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Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events

Cochrane Database Syst Rev. 2021 Apr 14;4:CD007694. doi: 10.1002/14651858.CD007694.pub3.


BACKGROUND: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.

OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.

SEARCH METHODS: We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers’ websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.

SELECTION CRITERIA: We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks’ duration.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.

MAIN RESULTS: Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).

AUTHORS’ CONCLUSIONS: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.

PMID:33852162 | DOI:10.1002/14651858.CD007694.pub3

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Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility

Reprod Sci. 2021 Apr 14. doi: 10.1007/s43032-021-00576-5. Online ahead of print.


A great need exists to develop tocolytic and uterotonic drugs that combat poor, labor-related maternal and fetal outcomes. A widely utilized method to assess novel compounds for their tocolytic and uterotonic efficacy is the isometric organ bath contractility assay. Unfortunately, water-insoluble compounds can be difficult to test using the physiological, buffer-based, organ bath assay. Common methods for overcoming solubility issues include solvent variation, cosolvency, surfactant or complexion use, and emulsification. However, these options for drug delivery or formulation can impact tissue function. Therefore, the goal of this study was to evaluate the ability of common solvents, surfactants, cosolvents, and emulsions to adequately solubilize compounds in the organ bath assay without affecting mouse myometrial contractility. We found that acetone, acetonitrile, and ethanol had the least effect, while dimethylacetamide, ethyl acetate, and isopropanol displayed the greatest inhibition of myometrial contractility based on area under the contractile curve analyses. The minimum concentration of surfactants, cosolvents, and human serum albumin required to solubilize nifedipine, a current tocolytic drug, resulted in extensive bubbling in the organ bath assay, precluding their use. Finally, we report that an oil-in-water base emulsion containing no drug has no statistical effect beyond the control (water), while the drug emulsion yielded the same potency and efficacy as the freely solubilized drug.

PMID:33852137 | DOI:10.1007/s43032-021-00576-5

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Differences in COVID-19 Vaccine Concerns Among Asian Americans and Pacific Islanders: The COMPASS Survey

J Racial Ethn Health Disparities. 2021 Apr 14. doi: 10.1007/s40615-021-01037-0. Online ahead of print.


BACKGROUND: Understanding concerns for receiving COVID-19 vaccines is key to ensuring appropriately tailored health communications to increase vaccine uptake. However, limited data exists about vaccine concerns among Asian Americans and Pacific Islanders (AAPI).

METHODS: Data from the COVID-19 Effects on the Mental and Physical Health of AAPI Survey Study (COMPASS), a cross-sectional, national survey for AAPI adults in the U.S. were used (N=1,646). Descriptive statistics were used to assess sample characteristics including proportions of AAPI with various COVID-19 vaccine concerns, categorized as none, side-effects only, unsafe only, and multiple reasons, and differences in vaccine concerns by socio-demographics. Ordinary multivariable logistic regression analyses were conducted to evaluate associations between a characteristic and having any vaccine concerns.

RESULTS: Overall, 76% of the respondents reported having at ≥1 concerns about the vaccine. The most common concern was side effects (65%). Vietnamese Americans reported less concerns (vs. Chinese Americans). Those who were 30-39 and 40-49 years old (vs. <30), females (vs. males), and experienced mild negative impacts from COVID-19 on family income/employment (vs. no change) reported more concerns about the vaccine. Those who had less vaccine concerns were those who reported higher (vs. low) health status, ≥60 years old (vs. <30), and separated/divorced/widowed (vs. single).

DISCUSSION: AAPI is a diverse population and this study revealed differences in vaccine concerns across AAPI groups. Findings revealed potential targets for patient education needs. Effective strategies to address various vaccine concerns across subgroups of AAPI will be crucial to ensure equity in vaccination uptake.

PMID:33852148 | DOI:10.1007/s40615-021-01037-0

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Does Bariatric Surgery Improve Faecal Incontinence? A Systematic Review and Meta-analysis

Obes Surg. 2021 Apr 14. doi: 10.1007/s11695-021-05360-7. Online ahead of print.


INTRODUCTION: Obesity increases the risk of pelvic floor disorders in individuals with obesity, including faecal incontinence. Faecal incontinence (FI) is a condition with important clinical and psychosocial consequences. Though it is associated with obesity, the effect of bariatric surgery on the prevalence and severity of FI is not well reported.

OBJECTIVE: To assess the effect of bariatric surgery on the prevalence and severity of FI in adult patients with obesity.

METHODS: This systematic review was conducted in accordance with the PRISMA statement. Two independent reviewers performed a literature search in MEDLINE, PubMed, Cochrane and Embase from 1 January 1980 to 12 January 2019. We included published English-language randomized control trials and observational studies assessing pre- and post-bariatric surgery prevalence or severity of FI. Random-effects models with DerSimonian and Laird’s variance estimator were used for meta-analysis.

RESULTS: Thirteen studies were included, eight assessing prevalence (678 patients) and 11 assessing severity of FI (992 patients). There was no significant difference in prevalence post-operatively overall, though it trended towards a reduction [pooled OR=0.55; =0.075]. There was a significant reduction of FI prevalence in women post-bariatric surgery [95% CI 0.22 to 0.94, p=0.034]. There was a statistically significant reduction in FI prevalence following Roux-en-Y gastric bypass and one anastomosis gastric bypass [0.46, 95% CI 0.26 to 0.81; p=0.007]. There was no significant reduction of incontinence episodes post-operatively [pooled mean difference =-0.17, 95% CI -0.90 to 0.56; p=0.65]. Quality of life (QOL) was not significantly improved post-bariatric surgery [mean differences for the following facets of QOL: behaviour -0.35, 95% CI -0.94 to 0.24; depression 0.04, 95% CI -0.12 to 0.2; lifestyle -0.33, 95% CI -0.98 to 0.33; p values of 0.25, 0.61 and 0.33, respectively].

DISCUSSION: There was a significant reduction in FI prevalence in women and those who underwent Roux-en-Y or one anastomosis gastric bypass. Our results for FI prevalence overall, FI severity and impact on quality of life were not statistically significant. Larger studies are needed in this under-researched area to determine the true effect of bariatric surgery on FI.

PMID:33852150 | DOI:10.1007/s11695-021-05360-7

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Gail model utilization in predicting breast cancer risk in Egyptian women: a cross-sectional study

Breast Cancer Res Treat. 2021 Apr 14. doi: 10.1007/s10549-021-06200-z. Online ahead of print.


PURPOSE: Herein, our purpose was to calculate the 5-year and lifetime risk of breast cancer and to assess new breast cancer potential contributors among Egyptian women utilizing the modified Gail model, while presenting a global comparison of risk assessment.

METHODS: This study included 7009 women from both urban and rural areas scattered across 40% of the Egyptian provinces. The 5-year risk categories were defined as low risk (≤ 1.66%) or high risk (> 1.66%), whereas the lifetime risk categories were defined as low risk (≤ 20%) or high risk (> 20%). Pearson’s Chi-squared test was performed to determine the association between participants’ characteristics and distinct risk categories. Binary logistic regression was carried out for correlation analysis.

RESULTS: The mean estimated risk for developing invasive breast cancer over 5 years was 0.86 (± 0.67), whereas the mean lifetime breast cancer risk score was 11.26 (± 5.7). Accordingly, only 614 (8.75%) and 470 (6.7%) women were categorized as individuals with high risk of breast cancer incidence in 5-year and lifetime, respectively. Only 192 participants (2.7%) conferred both high 5-year and high lifetime risk scores. Marital status, method of feeding, physical activity behavior, contraceptive use, menopause and number of children were found to have a statistically significant association with both 5-year and lifetime breast cancer risk categories.

CONCLUSION: We revealed that modified Gail model had a well-fitting and discrimination accuracy in Egyptian women when compared with other countries.

PMID:33852122 | DOI:10.1007/s10549-021-06200-z

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The cone method: Inferring decision times from single-trial 3D movement trajectories in choice behavior

Behav Res Methods. 2021 Apr 14. doi: 10.3758/s13428-021-01579-5. Online ahead of print.


Ongoing goal-directed movements can be rapidly adjusted following new environmental information, e.g., when chasing pray or foraging. This makes movement trajectories in go-before-you-know decision-making a suitable behavioral readout of the ongoing decision process. Yet, existing methods of movement analysis are often based on statistically comparing two groups of trial-averaged trajectories and are not easily applied to three-dimensional data, preventing them from being applicable to natural free behavior. We developed and tested the cone method to estimate the point of overt commitment (POC) along a single two- or three-dimensional trajectory, i.e., the position where the movement is adjusted towards a newly selected spatial target. In Experiment 1, we established a “ground truth” data set in which the cone method successfully identified the experimentally constrained POCs across a wide range of all but the shallowest adjustment angles. In Experiment 2, we demonstrate the power of the method in a typical decision-making task with expected decision time differences known from previous findings. The POCs identified by cone method matched these expected effects. In both experiments, we compared the cone method’s single trial performance with a trial-averaging method and obtained comparable results. We discuss the advantages of the single-trajectory cone method over trial-averaging methods and possible applications beyond the examples presented in this study. The cone method provides a distinct addition to existing tools used to study decisions during ongoing movement behavior, which we consider particularly promising towards studies of non-repetitive free behavior.

PMID:33852130 | DOI:10.3758/s13428-021-01579-5

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Population Pharmacokinetics of Sunitinib and its Active Metabolite SU012662 in Pediatric Patients with Gastrointestinal Stromal Tumors or Other Solid Tumors

Eur J Drug Metab Pharmacokinet. 2021 Apr 14. doi: 10.1007/s13318-021-00671-7. Online ahead of print.


BACKGROUND AND OBJECTIVE: Population pharmacokinetic analysis explored the pharmacokinetics of sunitinib and its primary active metabolite, SU012662, in children and evaluated the sunitinib dose(s) that produce comparable plasma exposures to adults receiving the approved daily dose.

METHODS: Data were from 65 children with gastrointestinal stromal tumors (GIST) or solid tumors. Pharmacokinetic models of sunitinib and SU012662 were developed using a systematic multi-step approach employing nonlinear mixed-effects modeling. The effect of predefined covariates on pharmacokinetic parameters was assessed. Final models were validated using visual predictive check and statistical techniques.

RESULTS: The final dataset comprised 439 sunitinib and 417 SU012662 post-baseline plasma observations. Base models were characterized by two-compartment models with first-order absorption and lag time. Body surface area (BSA) was the only covariate that affected (P < 0.001) pharmacokinetic parameters for sunitinib and SU012662 and was incorporated into the final models. Bootstrap results indicated that the final models represented the final dataset adequately. Based on the final models, a sunitinib dose of ~ 20mg/m2/day in children with GIST aged 6-17 years would be expected to lead to similar total plasma exposures of sunitinib and SU012661 as a dose of 50 mg/day in an adult with GIST on schedule 4/2.

CONCLUSIONS: In children with GIST or solid tumors receiving sunitinib, population pharmacokinetic analysis identified BSA as the only covariate that affected pharmacokinetic parameters and predicted a dose of ~ 20 mg/m2/day as achieving equivalent exposure to 50 mg/day in adults with GIST on schedule 4/2.

TRIAL REGISTRATION: identifiers (date registered): NCT01396148 (July 2011); NCT01462695 (October 2011); NCT00387920 (October 2006).

PMID:33852135 | DOI:10.1007/s13318-021-00671-7

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Effects of EGF-coated titanium surfaces on adhesion and metabolism of bisphosphonate-treated human keratinocytes and gingival fibroblasts

Clin Oral Investig. 2021 Apr 14. doi: 10.1007/s00784-021-03880-1. Online ahead of print.


OBJECTIVE: To assess the effects of epidermal growth factor (EGF)-coated titanium (Ti) discs on the adhesion and metabolism of keratinocytes and gingival fibroblasts exposed to nitrogen-containing bisphosphonates.

MATERIALS AND METHODS: Keratinocytes and fibroblasts were seeded (1 × 105 cells/disc) on Ti discs coated with EGF (100 nM). After 24 h, cells were exposed or not to sodium alendronate (SA) or zoledronic acid (ZA) at different concentrations (0 = control, 0.5, 1, or 5 μM) for 48 h. Cell adhesion to the substrates was evaluated by fluorescence microscopy. Cell viability (alamarBlue, n = 6) and synthesis of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and keratinocytes growth factor (KGF) (ELISA, n = 6) were assessed. Data were statistically analyzed by one-way ANOVA and Tukey tests (α = 0.05).

RESULTS: Higher cell adhesion rate was observed when keratinocytes and fibroblasts were seeded onto EGF-coated discs in comparison to uncoated discs. ZA treatment hindered the adhesion of both cell lines on the Ti discs as well as reduced the viability and synthesis of VEGF, KGF and MMP-2 by cells (p < 0.05). SA treatment did not affect cell viability, but interfered negatively on the adhesion and synthesis of EGF and KGF by the cells (p < 0.05). EGF-coated surface increased cell viability and synthesis of growth factors as well as downregulated the synthesis of MMP-2 in comparison to control (p < 0.05).

CONCLUSION: EGF applied on Ti surface improves the biological responses of oral mucosa cells exposed to SA and ZA.

CLINICAL RELEVANCE: EGF-coating on titanium may be a suitable strategy to improve oral mucosa cellular events related to biological sealing, especially for patients under bisphosphonate therapy.

PMID:33852064 | DOI:10.1007/s00784-021-03880-1

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Burden and trend of ischemic heart disease and colorectal cancer attributable to a diet low in fiber in China, 1990-2017: findings from the Global Burden of Disease Study 2017

Eur J Nutr. 2021 Apr 14. doi: 10.1007/s00394-021-02556-6. Online ahead of print.


PURPOSE: The burden of non-communicable diseases (NCDs) has increased in China. However, the contribution of dietary risks to the NCD burden has not been evaluated. This study aimed to estimate the burden of ischemic heart disease (IHD) and colorectal cancer (CRC) attributable to a diet low in fiber in China from 1990 to 2017.

METHODS: China data from the Global Burden of Disease Study (GBD) 2017 were used to assess the age-, sex-, and province-specific mortality and disability-adjusted life-years (DALYs) of IHD and CRC related to a diet low in fiber.

RESULTS: In 2017, a diet low in fiber contributed 170,143 [95% uncertainty interval (UI): 99,623-256,806] IHD deaths and 25,561 (95% UI: 13,726-39,215) CRC deaths, with the population attributable fractions (PAFs) were 9.7 and 13.7%, respectively. Males had higher risk-attributable mortality and DALY rates for IHD and CRC than females. An upward trend with age in rates of mortality and DALY was observed. All-age risk-attributable mortality and DALY rates increased significantly by 111.4 and 53.2% for IHD, and 94.4 and 59.6% for CRC from 1990 to 2017, respectively; however, the corresponding age-standardized rates for IHD and CRC showed relatively stable trends. Heilongjiang, Xinjiang, and Inner Mongolia were ranked as the top three provinces in terms of total risk-attributable NCD burden in 2017.

CONCLUSIONS: China has a large and growing NCD burden attributable to a diet low in fiber. Greater priority in disease prevention and control should be given to male and older adults throughout China, particularly in some western provinces.

PMID:33852070 | DOI:10.1007/s00394-021-02556-6

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Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance)

Breast Cancer Res Treat. 2021 Apr 14. doi: 10.1007/s10549-021-06221-8. Online ahead of print.


PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.

PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome.

RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment.

CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC.


PMID:33852121 | DOI:10.1007/s10549-021-06221-8