The role of mesolevel characteristics of the health care system and socioeconomic factors on health care use - results of a scoping review.

BACKGROUND: Besides macrolevel characteristics of a health care system, mesolevel access characteristics can exert influence on socioeconomic inequalities in healthcare use. These reflect access to healthcare, which is shaped on a smaller scale than the national level, by the institutions and establishments of a health system that individuals interact with on a regular basis. This scoping review maps the existing evidence about the influence of mesolevel access characteristics and socioeconomic position on healthcare use. Furthermore, it summarizes the evidence on the interaction between mesolevel access characteristics and socioeconomic inequalities in healthcare use. METHODS: We used the databases MEDLINE (PubMed), Web of Science, Scopus, and PsycINFO and followed the 'Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols extension for scoping reviews (PRISMA-ScR)' recommendations. The included quantitative studies used a measure of socioeconomic position, a mesolevel access characteristic, and a measure of individual healthcare utilisation. Studies published between 2000 and 2020 in high income countries were considered. RESULTS: Of the 9501 potentially eligible manuscripts, 158 studies were included after a two-stage screening process. The included studies contained a wide spectrum of outcomes and were thus summarised to the overarching categories: use of preventive services, use of curative services, and potentially avoidable service use. Exemplary outcomes were screening uptake, physician visits and avoidable hospitalisations. Access variables included healthcare system characteristics such as physician density or distance to physician. The effects of socioeconomic position on healthcare use as well as of mesolevel access characteristics were investigated by most studies. The results show that socioeconomic and access factors play a crucial role in healthcare use. However, the interaction between socioeconomic position and mesolevel access characteristics is addressed in only few studies. CONCLUSIONS: Socioeconomic position and mesolevel access characteristics are important when examining variation in healthcare use. Additionally, studies provide initial evidence that moderation effects exist between the two factors, although research on this topic is sparse. Further research is needed to investigate whether adapting access characteristics at the mesolevel can reduce socioeconomic inequity in health care use.

Correction: Impact of temperature-dependent non-PAN peroxynitrate formation, RO2NO2, on nighttime atmospheric chemistry.

Correction for 'Impact of temperature-dependent non-PAN peroxynitrate formation, RO2NO2, on nighttime atmospheric chemistry' by Michelle Färber et al., Phys. Chem. Chem. Phys., 2024, https://doi.org/10.1039/d3cp04163h.

Impact of temperature-dependent non-PAN peroxynitrate formation, RO2NO2, on nighttime atmospheric chemistry.

The formation of peroxynitrates (RO2NO2) from the reaction of peroxy radicals (RO2) and nitrogen dioxide (NO2) and their subsequent redissociation are typically not included in chemical mechanisms. This is often done to save computational time as the assumption is that the equilibrium is strongly towards the RO2 + NO2 reaction for most conditions. Exceptions are the reactions of the methyl peroxy radical due to its abundance in the atmosphere and of acyl-RO2 radicals due to the long lifetime of peroxyacyl nitrates RO2NO2 (PANs). In this study, the nighttime oxidation of cis-2-butene and trans-2-hexene in the presence of NO2 is investigated in the atmospheric simulation chamber SAPHIR, Forschungszentrum Jülich, Germany, at atmospherically-relevant conditions at different temperatures (≈276 K, ≈293 K, ≈305 K). Measured concentrations of peroxy and hydroperoxy radicals as well as other trace gases (ozone, NO2, volatile organic compounds) are compared to state-of-the-art zero-dimensional box model calculations. Good model-measurement agreement can only be achieved when reversible RO2 + NO2 reactions are included for all RO2 species using literature values available from the latest SAR by [Jenkin et al., Atmos. Chem. Phys., 2019, 19, 7691]. The good agreement observed gives confidence that the SAR, derived originally for aliphatic RO2, can be applied to a large range of substituted RO2 radicals, simplifying generalised implementation in chemical models. RO2NO2 concentrations from non-acyl RO2 radicals of up to 2 × 10 cm-3 are predicted at 276 K, impacting effectively the kinetics of RO2 radicals. Under these conditions, peroxy radicals are slowly regenerated downwind of the pollution source and may be lost in the atmosphere through deposition of RO2NO2. Based on this study, 60% of RO2 radicals would be stored as RO2NO2 at a temperature of 10 °C and in the presence of a few ppbv of NO2. The fraction increases further at colder temperatures and/or higher NO2 mixing ratios. This does not only affect the expected concentrations of RO2 radicals but, as the peroxynitrates can react with OH radicals or photolyse, they could comprise a net sink for RO2 radicals as well as increase the production of NOx (= NO + NO2) in different locations depending on their lifetime. Omitting this chemistry from the kinetic model can lead to misinterpreted product formation and may prevent reconciling observations and model predictions.

Acute pulmonary embolism and cancer: findings from the COPE study.

BACKGROUND: Patients with acute venous thromboembolism associated with cancer have an increased risk of recurrences and bleeding in the long term. RESEARCH QUESTION: To describe the clinical features and short-term course of patients with acute pulmonary embolism (PE) and active cancer, previous cancer or no cancer. STUDY DESIGN AND METHODS: Patients with acute PE included in COPE-prospective, multicentre study of adult patients with acute, symptomatic, objectively diagnosed PE-were classified as having active cancer, previous cancer, or no cancer. RESULTS: Overall, 832 patients had active cancer, 464 with previous cancer and 3660 patients had no cancer at the time of acute PE. The most prevalent primary sites of active cancer were urogenital (23.0%), gastrointestinal (21.0%), and lung (19.8%), with a high prevalence of metastatic disease (57.6%) and ongoing anticancer treatment (16.2%). At discharge, a direct oral anticoagulant was used in 43.1%, 78.8%, and 82.0% of patients with active cancer, previous cancer, and no cancer, respectively. Rates of death in-hospital and at 30 days were higher in patients with active cancer compared to patients with previous cancer and no cancer (7.9% vs. 4.3% vs. 2.2% and 13.8% vs. 5.2% vs. 2.6%, respectively). Rates of major bleeding were 4.8%, 2.6%, and 2.4%, respectively. Among patients with active cancer, lung or metastatic cancer were independent predictors of death; brain, hematological or gastrointestinal cancer had the highest risk of major bleeding. INTERPRETATION: Among patients with acute PE, those with active cancer have high risks for death or major bleeding within 30 days. These risks vary based on primary site of cancer. CLINICAL TRIAL REGISTRATION: clinicaltrial.gov identifier: NCT03631810.

Analytical methods for identifying sequences of utilization in health data: a scoping review.

BACKGROUND: Healthcare, as with other sectors, has undergone progressive digitalization, generating an ever-increasing wealth of data that enables research and the analysis of patient movement. This can help to evaluate treatment processes and outcomes, and in turn improve the quality of care. This scoping review provides an overview of the algorithms and methods that have been used to identify care pathways from healthcare utilization data. METHOD: This review was conducted according to the methodology of the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews Extension for Scoping Reviews (PRISMA-ScR) Checklist. The PubMed, Web of Science, Scopus, and EconLit databases were searched and studies published in English between 2000 and 2021 considered. The search strategy used keywords divided into three categories: the method of data analysis, the requirement profile for the data, and the intended presentation of results. Criteria for inclusion were that health data were analyzed, the methodology used was described and that the chronology of care events was considered. In a two-stage review process, records were reviewed by two researchers independently for inclusion. Results were synthesized narratively. RESULTS: The literature search yielded 2,865 entries; 51 studies met the inclusion criteria. Health data from different countries ([Formula: see text]) and of different types of disease ([Formula: see text]) were analyzed with respect to different care events. Applied methods can be divided into those identifying subsequences of care and those describing full care trajectories. Variants of pattern mining or Markov models were mostly used to extract subsequences, with clustering often applied to find care trajectories. Statistical algorithms such as rule mining, probability-based machine learning algorithms or a combination of methods were also applied. Clustering methods were sometimes used for data preparation or result compression. Further characteristics of the included studies are presented. CONCLUSION: Various data mining methods are already being applied to gain insight from health data. The great heterogeneity of the methods used shows the need for a scoping review. We performed a narrative review and found that clustering methods currently dominate the literature for identifying complete care trajectories, while variants of pattern mining dominate for identifying subsequences of limited length.

A Four Carbon Organonitrate as a Significant Product of Secondary Isoprene Chemistry.

Oxidation of isoprene by nitrate radicals (NO3) or by hydroxyl radicals (OH) under high NOx conditions forms a substantial amount of organonitrates (ONs). ONs impact NOx concentrations and consequently ozone formation while also contributing to secondary organic aerosol. Here we show that the ONs with the chemical formula C4H7NO5 are a significant fraction of isoprene-derived ONs, based on chamber experiments and ambient measurements from different sites around the globe. From chamber experiments we found that C4H7NO5 isomers contribute 5%-17% of all measured ONs formed during nighttime and constitute more than 40% of the measured ONs after further daytime oxidation. In ambient measurements C4H7NO5 isomers usually dominate both nighttime and daytime, implying a long residence time compared to C5 ONs which are removed more rapidly. We propose potential nighttime sources and secondary formation pathways, and test them using a box model with an updated isoprene oxidation scheme.

Identifying and Investigating Ambulatory Care Sequences Before Invasive Coronary Angiography.

BACKGROUND: The concept of care pathways is widely used to provide efficient, timely, and evidence-based medical care. Recently, the investigation of actual empirical patient pathways has gained attention. We demonstrate the usability of State Sequence Analysis (SSA), a data mining approach based on sequence clustering techniques, on comprehensive insurance claims data from Germany to identify empirical ambulatory care sequences. We investigate patients with coronary artery disease before invasive coronary angiography (CA) and compare identified patterns with guideline recommendations. This patient group is of particular interest due to high and regionally varying CA rates. METHODS: Events relevant for the care of coronary artery disease patients, namely physician consultations and medication prescriptions, are identified based on medical guidelines and combined to define states. State sequences are determined for 1.5 years before CA. Sequence similarity is defined for clustering, using optimal matching with theory-informed substitution costs. We visualize clusters, present descriptive statistics, and apply logistic regression to investigate the association of cluster membership with subsequent undesired care events. RESULTS: Five clusters are identified, the included patients differing with respect to morbidity, urbanity of residential area, and health care utilization. Clusters exhibit significant differences in the timing, structure, and extent of care before CA. When compared with guideline recommendations, 3 clusters show signs of care deficits. CONCLUSIONS: Our analyses demonstrate the potential of SSA for exploratory health care research. We show how SSA can be used on insurance claims data to identify, visualize, and investigate care patterns and their deviations from guideline recommendations.

Socioeconomic position and self-rated health among female and male adolescents: The role of familial determinants in explaining health inequalities. Results of the German KiGGS study.

OBJECTIVE: Although health inequalities in adolescence are well documented, the underlying mechanisms remain unclear. Few studies have examined the role of the family in explaining the association between the family's socioeconomic position and adolescents' self-rated health. The current study aimed to explore whether the association between socioeconomic position and self-rated health was mediated by familial determinants. METHODS: Using data from wave 2 of the"German Health Interview and Examination Survey for Children and Adolescents" (KiGGS) (1,838 female and 1,718 male 11- to 17-year-olds), linear regression analyses were conducted to decompose the total effects of income, education, occupational status, socioeconomic position index and adolescents' subjective social status on self-rated health into direct effects and indirect effects through familial determinants (family cohesion, parental well-being, parental stress, parenting styles, parental obesity, smoking and sporting activity). RESULTS: A significant total effect of all socioeconomic position indicators on self-rated health was found, except for income in male adolescents. In female adolescents, more than 70% of the total effects of each socioeconomic position indicator were explained by familial mediators, whereas no significant direct effects remained. The most important mediator was parental well-being, followed by family cohesion, parental smoking and sporting activity. In male adolescents, the associations between income, parental education, the socioeconomic position index and subjective social status were also mediated by familial determinants (family cohesion, parental smoking, obesity and living in a single-mother family). However, a significant direct effect of subjective social status remained. CONCLUSION: The analysis revealed how a family's position of socioeconomic disadvantage can lead to poorer health in adolescents through different family practices. The family appears to play an important role in explaining health inequalities, particularly in female adolescents. Reducing health inequalities in adolescence requires policy interventions (macro-level), community-based strategies (meso-level) and programs to improve parenting and family functioning (micro-level).

Role of contextual and compositional characteristics of schools for health inequalities in childhood and adolescence: a scoping review.

OBJECTIVES: To synthesise the evidence on the role of compositional or contextual characteristics of schools in the association between students' socioeconomic position and their health in primary and secondary education in developed economies. DESIGN: Scoping review. We included studies examining the role of at least one school or class characteristic on students' health inequalities and was published since 1 January 2000, in English or German. We searched PubMed/Medline, Web of Science and Education Resources Information Center. We provided a narrative synthesis and an overview of findings. School characteristics were grouped into five broad categories: school composition, school climate, school policies and organisation, food environment and facilities. RESULTS: Of 8520 records identified, 26 studies were included. Twelve studies found a moderating and 3 a mediating effect. The strongest evidence came from studies examining the moderating effect of school composition, that is, the negative impact of a low individual socioeconomic position on mental health and well-being was aggravated by a low average socioeconomic position of schools. Evidence concerning the role of school climate, school stratification (eg, performance base tracking) and sponsorship, food environment and sport facilities and equipment was generally weak or very weak and mostly based on singular findings. Overall, favourable meso-level characteristics mitigated the negative impact of low individual socioeconomic position on health outcomes. CONCLUSIONS: School characteristics affect health inequalities in children and adolescents to some degree, but future research is necessary to strengthen the existing evidence and address under-represented aspects in school characteristics and health outcomes.

Which Meso-Level Characteristics of Early Childhood Education and Care Centers Are Associated with Health, Health Behavior, and Well-Being of Young Children? Findings of a Scoping Review.

Characteristics of early childhood education and care (ECEC) centers might be relevant for children's health. This scoping review aims to provide an overview of the association between meso-level characteristics (MLCs) of ECEC centers with children's health, health behavior, and wellbeing. Five databases were searched for quantitative and qualitative research articles published in English or German since 1 January 2000 on health, health behavior, and wellbeing of children aged 0 to 6 years considering MLCs of ECEC centers. Two authors screened 10,396 potentially eligible manuscripts and identified 117 papers, including 3077 examinations of the association between MLCs and children's health indicators (Kappas > 0.91). Five categories of MLCs were identified: (1) structural characteristics, (2) equipment/furnishings, (3) location, (4) facilities/environment, (5) culture/activities/policies/practices, and 6) staff. Only very few studies found an association of MLCs with body weight/obesity, and general health and wellbeing. Especially physical activity and mental health were related to MLCs. In general, the location (rural vs. urban, neighborhood status) seemed to be a relevant health aspect. MLCs of ECEC centers appeared relevant for child health indicators to different degrees. Future research should focus on these associations, in detail, to identify concrete ECEC indicators that can support health promotion in early childhood.

Gas-Particle Partitioning and SOA Yields of Organonitrate Products from NO3-Initiated Oxidation of Isoprene under Varied Chemical Regimes.

Alkyl nitrate (AN) and secondary organic aerosol (SOA) from the reaction of nitrate radicals (NO3) with isoprene were observed in the Simulation of Atmospheric PHotochemistry In a large Reaction (SAPHIR) chamber during the NO3Isop campaign in August 2018. Based on 15 day-long experiments under various reaction conditions, we conclude that the reaction has a nominally unity molar AN yield (observed range 90 ± 40%) and an SOA mass yield of OA + organic nitrate aerosol of 13-15% (with ∼50 µg m-3 inorganic seed aerosol and 2-5 µg m-3 total organic aerosol). Isoprene (5-25 ppb) and oxidant (typically ∼100 ppb O3 and 5-25 ppb NO2) concentrations and aerosol composition (inorganic and organic coating) were varied while remaining close to ambient conditions, producing similar AN and SOA yields under all regimes. We observe the formation of dinitrates upon oxidation of the second double bond only once the isoprene precursor is fully consumed. We determine the bulk partitioning coefficient for ANs (K p ∼ 10-3 m3 µg-1), indicating an average volatility corresponding to a C5 hydroxy hydroperoxy nitrate.

Correlation of mesolevel characteristics of the healthcare system and socioeconomic inequality in healthcare use: a scoping review protocol.

INTRODUCTION: Although the impact of macrolevel characteristics of health systems on socioeconomic inequity in health has been studied extensively, the impact of access characteristics on a smaller scale of health systems has received less attention. These mesolevel characteristics can influence access to healthcare and might have the potential to moderate or aggravate socioeconomic inequity in healthcare use. This scoping review aims to map the existing evidence of the association of socioeconomic inequity in healthcare use and mesolevel access characteristics of the health system. METHODS AND ANALYSIS: In conducting the scoping review, we follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols Extension for Scoping Reviews. The search will be carried out in four scientific databases: MEDLINE (via PubMed), Web of Science, Scopus and PsycINFO. Main eligibility criteria are inclusion in the analysis of a measure of socioeconomic position, a measure of individual healthcare use and a mesolevel determinant of access to healthcare services. The selection process consists of two consecutive screening stages (first: title/abstract; second: full text). At both stages, two reviewers independently assess the eligibility of studies. In case of disagreement, a third reviewer will be involved. Cohen's kappa will be calculated to report inter-rater agreement between reviewers. Results are synthesised narratively, as a high heterogeneity of studies is expected. ETHICS AND DISSEMINATION: No primary data are collected for the presented scoping review. Therefore, ethical approval is not necessary. The scoping review will be published in an international peer-reviewed journal, and findings will be presented on national and international conferences.

Role of contextual and compositional characteristics of schools for health inequalities in childhood and adolescence: protocol for a scoping review.

INTRODUCTION: Childhood and adolescence are crucial life stages for health trajectories and the development of health inequalities in later life. The relevance of schools for health and well-being of children and adolescents has long been recognised, and there is some research regarding the association of contextual and compositional characteristics of schools and classes with health, health behaviour and well-being in this population. Little is known about the role of meso-level characteristics in relation to health inequalities. The aim of this scoping review is to retrieve and synthesise evidence about the mediating or moderating role of compositional or contextual characteristics of schools for the association between students' socioeconomic position and health in primary and secondary education. METHODS AND ANALYSIS: We will conduct a systematic search of electronic databases in PubMed/Medline, Web of Science and Education Resources Information Center. Studies must meet the following inclusion criteria: (1) The population must be students attending primary or secondary schools in developed economies. (2) The outcomes must include at least one indicator for individual health, health behaviour or well-being. (3) The study must include at least one contextual or compositional characteristic of the school context and one individual determinant of socioeconomic position. (4) The study must also examine the mediating or moderating role of the contextual or compositional characteristic of the school context for the associations between socioeconomic position and health, health behaviour or well-being. (5) The study must be published since 1 January 2000 in English or German language. We will provide a narrative synthesis of findings. ETHICS AND DISSEMINATION: We will not collect primary data and only include secondary data derived from previously published studies. Therefore, ethical approval is not required. We intend to publish our findings in an international peer-reviewed journal and to present them at national and international conferences.

Making shared decision-making (SDM) a reality: protocol of a large-scale long-term SDM implementation programme at a Northern German University Hospital.

INTRODUCTION: Shared decision-making (SDM) is not yet widely used when making decisions in German hospitals. Making SDM a reality is a complex task. It involves training healthcare professionals in SDM communication and enabling patients to actively participate in communication, in addition to providing sound, easy to understand information on treatment alternatives in the form of evidence-based patient decision aids (EbPDAs). This project funded by the German Innovation Fund aims at designing, implementing and evaluating a multicomponent, large-scale and integrative SDM programme-called SHARE TO CARE (S2C)-at all clinical departments of a University Hospital Campus in Northern Germany within a 4-year time period. METHODS AND ANALYSIS: S2C tackles the aforementioned components of SDM: (1) training physicians in SDM communication, (2) activating and empowering patients, (3) developing EbPDAs in the most common/relevant diseases and (4) training other healthcare professionals in SDM coaching. S2C is designed together with patients and providers. The physicians' training programme entails an online and an in situ training module. The decision coach training is based on a similar but less comprehensive approach. The development of online EbPDAs follows the International Patient Decision Aid Standards and includes written, graphical and video-based information. Validated outcomes of SDM implementation are measured in a preintervention and postintervention evaluation design. Process evaluation accompanies programme implementation. Health economic impact of the intervention is investigated using a propensity-score-matched approach based on potentially preference-sensitive hospital decisions. ETHICS AND DISSEMINATION: Ethics committee review approval has been obtained from Medical Ethics Committee of the Medical Faculty of the Christian-Albrechts-University Kiel. Project information and results will be disseminated at conferences, on project-hosted websites at University Hospital Medical Center Schleswig Holstein and by S2C as well as in peer-reviewed and professional journals.

Fast Photochemistry in Wintertime Haze: Consequences for Pollution Mitigation Strategies.

In contrast to summer smog, the contribution of photochemistry to the formation of winter haze in northern mid-to-high latitude is generally assumed to be minor due to reduced solar UV and water vapor concentrations. Our comprehensive observations of atmospheric radicals and relevant parameters during several haze events in winter 2016 Beijing, however, reveal surprisingly high hydroxyl radical oxidation rates up to 15 ppbv/h, which is comparable to the high values reported in summer photochemical smog and is two to three times larger than those determined in previous observations during winter in Birmingham (Heard et al. Geophys. Res. Lett. 2004, 31, (18)), Tokyo (Kanaya et al. J. Geophys. Res.: Atmos. 2007, 112, (D21)), and New York (Ren et al. Atmos. Environ. 2006, 40, 252-263). The active photochemistry facilitates the production of secondary pollutants. It is mainly initiated by the photolysis of nitrous acid and ozonolysis of olefins and maintained by an extremely efficiently radical cycling process driven by nitric oxide. This boosted radical recycling generates fast photochemical ozone production rates that are again comparable to those during summer photochemical smog. The formation of ozone, however, is currently masked by its efficient chemical removal by nitrogen oxides contributing to the high level of wintertime particles. The future emission regulations, such as the reduction of nitrogen oxide emissions, therefore are facing the challenge of reducing haze and avoiding an increase in ozone pollution at the same time. Efficient control strategies to mitigate winter haze in Beijing may require measures similar as implemented to avoid photochemical smog in summer.

Winter photochemistry in Beijing: Observation and model simulation of OH and HO2 radicals at an urban site.

A field campaign was conducted from November to December 2017 at the campus of Peking University (PKU) to investigate the formation mechanism of the winter air pollution in Beijing with the measurement of hydroxyl and hydroperoxyl radical (OH and HO2) with the support from comprehensive observation of trace gases compounds. The extent of air pollution depends on meteorological conditions. The daily maximum OH radical concentrations are on average 2.0 × 106 cm-3 and 1.5 × 106 cm-3 during the clean and polluted episodes, respectively. The daily maximum HO2 radical concentrations are on average 0.4 × 108 cm-3 and 0.3 × 108 cm-3 during the clean and polluted episodes, respectively (diurnal averaged for one hour bin). A box model based on RACM2-LIM1 mechanism can reproduce the OH concentrations but underestimate the HO2 concentrations by 50% during the clean episode. The OH and HO2 concentrations are underestimated by 50% and 12 folds during the polluted episode, respectively. Strong dependence on nitric oxide (NO) concentration is found for both observed and modeled HO2 concentrations, with the modeled HO2 decreasing more rapidly than observed HO2, leading to severe HO2 underestimation at higher NO concentrations. The OH reactivity is calculated from measured and modeled species and inorganic compounds (carbon monoxide (CO), NO, and nitrogen dioxide (NO2)) make up 69%-76% of the calculated OH reactivity. The photochemical oxidation rate denoted by the OH loss rate increases by 3 times from the clean to polluted episodes, indicating the strong oxidation capacity in polluted conditions. The comparison between measurements at PKU site and a suburban site from one previous study shows that chemical conditions are similar in both urban and suburban areas. Hence, the strong oxidation capacity and its potential contribution to the pollution bursts are relatively homogeneous over the whole Beijing city and its surrounding areas.

The efficacy and safety of continuous intravenous administration of remifentanil for birth pain relief: an open study of 205 parturients.

In an observational study, we prospectively evaluated the efficacy and safety of remifentanil in 205 parturients. Remifentanil was administered as a continuous infusion. The initial infusion of 0.025 microg x kg(-1) x min(-1) was increased in a stepwise manner to a maximum dose of 0.15 microg x kg(-1) x min(-1). Maternal pain, other maternal and fetal variables, side effects, and satisfaction were recorded. The mean (+/-sd) visual analog score before the start of the infusion was 9.4 +/- 1.2 cm and decreased to 5.1 +/- 0.4 cm after 5 min and 3.6 +/- 1.5 cm after 30 min. The maternal side effects were minimal and no fetal or neonatal side effects were noted.