions in myocardial infarction, stroke, and mortality with ChEI use, as well as a lower 2-year mortality with galantamine seen in a prior randomized-controlled trial. They note that previous trials of ChEIs have had considerably shorter follow-up durations. In summary, this exchange highlights the uncertain causal association between ChEI use and lower mortality in patients with AD, and the challenges of convincingly demonstrating such an association with observational data. Robust validation of this association would have important implications for the care of patients with AD.

Reader Response: Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality.

I read the article by Xu et al.1 with interest. However, I would like to raise a few questions about the study. The published literature shows a strong difference between patients who received a prescription for a cholinesterase inhibitor (ChEI) and those who did not.2 The authors also mention that they had trouble matching the 2 groups because their groups differed significantly. Although the authors tried to correct for this, it does not seem that the stage or severity of comorbidities was considered in this study, despite its critical clinical relevance to survival estimates. The mortality reduction found by the authors was immense and has not been found in previous prospective studies.3,4 At this time, there is no known molecular mechanism that could explain such a strong effect. Could this result be a simple case of reverse causality, based on an inadequately control for prescription bias?

P–690 Clinical predictors of a high oocyte maturation rate in IVF treatment cycles

Abstract Study question Which clinical parameters predict a high oocyte maturation rate in patients undergoing IVF treatment? Summary answer Time between oocyte collection and insemination demonstrated significant association with oocyte maturation and represents a parameter that could be optimised in IVF cycles. What is known already Oocyte maturation is an important factor determining IVF outcomes and can be a rate-limiting step for patients undergoing treatment. A number of clinical and laboratory variables may affect this process, including the choice of trigger prior to oocyte collection, and certain laboratory procedures. Identification of which of these are predictors of maturation in individual centres enables local protocols to be optimised. Study design, size, duration This is a retrospective study of 714 oocyte collections from 661 women between January 2020 to November 2020 treated in a large, single centre in the UK. Subsequent fertilisation on fresh oocytes consisted of 371 IVF and 343 ICSI cycles. Participants/materials, setting, methods Patient and treatment data was collected by clinical staff at time of treatment. Either GnRH agonist, hCG or double trigger were administered 36 hours before collection. Prior to ICSI, oocyte maturation was assessed by visualisation of polar body (PB) extrusion. After IVF, the number of 2PNs plus unfertilised oocytes with PB extrusion were assessed. Univariate analyses consisted of Mann-Whitney test, t-test, Fisher’s Exact test or ANOVA. Potential predictors were investigated by logistic regression. Main results and the role of chance The end point was maturation rate, defined as high (greater or equal to 70%) or low (less than 70%). Factors predictive of a high rate included insemination more than 4 hours after collection. Oocytes inseminated over 4 hours post-collection displayed significantly higher maturation rates than oocytes inseminated less than 2 hours after collection (69% and 61% respectively; P = 0.01). Oocytes inseminated between 2–4 hours also had higher maturation than those inseminated less than 2 hours post-collection, but this did not reach significance (67% and 61%, respectively; P = 0.06). Further, oocytes fertilised by ICSI had significantly higher maturation than conventional IVF (77% and 67%, respectively, P &amp;lt; 0.001). No significant difference in oocyte maturation between triggers was observed. Similarly, neither age, AMH, a diagnosis of PCOS or number of oocytes collected predicted oocyte maturation in univariate analysis. Logistic regression analysis showed only time between oocyte collection and insemination (aOR 2.12; 95% CI 1.03–4.38; P = 0.04) to be a significant independent predictor. Limitations, reasons for caution Varying means of data collection across clinics and between clinical staff inevitably leads to provision of incomplete data and should be taken into consideration alongside interpretation. Prescription bias of specific triggers to certain patient demographics should be noted. Wider implications of the findings: Collectively, these results suggest that greater time between oocyte collection and insemination could be recommended to IVF clinics that wish to optimise their oocyte maturation. Triggering final maturation with GnRH agonist versus hCG or dual trigger did not have a significant effect on oocyte maturation when adjusted for confounders. Trial registration number Not applicable

Discourse and Form Constraints on Licensing Object-First Sentences in German

In German, the subject usually precedes the object (SO order), but, under certain discourse conditions, the object is allowed to precede the subject (OS order). This paper focuses on main clauses in which either the subject or a discourse-given object occurs in clause-initial position. Two acceptability experiments show that OS sentences with a given object are generally acceptable, but the precise degree of acceptability varies both with the object‘s referential form (demonstrative objects leading to higher acceptability than other types of objects) and with formal properties of the subject (pronominal subjects leading to higher acceptability than non-pronominal subjects). For SO sentences, acceptability was reduced when the object was a d-pronoun, which contrasts with the high acceptability of OS sentences with a d-pronoun object. This finding was explored in a third acceptability experiment comparing d-pronouns in subject and object function. This experiment provides evidence that a reduction in acceptability due to a prescriptive bias against d-pronouns is suspended when the d-pronoun occurs as object in the prefield. We discuss the experimental results with respect to theories of German clause structure that claim that OS sentences with different information-structural properties are derived by different types of movement.

Could Contracts between Pharmaceutical Firms and French Veterinarians Bias Prescription Behaviour: A Principal-Agency Theory Approach in the Context of Oligopolies

In France, veterinarians can both prescribe and deliver veterinary medicines, which is a questionable situation from the perspective of antimicrobial use (AMU) reduction to avoid antimicrobial resistance (AMR). This situation places veterinarians in direct commercial relationships with the pharmaceutical industry as purchase contracts are signed between veterinarians and pharmaceutical companies. The aim of the present work is to analyse the relationships between veterinarians and pharmaceutical firms in the oligopoly market context of French veterinary medicine to determine whether the prescription behaviour of practitioners can be biased by joint prescription and delivery. Therefore, we develop an analysis based on principal-agent theory. Contracts between pharmaceutical companies and veterinarians during the 2008–2014 period were analysed based on 382 contracts related to 47 drugs belonging to eight main pharmaceutical firms (2320 observations). The price per unit after rebate of each drug and contract was calculated. The descriptive analysis demonstrated high disparity among the contracts across pharmaceutical firms with regard to the provisions of the contracts and how they are presented. Then, linear regression was used to explain the price per unit after rebate based on the explanatory variables, which included the yearly purchase objective, year, type of drug and type of rebate. The decrease in price per unit after rebate for each extra €1000 purchase objective per drug category was established to be €0.061 per 100 kg body weight for anticoccidiosis treatments, €0.029 per 100 kg body weight for anti-inflammatories, €0.0125 per 100 kg body weight and €0.0845 per animal for antiparasitics, and €0.031 per animal for intramammary antimicrobials. Applying agency theory reveals that veterinarians can be considered agents in the case of monopolistic situations involving pharmaceutical firms; otherwise, veterinarians are considered principals (oligopolistic situations in which at least several medicines have similar indications). The present study does not provide evidence suggesting that joint prescription and delivery may introduce any potential prescription bias linked to conflicts of interest under the market conditions during the 2008–2014 period.

User of angiotensin-converting-enzyme inhibitor and/or angiotensin II receptor blocker might be associated with vascular calcification in predialysis chronic kidney disease patients: a retrospective single-center observational study

BackgroundVascular calcification is a prominent feature in chronic kidney disease (CKD) and diabetes mellitus. A recent report suggests that angiotensin II is protective to vascular calcification. Therefore, we investigated the relationship between vascular calcification and use of angiotensin-converting-enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) from a cross-sectional view.MethodsA total of 121 predialysis CKD patients (age 71 ± 12 y; male 72; estimated glomerular filtration rate (eGFR) 20.2 (11.8 - 40.3) mL/min/1.73 m2) who underwent thoracoabdominal plain computed tomography scan were included in this study. The total vascular calcification volume (Calc) was calculated with a three-dimensional imaging software and standardized by body surface area (BSA). The relevance between log [Calc/BSA] and ACEI/ARB use was investigated by multivariate linear regression analyses with or without a time-duration factor of ACEI/ARB use.ResultsThe Calc/BSA was 5.62 (2.01 - 12.7) mL/m2 in 121 patients. In multivariate analyses adjusted with age, sex, ACEI/ARB and log [eGFR], ACEI/ARB use is significantly and positively associated with log [Calc/BSA] (β = 0.2781, p = 0.0007). Even after the adjustment by age, sex, log [eGFR], phosphate, diabetes mellitus, systolic blood pressure, warfarin, hypertension, dyslipidemia, low-density lipoprotein cholesterol, diuretics and ACEI/ARB, ACEI/ARB use is significantly and positively associated with log [Calc/BSA] (β = 0.1677, p = 0.0487). When 90 patients whose time-duration of ACEI/ARB use was clear in medical records were studied, a multivariate analysis adjusted with age, sex, log [eGFR], and ACEI/ARB duration factors showed that the longer use of ACEI/ARB more than 2 years was significantly, independently and positively associated with log [Calc/BSA] (β = 0.2864, p = 0.0060).ConclusionsACEI/ARB user was associated with vascular calcification in predialysis patients with low eGFR. Prospective studies with larger numbers of patients or more in vitro studies are needed to confirm whether this phenomenon is due to the use of ACEI/ARB itself, the underlying disease condition or the prescription bias.

Prescription bias in the treatment of chronic systolic heart failure impacts outcome

Abstract Background There is evidence that medical therapy with beta-blockers (BB) and renin-angiotensin-system-inhibitors, uptitrated to target dosage (TD) decreases mortality and hospitalizations in HFrEF. However, physicians seemingly do not sufficiently follow the guidelines and a great number of patients do not receive recommended dosages. As humans are visually deceivable, it might be that absolute numerical values of equipotent recommended TD and the “milligram-based” subjective weighting of tolerability by the individual physician influences the maximal prescribed dosage. Purpose We sought to assess whether different numerical TD of equipotent medications affect prescription patterns, potentially biases uptitration and impacts outcome. Methods 3737 HFrEF outpatients were identified from a prospective registry. Maximal achieved dosages of BB, ACEi and ARB after one year of repeated visits for uptitration were assessed. BB, ACEi and ARB with largest numerical differences in TD (10mg/d bisoprolol/nebivolol vs 200mg/d metoprolol; 10mg/d ramipril vs 40mg/d lisinopril/enalapril/fosinopril; and 32mg/d candesartan vs 320mg/d valsartan) were compared using the individually achieved dose as percentage of the defined TD at one year of FUP. The association of maximal achieved TD with HF hospitalization and overall survival were determined. Results Median age was 65 years (IQR: 55–74), 2720 patients (73%) were male. Within the whole study population, 1434 patients (38%) received bisoprolol/nebivolol, 280 (8%) metoprolol. Ramipril was prescribed in 599 (16%) patients, lisinopril/enalapril/fosinopril in 1138 (30%). 409 patients (11%) were on candesartan, 173 (5%) on valsartan. Significant differences at baseline were not clinically meaningful and there were no contraindications for uptitration in all subgroups. After one year aiming for up-titration dosages increased significantly in all medication-groups (p&amp;lt;0.001 for all). However, significantly less patients were treated with the TD when TD was numerically higher (BB: metoprolol (57 (20%)) vs bisoprolol/nebivolol (446 (31%), p&amp;lt;0.001); ACEi: lisinopril/enalapril/fosinopril (231 (20%) vs ramipril (313 (52%), p&amp;lt;0.001); ARB: valsartan (45 (26%) vs candesartan (166 (41%), p&amp;lt;0.001)). At 45 (IQR: 32–68) months of FUP, 859 (23%) of the patients were hospitalized for HF or died. Achievement of TD significantly improved outcome (Fig. 1A-C) and showed association with mortality and HF-hospitalization (BB: adj.HR=0.87, 95% CI: 0.79–0.95, p&amp;lt;0.001; ACEi: adj.HR=0.89, 95% CI: 0.81–0.97, p=0.023; ARB: adj.HR=0.74, 95% CI: 0.69–0.91, p=0.009). Conclusion The present analysis described the influence of the numerical values of recommended TD of equipotent drugs on the prescription behavior of the treating physician and on outcome. This psychological phenomenon was identified a substantial confounder at least partly responsible for the underuse of BB, ACEi and ARB in HF. Moreover, it was never shown that this cognitive illusion based on risk aversion is linked to outcome. Figure 1 Funding Acknowledgement Type of funding source: None

Novel anticoagulants in an older and frail population with atrial fibrillation: the effect of inappropriate dosing on clinical outcomes.

An individualized approach should be taken regarding the use of novel oral anticoagulants (NOAC) in frail and older patients with atrial fibrillation (AF). We hypothesized that there would be a high proportion of underdosed patients among an older and frail population, where bleeding risk is higher. We retrospectively analyzed patients admitted to an Internal Medicine ward with a previous diagnosis of AF and discharged with a NOAC (n = 327). We compared survival and incidence of dosing-related events (stroke, systemic embolism, and major bleeding) at 1-year between inappropriately underdosed patients (dose reduction without a formal indication) and the rest of the population. A total of 167 patients (51%) received a reduced dose despite lacking formal criteria for dose reduction. Before adjustment, underdosed patients, in comparison with non-underdosed patients, had a higher mortality at 1 year (HR = 1.6, 95% CI 1.2-2.1, p = 0.003) and a higher combined stroke, systemic embolism, and major bleeding event rate at 1-year (HR = 3.2, 95% CI 1.3-8.0, p = 0.015). After adjustment, combined stroke, systemic embolism, and major bleeding event rate was higher in underdosed patients (HR 3.7, 95% CI 1.1-12.3, p = 0.030), but survival was not different in the adjusted model (HR 1.4, 95% CI 0.9-2.1, p = 0.110). Underdosed patients have a significant survival disadvantage and this may be due to clinician prescription bias, since this difference does not remain after adjusting for confounders. Combined stroke, systemic embolism, and major bleeding event rate was higher in underdosed patients.

THU0145 INDICATIONS AND INCIDENCE OF TREATMENT WITH ANTIDEPRESSANTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND MATCHED CONTROLS

Background:The incidence of depression is about 1.5-2 times higher in patients with rheumatoid arthritis (RA) versus controls. (1, 2) Previous data on treatment with antidepressants has pointed to an almost equal distribution of indications between depression and other indications. (3)Objectives:To describe and compare indications and the incidence of treatment with antidepressants in patients with RA and matched controls.Methods:The study involved an inception cohort of patients with incident RA ascertained from 1995 to 2002 according to the American College of Rheumatology 1987 classification criteria (4) and randomly drawn, population controls with the same age, sex, and area of residence (ratio 1:5). Indications on redeemed prescriptions were included in the Danish National Prescription Register from 2004 and we collected data on all prescriptions for antidepressants (Anatomical Therapeutic Classification code N06A) and counted person-years (PY) at risk from 01.01.2004 to 31.12.2017, death, or migration. The incidence of first treatment was evaluated as defined daily dose (DDD) for two definitions of exposure (DDD&gt;0, DDD&gt;178) within one calendar year together with the positive indication depression after one year of run-in.Results:The current analyses involved 431 RA patients and 2167 controls (median age at inclusion: 59 years, 70% females; RA patients: 20% erosive, 74% rheumatoid factor positive). The most frequent indication for treatment with antidepressants was depression (Table 1).Table 1.Indication on prescriptions for antidepressants, % (95% confidence interval (CI))Rheumatoid arthritis (n=6,955)Controls(n=33,740)Depressive disorders62.3 (61.2-63.5)62.7 (62.2-63.2)Anxiety disorders5.4 (4.9-6.0)3.9 (3.7-4.1)Nervous system medications6.5 (5.9-7.1)6.8 (6.6-7.1)Other indications0.2 (0.0-0.3)0.2 (0.2-0.2)No or missing indications25.6 (24.6-26.7)26.3 (25.9-26.8)There were no significant differences in the incidence of treatment with the indication depression in patients versus controls(Table 2).Table 2.Incidence rate ratio for treatment with antidepressantsDDD&gt;0DDD&gt;178Rheumatoid arthritis (Events/PY)Controls (Events/PY)Incidence rate ratio (95% CI)Rheumatoid arthritis (Events/PY)Controls (Events/PY)Incidence rate ratio (95% CI)Overall98/3,720471/19,2291.08(0.86-1.34)73/3,893339/20,3381.13 (0.87-1.46)SexFemales79/2,616354/13,4601.15 (0.89-1.47)61/2,753264/14,2991.20 (0.89-1.59)Males19/1,104117/5,7690.85 (0.49-1.39)12/1,14175/6,0390.85 (0.42-1.57)Age15-345/17524/9621.15 (0.34-3.07)4/18821/1,0221.04 (0.26-3.07)35-443/52231/2,3490.44 (0.85-1.40)3/52420/2,5010.72 (0.14-2.42)45-5414/73164/3,8711.16 (0.60-2.09)10/77340/4,1221.33 (0.59-2.71)55-6425/1,198128/6,2001.01 (0.63-1.56)17/1,25384/6,4981.05 (0.58-1.78)65-7437/849158/4,5981.27 (0.86-1.82)28/892120/4,8741.28 (0.81-1.94)75+14/24666/1,2481.08 (0.56-1.94)11/26554/1,3211.02 (0.48-1.97)Conclusion:The main indication for prescribing antidepressants in patients with RA was depression. Patients with RA were not exposed to antidepressants more often than controls. This could be due to prescription bias or reflect pertinent choice of treatment in patients with RA.

P4751Underdosing fragile patients - Are we helping or harming?

Abstract Background An individualized approach should be taken regarding the utilization of direct oral anticoagulants (DOAC) in frail and elderly populations with atrial fibrillation (AF). We hypothesized that among an elderly and frail population, where the risk of bleeding, both real and perceived, is very high, the proportion of patients with a dose regimen different from the formal indication would be particularly high due to potential underdosing. Methods We conducted a retrospective, observational study enrolling 327 patients with AF admitted to an Internal Medicine ward during a 1-year period and discharged with a DOAC prescription. We divided the population in 2 groups: patients prescribed a reduced dose without formal dose reduction criteria (underdosed, n=170) and the rest of the population (n=157), which included adequately dosed patients, both with normal dose (n=99) and correctly reduced dose (n=43) and overdosed patients (n=15). A 1-year follow-up was completed for all patients, assessing the following outcomes: all-cause mortality, stroke, systemic embolism and major bleeding. Results Patients were elderly (81.9±7.68) and frail (Katz index 3.35±2.36). Apixaban was the most commonly prescribed NOAC (38.8%), followed by rivaroxaban (36.4%) and dabigatran (24.8%). Among underdosed patients, apixaban was prescribed in 45.3% of patients, dabigatran in 29.4% and rivaroxaban 25.3%. Although only 18.3% of patients had clinical criteria for dose reduction, 65.4% were discharged with reduced dose and thus 52% were underdosed. Regarding 1-year outcomes, mortality (40.8% vs 25.5%, RR=1.6, p=0.003) and the combined stroke, systemic embolism and major bleeding event rate (10.1% vs 3.2%, RR=3.16, p=0.015) were higher for underdosed patients. Among underdosed patients, comparing with the rest of the population, the increased ischemic events rate (ischemic stroke and systemic embolism) did not reached statistical significance (3.7% vs. 1.9%, p=0.5), but it did for hemorrhagic events (major bleeding and hemorrhagic stroke) (6.1% vs 0.6%, p=0.01) On multivariate analysis, even after considering adjustment for age, Katz and CHAD2VAS2C scores, renal function and DOAC prescribed, DOAC underdosing was associated with a higher risk of both ischemic and hemorrhagic events (HR = 3.51, 95% CI 1.08–11.38). However, it lost its independent negative effect regarding mortality (HR 1.32, 95% CI 0.87–1.99). Survival and event rate in underdosed Conclusions There is a significant proportion of frail and elderly patients with AF that are underdosed. This subset has a significant survival disadvantage, eventually reflecting prescription bias. However, underdosed patients have also a higher event rate of both ischemic and hemorrhagic events, suggesting that underdosing fragile patients is not an effective strategy and that instead it may be hazardous.

Impact of residential area on the management of rheumatoid arthritis patients initiating their first biologic DMARD: Results from the Ontario Best Practices Research Initiative (OBRI).

Access to care and management of Rheumatoid Arthritis (RA) patients may differ based on residential area. We described differences in the profile of patients initiating their first biologic disease modifying antirheumatic drug (bDMARD) based on their residential area type.Cross-sectional analysis of 793 adult RA patients in the longitudinal Ontario Best Practices Research Initiative (OBRI) registry initiating their first bDMARD <30 days prior to or anytime post-enrolment. Patient residential and clinic areas (rural vs. urban) were classified using 2 methods: postal codes and Statistics Canada population centres. Sociodemographics, disease characteristics, and RA medications (tumor necrosis factor inhibitor [TNFi] vs. non-TNFi, concurrent use of conventional synthetic DMARDs [csDMARDs], and intravenous [IV] vs. subcutaneous [SC] bDMARD) at initiation of first bDMARD were contrasted between residential area types.Other than marital status, first language, and race (higher proportion of married, English speaking, Caucasian patients in rural areas), no significant differences were observed in the demographic and disease characteristics of patients living in rural and urban areas. In multivariate analysis, there was no association between residential area type and type of bDMARD use, concurrent csDMARD(s) use or route of bDMARD. However, patients living farther from their treating clinic were significantly less likely to initiate IV bDMARD. Female rheumatologist and rural clinic location were independently associated with lower odds of IV bDMARD use.The use of SC vs. IV bDMARD was associated with being seen in a clinic located in a rural area, being treated by a female rheumatologist, and living farther from treating clinic. These results suggest possible prescription bias in bDMARD selection and/or patient preferences due to convenience.

Fall-Risk-Increasing Drugs: A Systematic Review and Meta-Analysis: II. Psychotropics

Background and objectiveFalls are a major public health problem in older adults. Earlier studies showed that psychotropic medication use increases the risk of falls. The aim of this study is to update the current knowledge by providing a comprehensive systematic review and meta-analysis on psychotropic medication use and falls in older adults. Methods and designThis study is a systematic review and meta-analysis. A search was conducted in Medline, PsycINFO, and Embase. Key search concepts were “falls,” “aged,” “medication,” and “causality.” Studies were included that investigated psychotropics (antipsychotics, antidepressants, anxiolytics, sedatives, and hypnotics) as risk factors for falls in participants ≥60 years of age or participants with a mean age of ≥70 years. Meta-analyses were performed using generic inverse variance method pooling unadjusted and adjusted odds ratio (OR) estimates separately. ResultsIn total, 248 studies met the inclusion criteria for qualitative synthesis. Meta-analyses using adjusted data showed the following pooled ORs: antipsychotics 1.54 [95% confidence interval (CI) 1.28–1.85], antidepressants 1.57 (95% Cl 1.43–1.74), tricyclic antidepressants 1.41 (95% CI 1.07–1.86), selective serotonin reuptake inhibitors 2.02 (95% CI 1.85–2.20), benzodiazepines 1.42 (95%, CI 1.22–1.65), long-acting benzodiazepines 1.81 (95%, CI 1.05–3.16), and short-acting benzodiazepines 1.27 (95%, CI 1.04–1.56) Most of the meta-analyses resulted in substantial heterogeneity that did not disappear after stratification for population and healthcare setting. ConclusionsAntipsychotics, antidepressants, and benzodiazepines are consistently associated with a higher risk of falls. It is unclear whether specific subgroups such as short-acting benzodiazepines and selective serotonin reuptake inhibitors are safer in terms of fall risk. Prescription bias could not be accounted for. Future studies need to address pharmacologic subgroups as fall risk may differ depending on specific medication properties. Precise and uniform classification of target medication (Anatomical Therapeutic Chemical Classification) is essential for valid comparisons between studies.

Overall survival advantage of chemotherapy and radiotherapy in the perioperative management of large extremity and trunk soft tissue sarcoma; a large database analysis

PurposeIntergroup 9514 reported promising outcomes with neoadjuvant chemoradiotherapy for large extremity/trunk soft tissue sarcoma (ESTS). One decade later, optimum integration of chemotherapy and radiotherapy into the perioperative management of ESTS remains to be defined. MethodsThe National Cancer Data Base was used to identify 3422 patients who underwent resection for large (>8cm) high-grade STS between 2004 and 2013. Chi-square analysis was used to evaluate distribution of patient and tumor related factors within treatment groups while multivariate analyses were used to determine the impact of these factors on patient outcome. The Kaplan Meier method and Cox proportional hazards model were utilized to evaluate overall survival according to treatment regimen, with a secondary analysis based on propensity score matching to control for prescription bias and potential confounders imbalance. ResultsHazard ratio for death was reduced by 35% with radiotherapy and 24% with chemotherapy, compared to surgery alone. Combination therapy incorporating both modalities improved 5-yr survival (62.1%) compared to either treatment alone (51.4%). The sequencing of chemotherapy and radiotherapy or whether they were delivered as adjuvant vs. as neoadjuvant therapy did not affect their efficacy. Age>50years, tumor size>11cm, and tumor location on the trunk/pelvis were poor prognostic factors. ConclusionOur analysis suggests that adjunctive modalities are both critical in the treatment of large high-grade ESTS, improving survival when used individually and demonstrating synergy in combination, regardless of sequencing relative to each other or relative to surgery; thus providing a framework for future randomized trials.

Mid-Range Reading: Not a Manifesto

To judge by debates over distant reading, literary scholars might have something in common with the unadaptable tutor in george Eliot's The Mill on the Floss, the Rev. Mr. Stelling, who applies the same educational method to any boy in his charge: he sees Tom Tulliver's mind as a field to be plowed with the classics, not as a stomach that can't digest them. But if we look more closely at the range of projects in literary studies, from digital humanities to the new formalist poetics, we find few hidebound Stellings. Applying one's favorite method to all sizes and shapes of data is an obvious genre of error, and scholars and critics of all sorts studiously avoid it. In a maxim now popular among practitioners of digital humanities, when you have a hammer, everything looks like a nail. The humorous warning not to become enamored of shiny tools and ply them regardless of object (a schoolboy, all schoolboys) can come from people who use MALLET (MAchine Learning for LanguagE Toolkit) or other software to produce statistical analyses of words or of white spaces in nineteenth-century newspapers. As researchers who are primed to question the prescriptive bias of our doxa, our samples, our models, and our tools, we nevertheless have incentives to overstate the predictable errors of competing approaches.