From 20c9a6729bb56ba13f93c1f904dcd6e0c583fd55 Mon Sep 17 00:00:00 2001 From: Daniel Frees Date: Sun, 6 Aug 2023 19:26:03 -0700 Subject: [PATCH] add testing data for larger captured text --- scrapemed/tests/testdata/7067710_abstract.txt | 15 +++ scrapemed/tests/testdata/7067710_body.txt | 110 ++++++++++++++++++ scrapemed/tests/testdata/7067711_abstract.txt | 1 + scrapemed/tests/testdata/7067711_body.txt | 58 +++++++++ 4 files changed, 184 insertions(+) create mode 100644 scrapemed/tests/testdata/7067710_abstract.txt create mode 100644 scrapemed/tests/testdata/7067710_body.txt create mode 100644 scrapemed/tests/testdata/7067711_abstract.txt create mode 100644 scrapemed/tests/testdata/7067711_body.txt diff --git a/scrapemed/tests/testdata/7067710_abstract.txt b/scrapemed/tests/testdata/7067710_abstract.txt new file mode 100644 index 0000000..813a646 --- /dev/null +++ b/scrapemed/tests/testdata/7067710_abstract.txt @@ -0,0 +1,15 @@ +SECTION: Introduction: + +A fixed-dose combination (FDC) of ibuprofen and acetaminophen has been developed that provides greater analgesic efficacy than either agent alone at the same doses without increasing the risk for adverse events. + +SECTION: Methods: + +We report three clinical phase I studies designed to assess the pharmacokinetics (PK) of the FDC of ibuprofen/acetaminophen 250/500 mg (administered as two tablets of ibuprofen 125 mg/acetaminophen 250 mg) in comparison with its individual components administered alone or together, and to determine the effect of food on the PK of the FDC. Two studies in healthy adults aged 18–55 years used a crossover design in which subjects received a single dose of each treatment with a 2-day washout period between each. In the third study, the bioavailability of ibuprofen and acetaminophen from a single oral dose of the FDC was assessed in healthy adolescents aged 12–17 years, inclusive. + +SECTION: Results: + +A total of 35 and 46 subjects were enrolled in the two adult studies, respectively, and 21 were enrolled in the adolescent study. Ibuprofen and acetaminophen in the FDC were bioequivalent to the monocomponents administered alone or together. With food, the maximum concentration (C_max) for ibuprofen and acetaminophen from the FDC was reduced by 36% and 37%, respectively, and time to C_max (i.e. t_max) was delayed. Overall drug exposure to ibuprofen or acetaminophen in the fed versus fasted states was similar. In adolescents, overall exposure to acetaminophen and ibuprofen was comparable with that in adults, with a slightly higher overall exposure to ibuprofen. Exposure to acetaminophen and ibuprofen in adolescents aged 12–14 years was slightly higher versus those aged 15–17 years. Adverse events were similar across all treatment groups. + +SECTION: Conclusions: + +The FDC of ibuprofen/acetaminophen 250/500 mg has a PK profile similar to its monocomponent constituents when administered separately or coadministered, indicating no drug–drug interactions and no formulation effects. Similar to previous findings for the individual components, the rates of absorption of ibuprofen and acetaminophen from the FDC were slightly delayed in the presence of food. Overall, adolescents had similar exposures to acetaminophen and ibuprofen as adults, while younger adolescents had slightly greater exposure than older adolescents, probably due to their smaller body size. The FDC was generally well tolerated. \ No newline at end of file diff --git a/scrapemed/tests/testdata/7067710_body.txt b/scrapemed/tests/testdata/7067710_body.txt new file mode 100644 index 0000000..ca4e35a --- /dev/null +++ b/scrapemed/tests/testdata/7067710_body.txt @@ -0,0 +1,110 @@ +SECTION: Key Points: + + + +SECTION: Introduction: + +Ibuprofen and acetaminophen are among the most widely used non-prescription over-the-counter (OTC) analgesic/antipyretic drugs, both in the US and globally [1, 2]. The efficacy of these agents for the treatment of mild-to-moderate acute pain and fever in the OTC setting is well established [2–5]. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits the cyclooxygenase (COX)-1 and -2 isoenzymes and hence the synthesis of pro-inflammatory prostaglandins, whereas acetaminophen is believed to act through inhibition of a subclass of COX enzyme isoforms in the central nervous system [6]. Additionally, acetaminophen has been reported to have effects on descending inhibitory serotonergic pain pathways to inhibit the l-arginine nitric oxide pathway; effects on cannabinoid receptors may also be operant [7]. Both ibuprofen and acetaminophen are associated with a ceiling effect for pain relief, i.e. a point at which higher single doses of either agent provide comparable changes in pain scores versus lower doses; respective dose ceilings are 400 mg for ibuprofen [8, 9] and 1000 mg for acetaminophen [10]. Conversely, the risk of adverse events (AEs) with ibuprofen and acetaminophen, such as gastrointestinal toxicity and acute liver failure, respectively, increases with greater doses of each agent [11, 12]. + +Previous phase III clinical studies have demonstrated better efficacy of a fixed-dose combination (FDC) of ibuprofen and acetaminophen relative to monoactives in the same doses [13, 14]. Combining ibuprofen and acetaminophen may also allow for the effective use of lower doses of both agents, potentially reducing safety concerns associated with these drugs when administered alone at higher doses [11]. Indeed, combinations of ibuprofen and acetaminophen have been previously studied and have been shown to be effective in the management of acute pain and reduction of fever [3, 13–16]. Furthermore, these studies also demonstrated a safety profile of the ibuprofen/acetaminophen combination comparable or superior to the individual components [3, 13–15]. + +Pharmacokinetic (PK) studies have demonstrated no alterations in plasma drug concentrations, indicating no drug–drug interactions, when ibuprofen and acetaminophen are administered concomitantly [6, 17]; therefore, no additional safety concerns are expected when ibuprofen and acetaminophen are used in combination compared with either agent alone. In this study, we report on three separate clinical PK studies of a new FDC of ibuprofen and acetaminophen containing lower doses of the two ingredients (250 mg ibuprofen/500 mg acetaminophen, administered as two tablets of 125 mg ibuprofen/250 mg acetaminophen) than the maximum recommended doses of the single-ingredient products. Analgesic studies of this FDC have demonstrated efficacy superior to the individual components and comparable to the maximal analgesic dose of ibuprofen (400 mg; Kellstein and Leyva, unpublished data). The objectives of the three studies detailed herein were (1) to determine the relative bioavailability of ibuprofen and acetaminophen from this new FDC compared with its individual monocomponents administered together or separately in adults; (2) to evaluate the effects of food on PK in adults; and (3) to determine exposure to ibuprofen and acetaminophen from the FDC in adolescents. + +SECTION: Methods: + + SECTION: Study Design: + + Three clinical phase I PK studies were conducted. Study 1 (conducted from January to March 2016) and Study 2 (conducted from December 2015 to March 2016) were performed at the Pfizer Clinical Research Unit (New Haven, CT, USA) and were open-label, four-way crossover studies that enrolled healthy adults. The third study (Study 3) was carried out from August to November 2016 at three clinical research centers across the US (WCCT Global, Costa Mesa, CA; Pharmaceutical Research Associates, Salt Lake City, UT; and Altasciences/Vince and Associates Clinical Research, Overland Park, KS) and was an open-label, single-dose study in healthy adolescents. The studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization Good Clinical Practice guidelines, as well as local regulatory requirements. All subjects (or parents or guardians in the adolescent study) provided written informed consent, and informed assent was obtained from each minor subject. The studies were managed by Pfizer Inc. and conducted by investigators employed or contracted by, and under the direction of, Pfizer Inc. Data management and analyses were conducted by Pfizer Inc., and investigators had full access and control over data interpretation for this study. + + Subjects included in the two adult studies (i.e. Studies 1 and 2) were healthy male and female volunteers aged 18–55 years, inclusive. Included subjects had a body mass index (BMI) of 17.5–30.5 kg/m^2, inclusive, and a total body weight of > 50 kg. For inclusion in Study 3, subjects were healthy males and females 12–17 years of age, inclusive, with at least one painful condition (e.g. headache, dysmenorrhea, or musculoskeletal pain) that required the use of an oral OTC analgesic five or more times in the previous 4 weeks. Total body weight, stature, and BMI must have been within the 10th and 90th percentile for age and sex. Female subjects of childbearing potential and males able to father children must have been willing to use a highly effective method of contraception for the duration of the study and for 28 days after the last dose of study medication. + + Exclusion criteria were similar in each of the three studies. Pregnant or breastfeeding subjects were not allowed to participate in any of the studies. The presence or history of significant disease, bleeding disorder, signs of dehydration (adolescents), or any other condition in which study medication may have increased risk; any condition that could have affected drug absorption (e.g. gastrectomy); a positive urine drug screen; history of regular alcohol consumption (adults); alcohol use within 24 h (adults) or 48 h (adolescents) of dosing; or use of tobacco within 6 months of screening (adults) or within 24 h prior to dosing (adolescents) was exclusionary. Treatment with an investigational drug within 30 days, use of prescription and non-prescription drugs or dietary supplements within 7 days, or use of nutritional supplements within 14 days prior to the first dose of study drug was prohibited. Subjects with hypertension (i.e. blood pressure ≥ 140/90 mmHg in adults or ≥ 95th percentile for age and height in adolescents); QT or QRS prolongation of > 450 ms or > 120 ms, respectively; aspartate or alanine aminotransferase ≥ 3 × or total bilirubin ≥ 1.5 × the upper limit of normal; blood donation of approximately 1 pint (adults) or exceeding 130 mL or 3 mL/kg (adolescents) within 56 days; hypersensitivity to aspirin, acetaminophen, ibuprofen, or any other NSAID; consumption of grapefruit or related citrus fruits within 7 days prior to dosing; use of acetaminophen, ibuprofen, or any other NSAID within 48 h prior to the first dose of study medication; or use of caffeine or alcohol within 24 h of admission prompted study exclusion. Subjects with a positive test for hepatitis B, hepatitis C, or human immunodeficiency virus were excluded. + + + SECTION: Determination of Sample Size: + + In a previous publication [6] studying the PK profile of a novel FDC tablet formulation of ibuprofen and paracetamol (ibuprofen 400 mg/acetaminophen 1000 mg) under fasted and fed conditions, it was observed that the fed versus fasted ratio of C_max was lower than 80% for both ibuprofen and acetaminophen, suggesting that it was unlikely to achieve bioequivalence regardless of the sample size used for this parameter. Therefore, the sample size calculation in Study 1 was focused on having adequate power for declaring bioequivalence in terms of area under the concentration-time curve from time zero to infinity (AUC_∞). The sample size calculation was based on the results of the log-transformed AUC_∞ in acetaminophen, the analyte with the higher variability in this study. + + In order to provide at least 85% power for declaring bioequivalence for AUC_∞ in Study 1, 32 subjects were required to complete the study. This sample size estimate assumed a root mean square of error (RMSE) of 0.120 and that the true bioavailability of the test formulation was within 15% of that for the reference formulation [6]. To ensure at least 32 subjects completed all four periods of the study, approximately 36 subjects were to be enrolled. + + For Study 2, acetaminophen and log-transformed C_max, the analyte and the parameter with the highest variabilities observed in previous Pfizer Consumer Healthcare (PCH) studies, were used in the sample size calculation. Additionally, it was assumed that the true bioavailability of the test formulation (FDC ibuprofen/acetaminophen 250/500 mg) was within 5.0% of that for the reference formulation and that it was similar between the two analytes, ibuprofen and acetaminophen. This was observed in a previous publication studying the PK profiles of a novel FDC tablet of ibuprofen and acetaminophen (ibuprofen 400 mg/acetaminophen 1000 mg) [6]. + + Using these assumptions and an RMSE of 0.2742 (observed in a previous PCH study [#PA-96-01], which studied the PK profiles of different acetaminophen formulations of 1000 mg; unpublished data), it was estimated that a sample size of approximately 40 subjects would provide at least 85% power to establish bioequivalence in Study 2. To ensure approximately 40 subjects completed all four periods of the study, at least 44 subjects were to be enrolled. + + For Study 3, review of previous PK data for ibuprofen and acetaminophen revealed that acetaminophen and the apparent oral clearance (CL), as calculated by the dose administered/AUC_∞ (CL/F), were the analyte and PK parameter, respectively, with the higher variability. Taking into consideration regulatory guidance from the US FDA as well as historical PK data, and using the method proposed by Wang et al. [18], it was estimated that a sample size of nine subjects within each of the age groups (12–14 years and 15–17 years) would provide at least 90% power to target the 95% confidence interval (CI) to be within 60% and 140% of the geometric mean estimate of CL/F for FDC ibuprofen/acetaminophen in each age subgroup, assuming an approximate between-subject coefficient of variability of 30% for the untransformed CL for acetaminophen based on a previous adult PK study conducted by PCH. To allow for dropouts in this multicenter study, approximately 22 subjects were to be enrolled to ensure that a minimum of 18 subjects completed the study (at least 9 within each age subgroup). + + + SECTION: Study Treatments: + + Subjects were administered a single dose of study drug at baseline as described below. In Study 1, subjects were randomized to receive a single dose of 2 × FDC ibuprofen/acetaminophen 125 mg/250 mg (i.e. FDC ibuprofen/acetaminophen 250/500 mg; ^©2019 GSK group of companies or its licensor, Madison, NJ, USA) either after a 10-h fast or following a high-fat breakfast, or ibuprofen 200 mg (Advil^®; ^©2019 GSK group of companies or its licensor), or acetaminophen extended release (ER) 650 mg (Tylenol^® 8 HR; Johnson & Johnson Consumer Inc, New Brunswick, NJ, USA), both fasted. Acetaminophen 650 mg ER and ibuprofen 200 mg were used for comparison based on regulatory requirements. In Study 2, subjects were randomized to 2 × FDC ibuprofen/acetaminophen 125/250 mg, coadministered monocomponents ibuprofen 250 mg (^©2019 GSK group of companies or its licensor) and acetaminophen 500 mg (Tylenol^® Extra Strength; McNeil Consumer Healthcare, Ft. Washington, PA, USA), ibuprofen 250 mg alone, or acetaminophen 500 mg alone following an overnight fast of at least 10 h. Studies 1 and 2 had a crossover design; subjects received all four treatments, with a 2-day washout between each treatment period. Subjects remained in the clinic for the duration of the study. In Study 3, all subjects received a single dose of 2 × FDC ibuprofen/acetaminophen 125/250 mg (i.e. FDC ibuprofen/acetaminophen 250/500 mg) after an overnight fast. + + + SECTION: Phamacokinetic (PK) Sampling, Analysis, and Calculations: + + In each study, a predose PK sample was obtained approximately 60 min before each treatment period. PK sampling was conducted at 10, 20, 30, 40, 50, 60, 75, and 90 min and 2, 3, 4, 6, 8, 10, 12, 18, and 24 h after dosing in Study 1, and at the same time points through 12 h in Study 2. Samples were obtained at 10, 20, 30, 45, 60, 75, and 90 min and at 2, 3, 6, 9, and 12 h in Study 3. + + For all three studies, plasma samples were analyzed for total ibuprofen and acetaminophen using a validated analytical assay employing a high-performance liquid chromatography tandem mass spectrometric method by PPD (Middleton, WI, USA). The lower limit of quantitation (LLOQ) of the assay for ibuprofen and acetaminophen was 0.2 and 0.1 μg/mL, respectively. Clinical specimens with plasma ibuprofen or acetaminophen concentrations below the LLOQ were reported as below the LLOQ. In Studies 1 and 2, PK metrics were calculated for each subject using non-compartmental analysis of plasma concentration-time data using the internally validated software system electronic non-compartmental analysis (eNCA) version 2.2.4. In Study 3, PK metrics were calculated using Phoenix WinNonlin version 6.4 (Pharsight Corporation, Mountain View, CA, USA). + + PK metrics calculated included C_max, time to maximum concentration (t_max), area under the concentration-time curve from time zero to the last quantifiable concentration (AUC_last), AUC_∞, and terminal half-life (t_½). The comparability of PK metrics in Studies 1 and 2 was determined by constructing 90% CIs around the estimated difference between test and reference treatments using a mixed-effects model based on natural log-transformed data. The mixed-effects model was implemented using SAS PROC MIXED (SAS Institute, Inc., Cary, NC, USA) with the restricted maximum likelihood estimation method and the Kenward–Roger degrees of freedom algorithm. Because the monocomponent doses in Study 1 were different from those of the FDC, PK metrics were dose normalized to ibuprofen 250 mg and acetaminophen 500 mg for the purposes of comparison. + + Safety, including AEs, was monitored throughout the in-patient portion of the studies and during a follow-up phone call 14 days after the last investigational drug dose in each study. + + +SECTION: Results: + + SECTION: Baseline Characteristics: + + Baseline characteristics for the three studies are shown in Table 1. A total of 35 subjects were randomized in Study 1 and 46 in Study 2. In Study 3, 21 subjects were assigned to treatment. In all three studies, the proportion of males and females was approximately 50%. In Study 3, the majority (62%) of subjects were White, whereas in Studies 1 and 2, the largest proportion of subjects were Black (54% and 41%, respectively). One subject in Study 1 discontinued study drug during the first treatment period due to an inability to swallow study medication, and two subjects in Study 2 discontinued study drug during the first treatment period due to difficulties in collecting PK samples; no PK profiling was possible for these two subjects. All 21 subjects in Study 3 completed treatment and were analyzed for PK metrics and safety. + + + SECTION: PK Profiles: + + PK concentration-time profiles for ibuprofen and acetaminophen in the three studies are shown in Figs. 1 and 2, respectively. + + SECTION: Study 1: Comparison of Fixed-Dose Combination (FDC) to Single-Ingredient Products and Food Effects: + + PK metrics for ibuprofen and acetaminophen in Study 1 are summarized in Table 2. Under fasted conditions, the median plasma ibuprofen dose-normalized concentration-time profiles were similar for FDC ibuprofen/acetaminophen 250/500 mg and ibuprofen 200 mg alone (Fig. 1a) except for a shorter ibuprofen t_max for the FDC (1.38 h vs. 2.00 h, respectively) (Table 2). As seen in Table 3, the ratios of AUC_∞ (99.93%), AUC_last (100.63%), and C_max (102.44%) of FDC ibuprofen/acetaminophen 250/500 mg versus ibuprofen 200 mg under fasted conditions, and their 90% CIs, were completely contained within the limits of 80–125%, indicating bioequivalence under fasted conditions. + + There was no meaningful food effect on the overall extent of absorption of ibuprofen from the FDC. The ratios for FDC fed/FDC fasted of the adjusted dose-normalized geometric means for AUC_∞ and AUC_last were 86.61% and 85.96%, respectively. The 90% CIs for these AUC values (Table 3) were within the acceptance range for bioequivalence of 80–125%. However, the rate of absorption was delayed with food compared with fasting; the ratio for dose-normalized C_max for ibuprofen was 63.86% (Table 3), indicative of an approximately 36% lower peak concentration of ibuprofen when the FDC was administered in the fed state. Similarly, the t_max was delayed for ibuprofen when the FDC was administered with food: 3.00 h with food and 1.38 h fasted. The t_½ was similar with or without food (2.4 h vs. 2.2 h, respectively) (Table 2). + + Under fasted conditions, the median plasma acetaminophen dose-normalized concentration-time profiles were similar for FDC ibuprofen/acetaminophen 250/500 mg and acetaminophen ER 650 mg alone (Fig. 2a), with the exception of a shorter t_max for the FDC (0.58 h vs. 1.50 h, respectively) (Table 2). The overall relative bioavailability of the two treatments was equivalent based on dose-normalized test/reference ratios for AUC_∞ (108.60) and AUC_last (108.27) and their associated 90% CIs (Table 4). The ratio for dose-normalized C_max was 177.48%, indicating an approximately 77% higher peak concentration of acetaminophen derived from the FDC ibuprofen/acetaminophen 250/500 mg fasted treatment compared with that of acetaminophen ER 650 mg fasted treatment (Table 4), a finding that was not unexpected given use of the ER acetaminophen formulation in this comparison. + + There was no effect of food on the extent of absorption of the acetaminophen from the FDC. The ratios of acetaminophen fed/acetaminophen fasted (Table 4) of dose-normalized geometric means for AUC_∞ and AUC_last were 95.01% and 94.29%, respectively; the 90% CIs for each were within the acceptance range for bioequivalence of 80–125%, indicating no relevant effect of food on these metrics. As with ibuprofen, the absorption rate of acetaminophen was delayed when the FDC was taken with food compared with fasting. The ratio for dose-normalized C_max was 63.22%, indicating an approximately 37% lower peak concentration for acetaminophen after administration of the FDC in the fed state compared with the fasted state (Table 4). Similarly, t_max was 2.49 h with food and 0.58 h when fasted. The t_½ for acetaminophen was similar with and without food (4.7 h vs. 4.6 h, respectively) (Table 2). + + + SECTION: Study 2: Comparison of FDC with Individual Components and Formulation Effects: + + PK metrics for ibuprofen and acetaminophen in Study 2 are summarized in Table 5. As shown in Fig. 1b, the median plasma ibuprofen concentration-time profiles were similar for FDC ibuprofen/acetaminophen 250/500 mg, monocomponent ibuprofen 250 mg + acetaminophen 500 mg administered together, and ibuprofen 250 mg alone. The C_max was 12% higher following the FDC ibuprofen/acetaminophen 250/500 mg treatment than following treatment with either the coadministered monocomponents or ibuprofen 250 mg (Table 5). The relative bioavailability of treatments was similar based on AUC_∞, AUC_last, and C_max (Table 6), where the respective ratios of adjusted geometric means of ibuprofen were 102.53%, 103.00%, and 112.42% after administration of the FDC relative to the coadministered monocomponents. Similar results were obtained for the FDC relative to ibuprofen 250 mg alone. The ratios of adjusted geometric means of AUC_∞, AUC_last, and C_max were 102.60%, 103.08%, and 112.02%, respectively, following administration of FDC relative to ibuprofen 250 mg alone. The 90% CIs for each of these test/reference ratios reported were contained within the bioequivalence acceptance range of 80–125%, indicating bioequivalence. + + As shown in Fig. 2b, the median plasma acetaminophen concentration-time curves for FDC ibuprofen/acetaminophen 250/500 mg, monocomponent ibuprofen 250 mg + acetaminophen 500 mg, and acetaminophen 500 mg alone were similar for all treatments, and the bioavailability of treatments was also similar based on AUC_∞, AUC_last, and C_max and their associated 90% CIs (Table 6). The ratios of adjusted geometric means of acetaminophen AUC_∞, AUC_last, and C_max were 99.79%, 100.00%, and 94.32 after administration of FDC relative to the coadministered monocomponents; each respective 90% CI fell within the limits indicative of bioequivalence. For the comparison of FDC with acetaminophen 500 mg alone, the ratios of adjusted geometric means of acetaminophen AUC_∞, AUC_last, and C_max were 104.00%, 104.12%, and 101.64%, respectively; all CIs were contained within the bioequivalence acceptance range of 80–125% (Table 6), also indicating bioequivalence. + + + SECTION: Study 3: Evaluation of PK in Adolescents: + + PK metrics for ibuprofen and acetaminophen following administration of the FDC to adolescents in Study 3 are summarized in Table 7. Results are presented for all subjects and for the age groups 12–14 years and 15–17 years separately. The overall ibuprofen exposure (AUC values) following administration of the FDC was similar for both the younger and older age groups. However, the younger group had a C_max that was approximately 23% higher and occurred 1 h earlier relative to the older subjects (t_max: 1 vs. 2 h, respectively). Overall acetaminophen exposure was approximately 30% higher in the younger age group compared with the older age group. As with ibuprofen, C_max for acetaminophen was higher in the younger group (approximately 42%) and t_max was 0.5 h faster relative to the older group (0.5 vs. 1 h, respectively). The mean t_½ values were similar across all age groups. + + Although not designed for a direct comparison, a numerical comparison of the results for the FDC in the fasted state in adolescents (Table 7) with those in adults (Table 2) indicated that the overall (AUC) and maximal (C_max) exposures to ibuprofen and acetaminophen in the adolescent group were similar to those in adults; overall exposure (AUC) to ibuprofen was slightly higher (95 µg∙h/mL vs. 77–78 µg∙h/mL) in adolescents. + + + + SECTION: Safety: + + AEs across the three trials were all mild or moderate in intensity; treatment-emergent AEs are summarized in Table 8. In Study 1, seven subjects (20%) reported 10 AEs; three AEs in two subjects were determined to be treatment-related: one subject experienced nausea (after ibuprofen 200 mg) and somnolence (after FDC fasted), and another reported headache (after FDC fed). All of these treatment-related AEs were mild and resolved. In Study 2, 10 subjects (21.7%) experienced 15 AEs. Six of these AEs in three subjects were determined to be treatment-related: two subjects experienced treatment-related constipation, and a third experienced abdominal distention, upper abdominal pain, dyspepsia, and nausea. Two of these AEs occurred during treatment with the monocomponents administered together, one during treatment with ibuprofen 250 mg, and three during treatment with acetaminophen 500 mg. All of these treatment-related AEs were mild and resolved. In Study 3, two subjects (9.5%) experienced five mild treatment-emergent AEs. One AE of dizziness was considered to be related to treatment with the FDC. No dose reductions or discontinuations due to AEs, no serious AEs, and no deaths occurred in any of the three studies. Likewise, no clinically significant changes in vital signs were apparent in any study. The safety profile of the FDC observed during each study was consistent with the known safety profile of the individual components. + + +SECTION: Discussion: + +This series of PK studies demonstrates that the FDC ibuprofen/acetaminophen 250/500 mg (administered as 2 × ibuprofen/acetaminophen 125/250 mg) is bioequivalent to its individual monocomponents when administered separately or together. These data substantiate the lack of drug–drug PK interactions or formulation effects, respectively, with the combination. Acetaminophen in the FDC is bioequivalent to dose-normalized acetaminophen ER 650 mg for AUC. However, an increase in acetaminophen C_max was seen with the FDC compared with the acetaminophen ER 650 mg comparator. This result was expected as the FDC is an immediate-release formulation, whereas the acetaminophen 650 mg used was an ER formulation with delayed absorption. Ibuprofen in the FDC was also bioequivalent to dose-normalized ibuprofen 200 mg for AUC and C_max. These results therefore demonstrate that the exposure to ibuprofen and acetaminophen in the FDC is similar to those of commercially available formulations of the individual components, indicating there should be no increased safety concerns. + +A food effect on the rate of absorption was observed with the FDC, with C_max for ibuprofen and acetaminophen decreased 36% and 37%, respectively, in the presence of food. T_max was also delayed by approximately 1.6 h for ibuprofen and 1.9 h for acetaminophen in fed, compared with fasting, conditions. This is consistent with a previous study in which an FDC of ibuprofen/acetaminophen at a total dose of 400/1000 mg, respectively, exhibited decreased C_max values in the fed versus fasted state (ratios of 76% and 61% for ibuprofen and acetaminophen, respectively) and delayed median t_max by 0.75 h and 1 h, respectively [6]. Studies of ibuprofen alone and acetaminophen alone have also demonstrated decreased C_max and delayed t_max when either is administered with food [19, 20]. Although the overall extent of absorption (AUC) of ibuprofen from the FDC was slightly reduced (14%) in the presence of food compared with ibuprofen alone, both AUC_∞ and AUC_last met the bioequivalence standard of 80–125%. The overall exposure to acetaminophen was not affected by food, therefore it is unlikely that the slightly reduced AUC of ibuprofen observed in the fed state would be clinically meaningful in terms of analgesic efficacy. However, the effect of food on efficacy has not been evaluated as the dental pain studies of the FDC were conducted with food restrictions, as is the standard methodology. + +The majority of PK studies of ibuprofen and acetaminophen have focused on adults and younger subjects, with limited data available in adolescents aged 12–17 years [6, 21–28]. As a result, population PK estimates and allometric adjustments or scaling have typically provided the rationale for dosing in this younger age group [27, 28]. The present study of FDC ibuprofen/acetaminophen 250/500 mg therefore adds new and relevant information by reporting ibuprofen and acetaminophen PK in this age group. Importantly, no clinically important differences in PK exposure were observed for adolescents in comparison with adult subjects 18 years of age and older. Indeed, while these studies were not designed to be compared, the overall plasma concentration-time curves for both components of the FDC (in the fasted state) were similar across all three studies, and comparison of AUC and C_max values between the adolescent and adult studies also indicates similar exposures to both components, with a slightly higher overall exposure to ibuprofen in adolescents. This provides support for similar dosing recommendations for adolescents as in adults. + +In the younger age subgroup of subjects aged 12–14 years, ibuprofen and acetaminophen exposures were slightly increased following a single dose of the FDC compared with the older age group aged 15–17 years. This difference was as expected given the smaller body surface area and lower body weight of the younger subjects, and the differences were not clinically meaningful. + +These studies confirm the results of previous studies indicating no drug–drug PK interaction between ibuprofen and acetaminophen [6, 17]; therefore, no additional safety concerns are expected compared with the administration of either agent alone. The data also indicate no formulation effect when combining the two ingredients into one tablet. Consistent with these findings, the FDC ibuprofen/acetaminophen 250/500 mg was safe and generally well tolerated in these studies. All AEs were mild or moderate in severity, with no discontinuations due to AEs. AEs were equally distributed between treatment arms, with no new safety concerns compared with the individual components. Importantly, exposure in adolescents was similar to that in adults, and the FDC was generally well tolerated, indicating that this formulation can be safely used in this population. However, it should be noted that these were small, short-duration studies, and rare and serious AEs such as gastrointestinal bleeding and liver failure would not be expected. However, a large, longer-duration study (13 weeks) evaluating a similar FDC of ibuprofen/acetaminophen (200/500 mg) found a safety profile that was at least as favorable as maximum single OTC doses of the individual components (ibuprofen 400 mg, acetaminophen 1000 mg) [15]. + +SECTION: Conclusions: + +The FDC ibuprofen/acetaminophen 250/500 mg has a PK profile similar to its monocomponent constituents when administered alone or coadministered. Overall exposure to ibuprofen and acetaminophen was bioequivalent under fed versus fasted conditions, although, as expected, food delayed absorption, similar to what has previously been observed for each individual monocomponent. In adolescents, overall exposure to ibuprofen from the FDC, as measured by AUC, was similar in individuals 12–14 years of age and 15–17 years of age, but C_max was 23% higher and t_max was achieved earlier in the younger age group of patients. In contrast, acetaminophen exposure (i.e. AUC) was 30% higher in the younger group after administration of the FDC; C_max was 42% higher and t_max occurred earlier in the younger age group of patients than in older adolescents. Exposure to ibuprofen and acetaminophen in the overall group of adolescents was similar to that in adults, supporting the same dosing in that population. + diff --git a/scrapemed/tests/testdata/7067711_abstract.txt b/scrapemed/tests/testdata/7067711_abstract.txt new file mode 100644 index 0000000..5aed0a8 --- /dev/null +++ b/scrapemed/tests/testdata/7067711_abstract.txt @@ -0,0 +1 @@ +Before the mid-twentieth century, there was no comprehensive narrative about empirical conditions in Swedish seas. Around 1970, this view changed profoundly. In line with growing research and the emergence of ‘the environment’ as a defining concept, conditions in Swedish seas were framed as a ‘narrative of decline’. Marine scientists have since recorded more diverse developments than are described by an overall declensionist narrative. Data show trends of interrupted decline, variability and even recovery, taking place at least partly in response to effective policy and legislation. We suggest that beyond the specialised fields of marine sciences and marine environmental history, the overarching narrative of decline has persisted, paying little attention to local and regional particularities as well as cultural and political dimensions of the marine environment. This overly uniform narrative risks obscuring historical reality and, hence, fails to adequately inform policy and the public about developments and outcomes of interventions in Swedish seas. \ No newline at end of file diff --git a/scrapemed/tests/testdata/7067711_body.txt b/scrapemed/tests/testdata/7067711_body.txt new file mode 100644 index 0000000..b361f16 --- /dev/null +++ b/scrapemed/tests/testdata/7067711_body.txt @@ -0,0 +1,58 @@ +SECTION: Introduction: A narrative of decline: + +Knowledge of the status of fish stocks, other sea resources, vegetation and environmental conditions in the Swedish coastal seas was once fragmented and fragile. While local knowledge among fishermen and coastal communities have always been important, the perceived need to increase knowledge on a national scale is more recent. An early effort was made in the mid-eighteenth century, when the Royal Swedish Academy of Sciences showed interest in and promoted marine science, for instance by initiating a study on herring fishing in the Stockholm Archipelago (Humble 1745). The reason was an overwhelming negative deficit in trade of fish products, which concerned the Swedish government at the time and spurred several actions to improve the standards of the fishing industry (Awebro 2008). By the late 1800s, collection of data started to stabilise and become more systematic, and has improved continuously since then. Before the mid-twentieth century, there was no comprehensive narrative about the conditions recorded; variability was the overarching understanding and some long-term climatic trends on the centennial and millennial scales were observed (Hagen and Feistel 2005). + +Between ca. 1950 and 1970, this view changed profoundly in line with growing marine and oceanographic research and more generally with the rise of a new understanding of ‘the environment’ as a certain entity that is measurable and with directional and definable ‘rates of change’. Based on this new understanding of the environment as a common name for a growing ‘catalogue’ of ‘problems’, including e.g. overpopulation, erosion, pollution, resource depletion and overfishing (Warde et al. 2018), the growing body of data on marine conditions was reframed as a ‘narrative of decline’. This was a global phenomenon, but it was also applied specifically to Swedish coastal seas. The narrative was particularly pronounced for the Baltic Sea but also comprised the North Sea and Skagerrak. The re-interpretation from variability to decline can be regarded as fully established by the early 1970s with main components including pollutants, especially hazardous substances, eutrophication and sea traffic issues, including oil spills (e.g. Dybern 1970; Jansson 1980). + +With regard to marine biota, it has been known since ancient times that fishing and catch size affected fish stocks locally (Muscolino 2012). Real concern for the risk of undermining marine resources or even losing species is a much later phenomenon, though it was perceived as early as the eighteenth century, which saw the disappearance of the sea cow. Rudyard Kipling famously wrote about it in the story of Kotick, the white seal in The Jungle Book (1894), which was a critique of American stewardship (or lack of it) in Alaska, bought from Russia in 1867. Depletion of fish stocks became a matter of more widespread political and scientific concern with the arrival of trawl fishing in the North Sea in the late nineteenth century. ‘Overfishing’ as a scientific concept was introduced around that time, albeit first vaguely defined and much debated (Petersen 1900). In 1902, as a result of the concern for overfishing, the International Council for the Exploration of the Seas (ICES) was formed. In 1911, international cooperation to avoid extinction of the fur seal resulted in the North Pacific Fur Seal Convention, signed by the US, Russia, Japan and Great Britain. Minimal fishing in European seas during World War I demonstrated a recovery of fish stocks that reinforced the importance of previous human impact and as a result, demands on constraint and planning of harvesting were raised. Concepts such as total acceptable catch or ‘optimum catch’ were proposed to indicate that, just as in forestry where Nachhaltigkeit (sustainable yield) had been a norm since the eighteenth century, restraint and precaution were economically beneficial in fisheries as well (Sahrhage and Lundbeck 1974/1992, p. 288). + +Ocean fishing went on unabated, however, and global annual harvests grew from less than 20 million tonnes after WWI to a peak of 90 million tonnes in 1988 (Muscolino 2012, p. 286). The sea around us, to quote the title of Rachel Carson’s 1953 widely read book, was still conceived of as too vast and too deep to be understood as anything but a dark, unknown and inhospitable wilderness where humans had barely started exploration, let alone wrought any significant havoc. In only a couple of decades, the master narrative of the ocean shifted completely, and evidence such as ever more frequent collapses of fish populations (sardines in Japan and California, cod in the Northwest Atlantic, herring in the Atlantic and the North Sea, anchovies in Peru, etc.) was mounting to suggest that the oceans were if not in immediate danger at least an integrated part of ‘the environment’, which was now understood as threatened and vulnerable. + +The oceans were part of the concerns brought to the table at the United Nations Conference on the Human–Environment (UNCHE) in Stockholm in 1972, a safe sign of the new and concerned outlook (e.g. Patin 1982). November the same year, another UN conference in London adopted principles to regulate dumping of waste and pollution in the oceans (Schenker 1973). By then whaling and overfishing of, for instance, the Norwegian herring stock or the Peruvian anchovy had already added strength to a sense of decline in the seas. More recently, climate change, plastic pollution and fishing in general have been added to the narrative as drivers of global marine environmental degradation. This narrative of decline has been more or less hegemonic since the 1970s and has served as the essential understanding of legislation and regulation of the state of the seas. The understanding of conditions in Swedish coastal seas is to a considerable extent a reflection of this emerging and eventually pervasive global narrative, with the 1974 Helsinki Convention for the Protection of the Marine Environment of the Baltic Sea Area an important landmark. However, the Swedish narrative also has its particular features and certainly its own empirical foundations, with the Baltic Sea as an especially grave case in point, with an all but ‘dead’ sea floor (Elmgren 2001). + +In recent years, marine scientists have recorded more diverse developments in Swedish seas than are described by an overall declensionist narrative. Data show trends of interrupted decline, variability and even recovery, taking place at least partly in response to effective policy and legislation, such as bans on several toxins (Nyberg et al. 2015). Nevertheless, beyond the scientific realm, an overarching declensionist narrative tends to persist. Elmgren et al. (2015) note that “The Baltic Sea is often portrayed as an environmental disaster area, by the media, by non-governmental environmental organisations, and by some scientists” (p. 339). Such a uniform declensionist narrative for Swedish seas is part of a much broader idea of global environmental degradation, which while important in some respects has also been criticised for downplaying historically and geographically specific environmental developments (e.g. Nixon 2011; Malm and Hornborg 2014), including outcomes of legislation and other forms of interventions—or lack thereof. + +While many of the overarching traits of a declensionist framework remain indisputable, empirical data and historical analysis suggest that Swedish seas are better represented by a narrative of complexity with reform, relative stability and even recovery as strong elements. While acknowledging serious environmental impacts, past and present, a framework that recognises complex and divergent developments can showcase that many governmental interventions are and have been successful when and where they have been practised. Marine historian Bolster (2006) has emphasised the importance of situated and specific environmental narratives for the oceans, stating that “Central to such stories will be the recognition, common to some historians, that complex variables create historically specific situations – not universal ones, or replicable ones, or natural ones, but historically specific situations” (p. 582). In this paper, we suggest that such narratives are largely missing from public perceptions and policy frameworks for Swedish seas. Diverse trajectories seem overshadowed by a simplified narrative of overall degradation, pointing to a lack of societal reflection on specific developments in marine conditions. This may in turn counteract possibilities and prerequisites for an open dialogue on Swedish marine environments regarding what is attainable, at what costs and on what time scales. We illustrate this viewpoint with a few examples from influential policy frameworks, but our aim is also to highlight a need for further interdisciplinary research into how scientific findings and measurements of environmental conditions in Swedish seas are recorded and registered in broader society and non-scientific discourses—such research could provide a more substantial review and examination of Swedish marine environmental narratives than we are able to pursue within the scope of this article. + +SECTION: Mixed messages: The empirical evidence: + +Some developments in Swedish coastal seas sustain a narrative of rapid and problematic change, even decline. Perhaps the area of most concern is climate change. Increased water temperature has been a major ecological driver in Swedish seas since the late 1800s. With inspiration from the famous British Challenger expedition between 1872 and 1876, the first hydrographic expedition in Swedish waters was conducted by R/V Gustaf af Klint in 1877. Soon these measurements became regular (Fonselius and Valderrama 2003). The time series show very clearly that bottom water temperatures have increased significantly over the twentieth century. Warmer climate conditions in the Baltic Sea have become especially pronounced since the 1980s, with a shift from a continental to maritime type of climate associated with large-scale changes in atmospheric circulation (Lehmann et al. 2011). Effects of higher temperatures are appreciable from records on ice cover in the Baltic Sea, Skagerrak and Kattegat, showing an apparent tendency of a reduction in ice cover over the last decades. While predictions of future climate changes and their consequences are uncertain, it is fair to say that climate and temperature records show a clear negative trend, and that the overall effects are cause for concern, in Swedish seas just like elsewhere. + +Recent losses of eelgrass (Zostera marina) manifest another negative trend. However, the most disastrous effects occurred already in the 1930s, when almost all eelgrass in the North Atlantic died off due to a wasting disease (Rasmussen 1977). Before this episode, about half of the shallow Kattegat was covered in eelgrass meadows. Less than a fifth of this distribution area has been recovered, inevitably also due to decreased water transparency, restricting the distribution vertically. + +In the Baltic Sea, eutrophication is a major ecological driver. Due to increased cultivation in the entire drainage area basin since the Middle Ages, the Baltic Sea, once oligotrophic with a rather low standing crop of fish and low productivity, has gradually become more enriched and hence more productive (e.g. Zillén and Conley 2010). During the nineteenth century, increased demand for agricultural products led to ever more intense cultivation (Hoffmann et al. 2000). Increased resource utilisation typically led to higher discharges of nutrients from farmed lands. However, elaborated techniques in handling manure and fertilisers have constrained discharges of nutrients in spite of a tremendous increase in productivity. Thus, quite counter-intuitively, nutrient discharges from farmed land in Sweden are still at about the same level as they were 150 years ago. Despite such counter-measurements, increased discharges from the Baltic Sea drainage area as a whole have caused increased eutrophication of the Baltic Sea since WWII; since about the 1990s, the trend has reversed in the southern Baltic Sea and Kattegat, as nutrient loading has eventually culminated and is presently decreasing (e.g. Andersen et al. 2017). + +The combined effects of eutrophication and increasing bottom water temperatures have led to successively more severe hypoxia in the deeper parts of the Baltic proper due to higher respiration rates. Since 1900, the area of hypoxia in the Baltic Sea has increased from 5000 km^2 to over 60 000 km^2 (Carstensen et al. 2014). However, the distribution of hypoxic and anoxic bottoms has been rather stable over the last 40–50 years. A major inflow in the mid-1990s oxygenated bottoms in the Gotland deep temporarily but the deeper parts became hypoxic rather soon again. For now, hypoxia trends in Baltic coastal environments are mixed; improvements in oxygen content are clearly visible in the hypoxia-prone Stockholm Archipelago, whereas the situation is steadily getting worse in the Gulf of Finland. Hypoxia also leads to leakage of phosphorous from the sediments, and thus nitrogen becomes limiting for algae, promoting cyanobacteria growth (Zillén and Conley 2010). + +Eutrophication is a complicated process and not entirely dependent on the availability of nutrients. Resilient ecosystems, including many trophic layers, are less likely to be disrupted by nutrient loading than simplified ecosystems. Trophic relationships within the Baltic, as well as in the Kattegat and Skagerrak Inshore, are indeed altered due to loss of predator fish biomass. Apex predators such as marine mammals and birds were initially also very common, but in the 1960s, high levels of toxic substances, mainly persistent organic pollutants, were found in Swedish waters and almost exterminated seal stocks in the 1970s. Other top predators such as sea eagles and peregrine falcons all but disappeared for similar reasons. As the contaminants have declined and hunting of seals became very restricted, marked recoveries have taken place (e.g. Olsson et al. 1994). The trend exemplified by the seal stocks is representative for overall conditions for hazardous substances in Swedish seas. A comprehensive study of toxins (PCBs, DDTs, HCHs and HCB) in marine biota in Swedish seas found that between 1969 and 2012 the levels decreased significantly, showing that measures taken in the form of bans and restrictions on different substances in the 1970s and 1980s have had the desired effect (Nyberg et al. 2015). While levels in the Baltic Sea remain elevated, with considerable variation between different substances and areas, the overall trend is one of recovery. + +Another central dimension of Swedish seas are fisheries. Swedish fishermen who fished in offshore waters with longlines for large sized cod, ling (Molva molva) and other species in the Skagerrak and Kattegat were confronted at an early stage with falling catches. Lowering of the biomass level, especially the disappearance of big fish, forced artisanal Swedish fishers to explore new fishing grounds as their low-productive fishery became economically unsustainable already in the 1860s, unless the landings per unit effort was exceptionally high (Cardinale et al. 2014). As the longliners left the Kattegat and Skagerrak for outlying areas, demersal trawling and other active forms of fishing were introduced on the Swedish west coast at the beginning of the twentieth century. With the exceptions of the two world wars and a conspicuous rebound in the fish stocks during the so-called gadoid outburst in the 1970s, demersal stocks have tended to decline since then (Engelhard et al. 2016). The former, highly productive Swedish Skagerrak coast, as well as the Kattegat on the whole, has become some of the most degraded areas in the world in terms of predatory fish. + +This continuous deterioration of the marine fish fauna along the Swedish coasts has, paradoxically, protected the fishing industry from being scrutinised (cf. Hultkrantz et al. 1997). Events during the 1980s, especially algal blooms, fish kills in connection to hypoxia in southern Kattegat and seal epizootic, which in the end turned out to be a natural phenomenon (e.g. Härkönen et al. 2006), contributed to a widespread beneficial view of fishermen as being part of a drama of ecological deterioration and dilapidation that they could not avert; they were victims rather than agents. This victimisation of a whole industry that after all had miniscule economic importance had consequences for sound fisheries management. As the enforcement of economic zones took place in the early 1980s, Swedish fishers traditionally fishing in the North Sea lost most of their former fishing opportunities. The simultaneous cod boom in the Baltic Sea partly solved the problem of excessive fishing capacity, as parts of the fishing fleet relocated there. The trawling limit, originally enforced in the early twentieth century to protect the coastal zone from over-exploitation, was also moved closer to the coast to present excess fishing capacity with new fishing opportunities (cf. Cardinale et al. 2014). + +In the North Sea, biological conditions for fish stocks, especially gadoids, are similarly far from optimal, in spite of a strong recovery (ICES 2015). Recruitment has been depressed since around 2000, so the recovery is entirely due to reductions in fishing pressure. The biomasses of many fish species are nonetheless at record levels. In agreement with the Johannesburg Declaration on Sustainable Development, fishing has been downsized as to get higher yields, i.e. adjustments towards the biometric goal of maximum sustainable yield (MSY). Although MSY has been criticised for a long time (Larkin 1977; Finley 2011), this recovery still indicates that keeping to a restricted harvest strategy may turn stocks productive once again in spite of unfavourable conditions. + +On the EU level, erratic decision-making marked fisheries governance during the first period of the common fishery policy (CFP) since its introduction in the mid-1980s, i.e. neglect of ICES catch advice, inadequate enforcement of rules, excessive subsidies to the fishing fleet and so forth (Sissenwine and Symes 2007). However, fishery management has improved considerably over the last decade. The most important measure has been to implement effort regulations since the turn of the century, whether in number of operating fishing vessels or number of days at sea (Fernandes and Cook 2013). Another important change is the introduction of the notion of ecosystem-based management, representing a more holistic approach to governance. However, while the idea has helped to shift perspectives, Elmgren et al. (2015) suggest that ecosystem-based management, while explicitly stated as a strategy for the Baltic Sea already in 1992, remains an idea more than a practice. + +In light of these empirical examples, we suggest that there is a discord between the historical data of ecological trends in Swedish seas and a unified narrative of environmental decline: the eutrophication process in the Baltic Sea has been halted and is showing signs of an early phase of reversal, the contamination of several hazardous substances including oil spills are decreasing, and apex species such as eagle, cormorant, falcon and seal populations are recovering (e.g. Herrmann et al. 2014). This is not to diminish that, on the other hand, fisheries are not recovering according to expectations, sediments will continue to leak unhealthy compounds for many years, and plastic particles are accumulating. Above all, a warmer climate will put ecosystems under increasing stress, accelerating problems such as the oxygen deficit in the Baltic Sea. + +SECTION: Diversity versus decline in policy frameworks: + +The empirical image of heterogeneous data lacking a uni-linear direction is in our view poorly represented in frameworks for Swedish marine policy. In an overview of successes and failures in the Baltic Sea, Elmgren et al. (2015) note that a narrative of declining or poor conditions tend to dominate in public and policy communications about conditions in Swedish seas; for example, a map produced by HELCOM in 2010 indicates bad environmental status in almost the entire Baltic Sea, failing “crucially, to present the real progress that has been made, proving that investing in the environment pays off” (p. 339). HELCOM’s earlier Baltic Sea Action Plan (2007, pp. 6–11) likewise fails to recognise past or partial improvements, such as decreased relative input of nutrients, focusing instead entirely on requirements needed to achieve the future ideal goal of “a Baltic Sea unaffected by eutrophication” by 2021; the vision of a final state of sustainability is emphasised at the expense of recognising situated and historical developments of continuously evolving human–environment relations. In HELCOM’s most recent “holistic assessment”, an introductory set of comprehensive parameters gives a similarly discouraging impression of overall environmental status as “not good”; a sub-basin specific overview suggests that in ten out of 17 basins there are no positive environmental trends at all, while in the remaining seven areas they are only minor improvements. The illustrations for both eutrophication and hazardous substances are also predominantly negative, in contrast to the detailed accompanying description which states that while hazardous substances continue to be a cause for concern “the number of improving trends outweighs the number of deteriorating trends” (HELCOM 2018). + +A series of reports from the Swedish Agency for Marine and Water Management likewise communicates current conditions as overwhelmingly unfavourable. Part one in the series (2012) summarises that overall conditions in Swedish seas are not consistent with good environmental status, without recognising any positive developments. The detailed description of the status of seal populations neglects to mention successful reduction of toxins, stating only briefly that an increase in numbers has taken place since the 1970s when seals were threatened both by hunting and pollutants but that overall status remains poor. Rather than highlighting reduction of several toxins as an example of successful policy making and environmental improvement, recognition of positive trends for hazardous substances is not made until halfway through the report. The foreword to part four in the same series states that despite long-term and comprehensive attempts to improve the marine environment signs still abound that conditions are not good and negative pressures are increasing (2015), concluding that the goal of good environmental status in Swedish seas by 2020 will not be attained. Nowhere in the foreword or in the following summary are any improvements or cases of recovery mentioned. Overall, these reports give an overly negative impression of developments in Swedish seas and fail to communicate the positive impacts management and legislation demonstrably can have when such efforts are enabled and followed through. + +These brief examples illustrate our impression that while academic disciplines such as marine sciences and marine historical ecology have made attempts to showcase and understand cases of recovery and improvement in Swedish seas, such efforts are much less noted and appreciated outside scientific contexts. Lack of coordination between itemised scientific trends and guiding frameworks for responsive policy are likely to have a negative impact on societal support for science-based marine policy. Overrepresentation of declensionist narratives may lead to poor public understanding and hence counteract informed debate regarding under which circumstances policies and other measures taken to improve environmental conditions may be successful, and what the reasons are for continued support and investment in such interventions. + +Fisheries management is a case in point for how non-alignment between scientific recordings and public and policy frameworks can lead to misdirected management strategies. Translation of the complex developments of fish stocks and their causes into what may be considered thoughtful policy is often poor. Most decisions for Swedish fish stocks are made through the EU’s common fisheries policy, where negotiations showcase diverse priorities between different concerned member states. Recently decided 2019 fishing quotas for the Baltic Sea indicate limited responses to scientifically recorded trends; while numbers for cod in the eastern Baltic are strongly negative, quotas were only reduced 16% (however the fishery became closed in the second half of the year 2019), while tentative indicators of positive developments for western Baltic cod lead to a sudden jump in quotas with an increase of over 70%, despite estimates that overall current cod fisheries in the Baltic Sea are only 10% of what they were 30 years ago (ICES 2017). The press release from the European Council for the recent quotas indicates that the decisions are influenced by the persistent framing of EU fisheries as a predominantly socio-economic concern as much as an ecological and environmental one, stating that the new quotas represent a step towards achieving sustainability in Baltic Sea fisheries “whilst at the same time respecting the socioeconomic viability of our coastal communities”. This understanding is different from contemporary scientific frameworks for fisheries in for example the US, where the ecological sustainability of fisheries has been established as the primary concern and a basic legal requirement before any fishing can occur. The importance of the socioeconomic perspective persists in the EU notwithstanding the fact that fisheries in the Baltic Sea are of an insignificant value in an economic sense. Moreover, capital-intensive, highly industrial fisheries are systematically favoured by strong economic subsidies and higher quotas than the Baltic coastal fisheries which may soon have disappeared in large parts of the Baltic. The ‘costs’ of downsizing the fishing effort of industrial fisheries thus represent nothing less than gains, also for the local fishing villages (cf. Svedäng and Hornborg 2015). + +SECTION: Appropriate narratives: + +Narratives are essentially sense-making devices—they frame scientific information and shape policy and public imaginations (e.g. Lakoff 2010). Often rooted in very old religious and philosophical tropes or patterns of societal temporalization, narratives of environmental decline have developed in recent decades into a dominant framework for understanding the relationship between people, societies and the natural world (e.g. Garrard 2012). The predominance of an overall narrative of decline is thus not unique to Swedish seas; in approval of coherence, broad-brush environmental narratives tend to favour simplicity over complexity and regularly fail to reflect the details of sometimes diverging directions of social and ecological change, as well as of scientific data and methods. Mixed messages, regional varieties, and far-reaching and drawn out environmental processes that are difficult to make sense of—to narrate—are often underrepresented in policy as well as public imaginations (Nixon 2011). + +Moreover, similarly to climate change, ocean environments are particularly challenging to perceive because they are invisible and inaccessible to most people—we see the shore and patches of the surface, the rest is hidden. In order to know and care about what happens in the sea we depend on information and narratives provided, directly or indirectly, by scientists (e.g. Chiarappa and McKenzie 2013). Recognition of the problem of “shifting baselines” (Jackson et al. 2011) originated in marine sciences and is especially relevant for the oceans, where many things are “invisible to the human eye yet absolutely essential for understanding the marine past” (Taylor 2013, p. 68). Recent efforts have been made to remedy the lack of knowledge about historical marine conditions, including in the Baltic Sea, for example, through the History of Marine Animal Populations (HMAP) Project (e.g. Lajus et al. 2013; MacDiarmid et al. 2016). + +The preference for simplicity and generalisation is apparent in some of the most compelling environmental narrative concepts, such as the “death of nature/end of nature” (e.g. McKibben 1989), or more recently those of “planetary boundaries” (Rockström et al. 2009) or the “Anthropocene” (Crutzen and Stoermer 2000). The most overarching and influential of all these narrative concepts has probably been that of “the environment” itself, which has remained a defining idea for about 70 years (Warde et al. 2018). There are also numerous examples of collapse stories from the modern history of the oceans that apply broad scale tropes and concepts of environmental decline and harmful human impact on marine ecosystems (e.g. Speer 1997). + +These concepts are obviously meaningful. They serve as convenient shorthand for certain overarching tendencies and phenomena within an infinitely complex earth system and an almost endless set of social–ecological relationships and their changes over time. They also function as providers of instrumental functions—heuristic, explanatory, warning and mobilising. But they also have shortcomings which need to be recognised and discussed. Criticised for downplaying local and regional particularities as well as cultural, political and other human dimensions (e.g. Malm and Hornborg 2014), such concepts risk enforcing an overly uniform narrative of environmental degradation, including regarding the state of Swedish seas. In fact, we argue that the overarching decline story has obscured historical reality of Swedish marine conditions and also that it has, hence, not adequately informed policy and the public. Overarching perspectives may overshadow successful and constructive efforts to manage and improve conditions on local and regional scales. The creation of marine protected areas is a case in point. The ban on trawling in Öresund, for example, has shown how local initiatives on limited geographical scales can have very positive effects, despite perceptions of marine life as highly mobile and interconnected (e.g. Højgård Petersen et al. 2018). Persuasive narratives can also be counterproductive by leading to premature conclusions. For example, concerns about toxins and eutrophication in Swedish seas formed a strong public narrative in the 1980s and 1990s. This narrative also became the dominant framework for understanding declines and changes in fish stocks, and as a result, the role of fishing practices was downplayed. Not until the 2000s was overfishing rather than toxins appreciated as the main reason for the decline of ground-fish on the Swedish west coast in particular, and relevant regulations called for (Svedäng 2003). A challenge is therefore to carefully differentiate between times when overarching uni-directional narratives are appropriate, and other times when local or otherwise specific conditions show results that are not in line with dominant trends, and thus better understood through other frameworks. +