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Background/aims: There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. Methods: This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). Results: The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. Conclusion: Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations. [ABSTRACT FROM AUTHOR]

Importance: Some practice guidelines warn against generic L-thyroxine preparation switching. Objective: To examine the rates of generic L-thyroxine preparation switching within one year of initiating L-thyroxine, and to examine factors associated with switching. Design and setting: Retrospective study using national data from a large administrative claims database from January 2008 through November 2018. Patients: Medicare or commercially insured adults (≥18 years) who filled a generic L-thyroxine preparation. Main outcome measures: At least one switch from one generic L-thyroxine preparation to another within 1 year of L-thyroxine initiation defined by prescription fills. Results: From January 2008 to November 2018, we included 483,390 patients who initiated generic L-thyroxine: mean (SD) age was 61.4 years (15.2), 75.2% were female, 72.6% were white. Within 1 year of initiating therapy, 98,013 (20%) switched to another L-thyroxine generic preparation at least once. In a multivariate logistic regression analysis, factors associated with switching included the number of pharmacies visited to fill L-thyroxine (>2 vs 1 adjusted OR [aOR] 7.15, 95% confidence interval [CI] 6.97–7.34), age ≥75 vs. <45 years (aOR 1.29, 95% CI 1.26–1.33), history of thyroid surgery (aOR 1.22, 95% CI 1.13–1.31), and first L-thyroxine fill date in 2018 vs. 2008 (aOR 3.32, 95% CI 3.14–3.51). Conclusions and relevance: One in five patients switched among generic L-thyroxine manufacturers within one year of treatment initiation. Generic L-thyroxine switching occurred more often when more pharmacies were used to fill L-thyroxine. Given existing guideline recommendations, additional studies should clarify the impact of generic L-thyroxine switching on thyroid hormone values. [ABSTRACT FROM AUTHOR]

Purpose: To compare cardiovascular outcomes and rates of fractures and falls among patients with persistent brand-name versus generic L-thyroxine use. Methods: Retrospective, 1:1 propensity-matched longitudinal study using a national administrative claims database to examine adults (≥18 years) who initiated either brand or generic L-thyroxine between 2008 and 2018, censored at switch or discontinuation of L-thyroxine formulation or disenrollment from the health plan. Main outcome measures included rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, stroke, spine and hip fractures, and rate of falls in the outpatient or inpatient setting. Hospitalizations for pneumonia were used as a negative control. Results: 195,046 adults initiated treatment with L-thyroxine between 2008 and 2017: 87% generic and 13% brand formulations. They were mostly women (76%), young (94.6% under age 65), white (66%), and 47% had baseline thyroid stimulating hormone levels between 4.5 and 9.9 mIU/L. Among 35,667 propensity-matched patients, there were no significant differences between patients treated with brand versus generic L-thyroxine in atrial fibrillation (HR 0.96, 0.58–1.60), myocardial infarction (HR 0.66, 0.39–1.14), congestive heart failure (HR 1.30, 0.78–2.16), stroke (0.72, 0.49–1.06), spine (HR 0.87, 0.38–1.99) and hip fractures (HR 0.86, 0.26–2.82), or fall outcomes (HR 1.02, 0.14–7.32). Hospitalization rates for pneumonia (used as negative control) did not differ between groups (HR 0.85, 0.61–1.19). There were no interactions between brand versus generic L-thyroxine, these outcomes, and thyroid cancer, age, or L-thyroxine dose subgroups. Conclusions: We found no significant differences in cardiovascular outcomes and rates of falls and fractures for patients who filled brand versus generic L-thyroxine. [ABSTRACT FROM AUTHOR]

Rationale: Systematic reviews (SRs) provide the best evidence of the effectiveness of treatment strategies for asthma. Carefully conducted SRs provide high-quality evidence for supporting decision-making, but the trustworthiness of conclusions can be hampered by limitation in rigor.Objectives: To appraise the methodological quality of a representative sample of SRs on asthma treatments in a cross-sectional study.Methods: A cross-sectional study was conducted to identify SRs on asthma treatment published between 2013 and 2019 by searching the Cochrane Database of Systematic Reviews, Embase, MEDLINE, and PsycINFO. SRs including at least one meta-analysis on asthma treatments were included. Methodological quality of included SRs was assessed with the Assessing the Methodological Quality of Systematic Reviews 2 instrument. Factors associated with methodological quality were explored using multivariate regression analysis.Results: One hundred thirty-six SRs were included and appraised, with a majority being non-Cochrane reviews (71.3%). Only 12 (8.8%) were of high overall quality; 9 (6.6%), 32 (23.5%), and 83 (61.0%) were of moderate, low, and critically low overall quality, respectively. More specifically, no SRs (0.0%) conducted a comprehensive literature search; only 3 (2.2%) justified why a particular primary study design was selected; 37 (27.2%) reported sources of funding among included studies; and 54 (39.7%) provided lists of excluded studies with justification. Cochrane reviews (adjusted odds ratio, 36.56; 95% confidence interval, 10.49-127.42) and SRs published after 2017 (adjusted odds ratio, 4.52; 95% confidence interval, 1.73-11.83) were positively associated with higher methodological quality.Conclusions: Methodological quality of SRs on asthma treatments are suboptimal. Future SRs should be improved by conducting comprehensive literature searches, justifying study design selection, providing a list of excluded studies, and reporting funding sources of included studies. [ABSTRACT FROM AUTHOR]

Conclusion: Contralateral temporal lobe activation decreases with aging, regardless of hearing status, with elderly individuals showing reduced right ear advantage.Background: Aging and hearing loss possibly lead to presbycusis speech discrimination decline.Objectives: To evaluate presbycusis patients’ auditory cortex activation under verbal stimulation.Method: Thirty-six patients were enrolled: 10 presbycusis patients (mean age = 64 years, range = 60–70), 10 in the healthy aged group (mean age = 66 years, range = 60–70), and 16 young healthy volunteers (mean age = 25 years, range = 23–28). These three groups underwent simultaneous 1 kHz and 90 dB single-syllable word stimuli and (blood-oxygen-level-dependent functional magnetic resonance imaging) BOLD fMRI examinations.Results: The main activation regions were superior temporal and middle temporal gyrus. For all aged subjects, the right region of interest (ROI) activation volume was decreased compared with the young group. With left ear stimulation, bilateral ROI activation intensity held. With right ear stimulation, the aged group’s activation intensity was higher. Using monaural stimulation in the young group, contralateral temporal lobe activation volume and intensity were higher vs ipsilateral, while they were lower in the aged and presbycusis groups. On left and right ear auditory tasks, the young group showed right ear advantage, while the aged and presbycusis groups showed reduced right ear advantage. [ABSTRACT FROM PUBLISHER]

Free-living amoebae of the genus Acanthamoeba are widespread protozoans that can cause serious infectious diseases. This study characterised phosphoglycerate dehydrogenase (PGDH) and phosphoserine aminotransferase (PSAT) in the phosphorylated serine biosynthetic pathway of Acanthamoeba castellanii. The PGDH gene encodes a protein of 442 amino acids with a calculated molecular weight of 47.7 kDa and an isoelectric point (p I) of 7.64. Meanwhile, the PSAT gene encodes a protein of 394 amino acids with a calculated molecular weight of 43.8 kDa and a p I of 5.80. Confocal microscopy suggests that PGDH is mainly diffused in the cytoplasm, whereas PSAT is located in the inner part of the cell membrane. The messenger RNA (mRNA) expression levels of PGDH and PSAT vary depending on growth state under consecutive culture conditions. No significant changes in the mRNA expression levels of both PGDH and PSAT occur after the incubation of l-serine with Acanthamoeba. This result indicates that exogenous serine exerts no influence on the expression of these genes and that the so-called feedback inhibition of both PGDH and PSAT in Acanthamoeba differs from that in bacteria or other organisms. We propose that the enzymes in the phosphorylated serine biosynthetic pathway function in amoeba growth and proliferation. [ABSTRACT FROM AUTHOR]

Abstract: Acanthamoeba spp. can be parasitic in certain situations and are responsible for serious human infections, including Acanthamoeba keratitis, granulomatous amoebic encephalitis, and cutaneous acanthamoebiasis. We analyzed the fatty acid composition of Acanthamoeba castellanii trophozoites and tested the inhibitory activity of the main fatty acids, oleic acid and arachidonic acid, in vitro. Oleic acid markedly inhibited the growth of A. castellanii, with trophozoite viability of 57.4% at a concentration of 200 μM. Caspase‐3 staining and annexin V assays showed that apoptotic death occurred in A. castellanii trophozoites. Quantitative PCR and dot blot analysis showed increased levels of metacaspase and interleukin‐1β converting enzyme, which is also an indication of apoptosis. In contrast, arachidonic acid showed negligible inhibition of growth of A. castellanii trophozoites. Stimulated expression of Atg3, Atg8 and LC3A/B genes and monodansylcadaverine labeling suggested that oleic acid induces apoptosis by triggering autophagy of trophozoites. [ABSTRACT FROM AUTHOR]