Pharmacokinetic/pharmacodynamic (PK/PD) integration models are used to investigate the antimicrobial activity characteristics of drugs targeting pathogenic bacteria through comprehensive analysis of the interactions between PK and PD parameters. PK/PD models have been widely applied in the development of new drugs, optimization of the dosage regimen, and prevention and treatment of drug-resistant bacteria. In PK/PD analysis, minimal inhibitory concentration (MIC) is the most commonly applied PD parameter. However, accurately determining MIC is challenging and this can influence the therapeutic effect. Therefore, it is necessary to optimize PD indices to generate more rational results. Researchers have attempted to optimize PD parameters using mutant prevention concentration (MPC)-based PK/PD models, multiple PD parameter-based PK/PD models, kill rate-based PK/PD models, and others. In this review, we discuss progress on PD parameters for PK/PD models to provide a valuable reference for drug development, determining the dosage regimen, and preventing drug-resistant mutations. MDR cause infections that threaten the health of humans, livestock, and wild animals. Some Gram-negative . In other words, MIC is a net result when the growth rate of microorganisms (the population of inoculum) equal to the kill rate of a given drug at the fixed concentration which different from the dynamic character of drug concentrations in vivo. So, MIC is a hybrid and contextual PD variable due to its nature and the conditions for obtaining it , the mutant frequency  may largely increase when amount of bacteria is exposed to antibacterial drugs, such as fluoroquinolones. These limitations may result in the emergence of MDR bacteria. Thus, developing new drugs and designing dosage regimens based only on MIC for PK/PD simulation is not sufficient. Therefore, it is necessary to explore PD parameters to more accurately investigate the antibacterial activities of drugs against pathogens.In PK/PD integration models, the most commonly applied PK/PD parameters are based on minimal inhibitory concentration (MIC). MIC is a standard ining it , 11. Thelux pump . The teslux pump –15. (a) In order to overcome the limitations of MIC-based PK/PD integration in clinical treatment, researchers have conducted numerous studies to optimize PD parameters, including mutant prevention concentration (MPC)-based PK/PD models, multiple PD parameter-based PK/PD models, and kill rate-based PK/PD models. Therefore, this review firstly covers the basic methods, concepts, and mathematical models of MIC-based PK/PD integration. And then introduces other PD parameter-based PK/PD integration approaches. This work provides a valuable guidance for optimizing the dosage regimen, developing new drugs, and preventing the emergence of MDR bacteria.in vitro, ex vivo, and in vivo PK/PD models. For in vitro PK/PD studies, peristaltic pump and hollow fiber models are the most commonly used methods for simulating PK processes of drugs in hosts. The peristaltic pump model was applied to simulate one-compartment, two-compartment model, and multiple-compartment models. The simplest peristaltic pump model consists of a storage compartment (blank medium), a central compartment , and an elimination compartment (waste medium) connected by rubber pipe, and the PK characteristics (elimination rate) of drugs in hosts are simulated by a peristaltic pump. A magnetic bar is applied to mix the medium, and a thermostat is used to ensure the optimal growth temperature for pathogens. After measuring the drug concentration and bacterial cell density, the antibacterial effect and PK/PD parameters are calculated and simulated to guide the design of the dosage regimen . After collecting these samples at different timepoints following drug administration, drug concentrations and time-kill curves are determined, and a mathematical equation is applied to analyze the relationships between PK/PD parameters and antibacterial effect. TCF is a type of extracellular fluid that is typically targeted during bacterial infection. Thus, TCF is an ideal medium for ex vivo PK/PD integration studies. TCF can be acquired through surgery by implanting a tissue cage between muscle and skin. After ~4 weeks, granulation tissue surrounds the tissue cage and produces TCF. The TCF model has been widely applied in pig, rabbit, cattle, camel, goat, and other animals  and the target organ infection model (TOIM). The TCIM was established by adding pathogens to the tissue cage model, a series of dosage regimens were subsequently administrated for treatment, and TCF samples were collected for drug concentration measurement and bacterial population counting at different timepoints. After calculating the PK/PD parameters and antibacterial effect , the relationship between PK/PD parameters and antibacterial effect was fitted and the dosage was predicted , and %T >MIC  , Cnterval) , 63–67  . Actuallnterval) –70. The nterval) , so, the process , 73. Formax model (Equation 1). This sigmoid concentration-response model is a strongly empirical model. This model is a useful tool to formalize our understanding of experimental data, but it has no clear relationship to real physical characteristics of the actual system being studied.To confirm the most appropriate PK/PD parameters and predict the values of PK/PD parameters for designing the dosage regimen, a mathematical model is needed. A commonly applied model for this purpose is the Sigmoid Emax is the maximum antibacterial effect of a drug, EC50 is the value of PK/PD parameters or drug concentrations at 50% Emax, C is the antibacterial concentration or PK/PD parameter, and N (Hill coefficient) is the slope of the fitted curves between PK/PD parameters or drug concentrations and antibacterial effect. The correlation coefficient (R2) is applied to evaluate the relationship between PK/PD parameters and antibacterial effect; the higher of the value of R2, the closer the PK/PD parameters are related to effect.where E10 CFU/mL) for PK/PD integration. In serious infections, susceptible bacteria may produce a natural gene mutation (first-step mutant bacteria) that are resistant to drugs. At low drug concentrations, susceptible bacteria will gradually be killed and first step mutant bacteria may reproduce rapidly, which may result in recurrence of infection and further resistant mutations. Therefore, a new PD variable was proposed for high bacterial cell densities. MPC is the MIC of drugs for high bacterial cell densities (1010 CFU/mL) that can inhibit the growth of first step mutant bacteria  theory was proposed based on MIC and MPC  to compare the difference between AUC24/MIC and AUC24/MPC as PK/PD parameters for inhibiting the generation of drug-resistant bacteria. The results showed that generation of drug-resistant mutants could be inhibited when AUC24/MPC values were between 22 and 25 . When applying AUC24/MIC as the target PK/PD parameter, the values were 8-fold different despite having the same MIC. Therefore, AUC24/MPC was more suitable than AUC24/MIC as the target PK/PD parameter to inhibit the generation of drug-resistant mutations. Zhang et al.  of linezolone concentration within the MSW and the emergence of drug-resistant bacteria. The results showed that the correlation between TMSW and T >MPC and area under the bacterial curve of mutation (AUBCM) was 0.99. Thus, TMSW was an important indicator for predicting the emergence and enrichment of drug-resistant bacteria. Xiong et al.  to describe the bactericidal effect . This model was used to investigate the maximum bactericidal effect (Kmax), the normal growth rate of bacteria (Kgrowth), drug concentration (Ct), the concentration that achieves a 50% maximum bactericidal effect (EC50), the delayed growth constant (Z), and the initial bacterial population (N). This model can dynamically describe changes in bacterial population over time under different drug concentrations. The results showed that the bactericidal effect of piperacillin was closely related to the time of drug administration; the more frequent the administration, the better the antibacterial effect. Compared with models base on MIC alone, this model can provide more detailed and accurate guidance for designing the dosage regimen.Nolting et al.  studied E. coli. In this model, ψ(a) is the net bacterial growth rate under different drug concentrations (a), ψmax is the maximum bacterial growth rate in drug-free medium, ψmin is the minimum bacterial net growth rate in drug-containing medium, N is the Hill coefficient , and zMIC represent the MIC values of different bacteria. The results showed that when MIC was the same, the larger the value of k, the better the bactericidal effect, and the smaller the value of ψmin, the better the bactericidal effect. In this model, four PD parameters were employed, which can more precisely reflect the antibacterial characteristics of drugs to help design a more accurate and rational dosage regimen. Foerster et al.  and the maximum kill rate was 0.11−1 h. Zhang et al. , and the maximum kill rate was 0.48 log10 CFU/mL/h. Maneke et al. , Key Technology Research and Development Program of Henan Province (212102110373), the Scientific Research Program of Henan Institute of Science and Technology (103010620002/004), Postdoctoral Research Foundation of Henan Institute of Science and Technology, Program for Innovative Research Team (in Science and Technology) in University of Henan Province (22IRTSTHN026), and Key Scientific Research Projects of Universities in 2020 (20B230002).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The ILC increased by 1.3% for GMAX and 0.5% for GMED (both p < 0.05). Neither of the AG protocols mitigated deconditioning of the gluteal muscles. Whereas all gluteal muscles atrophied, the ratio of lipids to intramuscular water increased only in GMAX and GMED muscles. These changes could impair the function of the hip joint and increased the risk of falls. The deconditioning of the gluteal muscles in space may negatively impact the hip joint stability of astronauts when reexpose to terrestrial gravity.Exposure to spaceflight and head-down tilt (HDT) bed rest leads to decreases in the mass of the gluteal muscle. Preliminary results have suggested that interventions, such as artificial gravity (AG), can partially mitigate some of the physiological adaptations induced by HDT bed rest. However, its effect on the gluteal muscles is currently unknown. This study investigated the effects of daily AG on the gluteal muscles during 60-day HDT bed rest. Twenty-four healthy individuals participated in the study: eight received 30 min of continuous AG; eight received 6 × 5 min of AG, interspersed with rest periods; eight belonged to a control group. T1-weighted Dixon magnetic resonance imaging of the hip region was conducted at baseline and day 59 of HDT bed rest to establish changes in volumes and intramuscular lipid concentration (ILC). Results showed that, across groups, muscle volumes decreased by 9.2% for gluteus maximus (GMAX), 8.0% for gluteus medius (GMED), and 10.5% for gluteus minimus after 59-day HDT bed rest (all  Because the musculoskeletal system has evolved within the Earth’s gravitational field, humans possess a complex weight-bearing system that facilitates bipedal standing balance, gait, and protection against joint injury during functional tasks . When weMuscle atrophy is one of the indicators of musculoskeletal deconditioning . SeveralMagnetic resonance imaging is used to quantify muscle architecture and properties of muscle tissue and has been used to evaluate changes in the size of several weight-bearing muscles, including calf muscles , quadricThe gluteal muscle group includes the gluteus maximus (GMAX), gluteus medius (GMED), and gluteus minimus (GMIN) muscle. The GMED and GMIN muscles are critical in weight-bearing to control the pelvis and the femoral head during single-leg stance and gait , 2014, aArtificial gravity (AG) has been shown to positively affect the human body , and, foThe primary aim of this study was to investigate whether exposure to 60-day HDT bed rest induced atrophy and increased ILC in the individual gluteal muscles. The second aim was to examine whether two daily AG protocols, intermittent and continuous, could mitigate any effects of 60-day HDT bed rest on the gluteal muscles. As AG is associated with a large acceleration gradient along the body axis, it was hypothesized that a mechanical compressive force on the gluteal muscles would stimulate the muscle cells, mitigating muscle deconditioning.International Guidelines for Standardization of Bed Rest Studies in the Spaceflight Context” , undertaken at the “:envihab” facility (German Aerospace Center) in Cologne , GermanyContext” . These gContext” . This doContext” .Participants were pain-free at BDC testing, and none reported a history of chronic or acute musculoskeletal disorders or other medical disorders that would affect the measures collected in the study. Each participant was randomly allocated to one of three intervention groups: a control (CTRL) group that was not exposed to AG, a group that underwent 30 min of continuous centrifugation (cAG) daily, or a group that underwent six sets of 5 min centrifugation (iAG) daily with 3 min of rest between each set.All participants completed the 60 days of HDT bed rest. They performed all activities, including hygiene, in the supine position and were discouraged from moving unnecessarily. They were permitted to lie supine or on their side but were instructed to have at least one shoulder touching the bed at all times. Caloric intake was balanced with the measured individual metabolic energy consumption to maintain body mass throughout bed rest. Water intake was restricted to 50 mL/kg of body mass. Smoking, alcohol, and caffeinated drinks were not permitted. Participants followed a day-night cycle of 7 a.m. awakening and “lights-out” at 11 p.m.The Ethics Committee of the Northern Rhine Medical Association approved this study . The study was registered in the German Clinical Trial Register (DRKS) under No. DKRS00015677. Written informed consent was obtained before study commencement.All centrifugation was performed using a short-arm human centrifuge of 3.8 m in radius , in accoMagnetic resonance imaging scans were conducted with the participants comfortably positioned in supine lying with their knees and hips supported in slight flexion by a pillow, using a 3 Tesla Magnetom Vision system . Scans were performed in the transverse plane to image the gluteal muscles 2 days before the HDT bed rest period for BDC and again on the 59th day of HDT bed rest (HDT59). For each participant at each time point, 128 transverse images were acquired, covering the region from the T11 vertebral level to the inferior-most portion of the GMAX . Images were obtained with the fat and water protons in-phase and out of phase, then fat (F) images and water images (W) were reconstructed. Measurements of the gluteal muscles on the MRIs were conducted after the study. MRIs were assigned a random code to ensure blinding of the measurer to time points and participant groups. Other imaging data from this study pertaining to the lumbar spine region, including muscle volume and ILC, have been published elsewhere .Regions of interest (ROI) were manually segmented around the gluteal muscles , using a3 for each participant. ILC measurements were averaged for each participant. For both volume and ILC, the left- and right-sided measurements were averaged before statistical analysis because both sides were assumed to be affected equally.For each gluteal muscle, the sum of cross-sectional areas was multiplied by the MRI slice’s thickness (0.4 cm) to obtain a muscle volume in cmStatistical analysis was performed in Statistical Package for Social Sciences . All results were presented as means with standard deviation (SD). Statistical significance was set at the (two-sided) 0.05 level. First, outcomes were assessed for normality using the Shapiro–Wilk test and visual inspection. A one-way analysis of variance (ANOVA) was used to test for between-group differences in participant and group characteristics at BDC. These characteristics included age, body mass, height, muscle volume, and ILC.Group , Sex , and Time (BDC and HDT59 – within-subject factor). Interactions between the factors were included in the model. Partial eta-squared  was calculated since it reflects the proportion of variance in each effect or interaction and the error that is accounted for by that effect  were analyzed using a three-way mixed-model ANOVA with t effect .Groups , Sex , and Muscles . Interactions between the factors were included in the model, and η2partial was calculated. The Greenhouse–Geisser approach was used to correct against violations of sphericity. Where appropriate, post hoc pairwise analyses were performed using Bonferroni corrected multiple comparisons, and corresponding confidence intervals (CIs) were generated. For missing data, no imputation was carried out.Since the muscle volume and ILC in the gluteal muscles were different at BDC, the relative delta (Δ) of muscle volume and ILC was calculated (Δ = 100 × (HDT59 − BDC)/BDC), and a three-way mixed-model ANOVA was used between All participants attended their scheduled imaging sessions, and the MRIs were successfully collected from all participants. Because of chemical-shift artifacts, some images for a given muscle were excluded. A total of 9 muscles were excluded across five participants , leaving 63 muscles with complete data included in the final analysis of volume and ILC .2,1: range of 0.938–0.994; 95% CI: 0.905–0.999).One operator conducted all MRI measurements, and the intra-rater reliability of the operator performing the transverse plane image measurements was evaluated before starting the analyses. The measurements were made twice with a minimum of 7 days apart .At BDC, one-way ANOVA revealed no Time – all p < 0.005; η2partial > 0.5) , with males showing higher muscle volume (CI 95%: 268.2–1579.7). No differences between sexes were detected in GMED and GMIN muscles . No main effect of Group or interactions between factors were found  (An overview of the three groups’ average muscle volumes at BDC and HDT59 is reported in l > 0.5) . Across l ≤ 0.2) .Muscle, Group, Sex, and interactions between factors  . Across all groups, the absolute change of ILC from BDC was 1.5 ± 1.0% in the GMAX muscle and 0.5 ± 0.9% in the GMED muscle. No main effect of Group, Sex, and interactions between factors were found .An overview of the average muscle ILCs for the three groups at BDC and HDT59 is reported in l > 0.3) . No chanMuscle  . No main effect of Group, Sex, or interactions between factors were detected.The three-way mixed-model ANOVA on relative Δ revealed a main effect of  = 0.23) . PairwisThis study demonstrated that 60-day HDT bed rest induced muscle atrophy of all three gluteal muscles. However, ILC was only increased for the GMAX and GMED muscles, whereas no changes were detected for the GMIN muscle, which suggests differential accumulation of fat in the gluteal muscles after a prolonged period of decreased axial loading. This study also showed that daily AG did not mitigate the changes in muscle size and ILC.The current results confirmed that prolonged HDT bed rest induced a reduction in the volume of all three gluteal muscles. The muscle volumes of the GMAX, GMED, and GMIN muscles were decreased by approximately 10, 8, and 11%, respectively. This decrease is similar to the 7% reduction in GMAX, calculated by averaging the results for the upper and lower volumes, a 4% reduction for GMED, and an 11% reduction for GMIN in a previous similar 60-day HDT bed rest study . The sliThere are some differences to other data that are accounted for by methodological factors. A shorter bed rest study (35-day HDT) with 10 male participants reported only a ∼2% decrease in the volume of the three gluteal muscles . In addiA novel finding of the current study was the observed increase in the ILC in the GMAX and GMED muscles following 60-days of bed rest. Surprisingly, the GMIN muscle did not demonstrate any significant change in ILC, which suggests different adaptations of the individual gluteal muscles to decreased axial loading. Anatomical differences of the gluteal muscles might explain this finding. Compared with the GMIN muscle, the GMAX and GMED muscles are designed to bear a higher mechanical load, evident by their greater moment arms and greater physiological cross-sectional areas . During An additional consideration that may affect gluteal muscles in bed rest studies is the fluid shift out of the intramuscular space, both superiorly due to decreased axial loading on the circulatory system and laterally due to compression of the posterior hip on the bed. This phenomenon has been demonstrated within 120 min of bed rest  and follContrary to the hypothesis of this study, 30 min of daily exposure to AG, either in a continuous bout or multiple intermittent bouts, was insufficient to mitigate gluteal muscle atrophy and increases in ILC. This lack of effect might be related to the limited duration of the exposure or the limited loading on the participants (1 Gz at the center of mass). During erect bipedal standing, the gluteal muscles have minimal myoelectric activity , 2014. IAlternatively, the absence of the effect of AG might relate to the neutral hip position of the participant while supine during the AG stimulus. Functionally, the GMAX muscle is mainly recruited to decelerate hip flexion from upright standing, such as during squatting, or to accelerate the body upward and forward from a hip flexion position, such as when climbing steps. The GMED and GMIN muscles mainly stabilize the hip joint and control pelvic drop during a single leg stance and gait, but minimal activity is recorded during a quiet bipedal stance . Thus, dA previous study showed that, during 60-day HDT bed rest, including 3 days of 30-min resistive exercise per week prevented gluteal muscle atrophy compared with results from the control group . SeveralThe NASA Human Research Roadmap highlights the importance of understanding human muscle physiology pre-, during and post-flight, and developing subsequent countermeasures against muscle deconditioning . With thFor future studies employing AG as an intervention, the daily duration of AG or the axial loading may need to be increased to mitigate gluteal muscle atrophy and increased ILC. However, increasing the load may be problematic, as some participants experience pre-syncopal symptoms even in 1 Gz . AlternaA more detailed spatial analysis of the gluteal muscles, which has previously been conducted for muscles of the cervical and lumbar spines , could pAlthough manual segmentation of muscles is a reliable way to measure volume and ILC , it is tThe results of the current study should be interpreted while considering its limitations. First, the small sample size reduced the statistical power of the study and increased the likelihood of Type 2 errors, thereby missing any small differences between the three intervention groups. Because of the small sample size in the groups, only large effect sizes from countermeasures can be observed, and more subtle effects are likely to go unnoticed. However, it is difficult to increase participant numbers in these specialized studies, as bed rest facilities have limited capacity and are expensive to conduct. The current study is the first of multiple planned bed rest studies investigating passive AG and AG supplemented by exercises , and thuAlthough bed rest is a useful analog for decreased axial loading, it only rotates the direction of gravity by 90° and does not eliminate gravity. During bed rest, participants most likely still recruited their gluteal muscles when performing daily activities, such as hygiene or bed transfers. Consequently, the decreased muscle volumes and increased ILCs may underestimate the true effect of microgravity. Future space studies are needed to investigate the translation of these findings.The Dixon sequence was the chosen MRI technique as it reliably quantifies the amount of fat in an image. However, since both muscle and collagen appear dark in the fat-suppressed images, the gluteal muscle volume may be overestimated in the manual segmentation process .Finally, higher AG levels could mitigate muscle atrophy and increased ILCs in the gluteal muscles, but a higher rate of rotation may interfere with the physiological and psychological responses of the participants, as a load of >1G AG may cause discomfort and pre-syncope. Furthermore, whilst gravitational dose–response curves for some animal biochemical systems have been described , these dThis study demonstrated atrophy in all three gluteal muscles and an increased ILC in the GMAX and GMED muscles at the end of 60-day HDT bed rest. The AG protocols used in this study had no evident effects on the gluteal muscles. The demonstrated changes in the gluteal muscles are a potentially modifiable target for countermeasures against gluteal muscle deconditioning for astronaut and patient populations.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Northern Rhine Medical Association . The patients/participants provided their written informed consent to participate in this study.NC, ED, DD, JS, TW, SS, PH, and JH: conceptualization and methodology. JZ: data collection. JE and MH: software. VT and ED: formal analysis and writing original draft preparation. VT, ED, JH, GC, JE, MH, JZ, KL, DD, AW, DB, JC, SS, TW, JS, PH, and NC: writing – review and editing. NC, AW, DB, and JC: funding acquisition. All authors have read and agreed to the published version of the manuscript.TW and JS were employed by company KBR GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


There is an increased cardiovascular (CV) risk in axial spondyloarthritis (axSpA), leading to increased CV mortality and morbidity in these patients. The factors that may explain this enhanced CV risk in axSpA are multiple, including traditional CV risk factors such as smoking, but also the inflammatory process and probably the use of non-steroidal anti-inflammatory drugs (NSAIDs). The CV involvement of axSpA may be detected at an early and pre-clinical stage, using non-invasive techniques. While NSAIDs play a deleterious role in the CV risk of axSpA, TNF inhibitors seem to have a beneficial impact, but this remains to be demonstrated in specific clinical studies. More data are needed to determine the potential effects of IL-17 inhibitors on the CV risk of axSpA. CV comorbidity has been mainly assessed in the radiographic form of axSpA, while limited data are available in patients with the non-radiographic form. The current management of axSpA must consider this CV comorbidity according to the EULAR recommendations. Rheumatologists play a determinant role in the detection of CV risk and current management of these patients is focused on the control of disease activity, suppression of inflammation, screening for and management of traditional CV risk factors, as well as the restriction of NSAID use. Axial spondyloarthritis (axSpA) refers to an interrelated group of inflammatory rheumatic diseases (IRD) that primarily affect the axial skeleton . RadiogrBesides extra-articular manifestations , additional comorbidities are described in axSpA, including cardiovascular (CV) involvement , 5. RheuIn this review, we analyze the evidence for CV mortality and morbidity in axSpA, as well as the traditional CV risk factors that may participate in the increased CV risk seen in axSpA patients.Mortality in axSpA is mostly described in AS, with limited information in nr-axSpA, due to the recent individualization of this subgroup , 8. Thiset al performed such an analysis in 2011, and updated it in 2015. In the first meta-analysis, based on 11 studies, there was no significant increase in myocardial infarction or stroke in AS   is consistently related to CV diseases and complications. In a large American administrative database comparing CV diseases in different IRD including 1,843 patients with AS, the prevalence ratios for ischemic heart disease, cerebrovascular disease and congestive heart failure ranged between 1.2 and 1.8 . In a reke in AS , while ike in AS . The mor34–1.66) . The COM34–1.66) . Finally34–1.66) .There are several possible explanations for the higher CV risk in axSpA: inflammation is a well-recognized factor for accelerated atherosclerosis in different IRD, including axSpA, while traditional CV risk factors may also play a role. In addition, specific axSpA-related cardiac manifestations (aortic insufficiency and atrioventricular conduction disturbances) may also contribute to the enhanced CV risk.It is now established that cigarette smoking has a negative influence on axSpA activity and severity . In the N = 20), 20% had hypertension   .A recent study found that patients with axSpA may present with increased weight: in that study, obesity was found in 22% of patients and overweight in 37%, according to the WHO criteria . HoweverThe relationships between lipid parameters and IRD are complex. Indeed, inflammation has a wide range of effects on lipids, both quantitatively and qualitatively. Under the pressure of inflammation, both LDL and HDL cholesterol tend to decrease, but with an imbalanced atherogenic index  . In paraNon-invasive techniques may be used for the identification of early arterial wall changes in IRD. Ultrasonography of carotid arteries is the most widely used method, giving results on intima media thickness (IMT), pulse wave velocity (PWV) and flow mediated dilatation (FMD). It is a valid method for the identification of pre-clinical atherosclerosis with the capacity to predict future CV disease and complications . This meThe CV impact of the treatments that are routinely used in axSpA may be bidirectional, i.e., beneficial and/or detrimental. Indeed, since atherosclerosis should be seen as an inflammatory disease, and the CV risk in IRD is largely influenced by inflammation, controlling inflammation would have a favorable impact on this comorbidity. In RA, it is well-established that methotrexate (MTX) and TNFα inhibitors (TNFi) positively influence the CV risk .It is well-recognized that all the NSAIDs have a negative impact on CV risk, contributing to an excess of CV complications . Among tSulfasalazine (SLZ) is used in selective cases of SpA, with limited efficacy in the peripheral form. Since SLZ has an aspirin moiety, it has been suggested that this drug may have a protective CV effect. In a Taiwanese population-based retrospective study, the use of SLZ provided a protective effect against CV diseases in patients with AS [HR: 0.65 (0.43–0.99)] .In RA, TNFi result in a 20–50% reduction in CV risk . There aThe experience with IL-17 inhibitors (IL-17i) in axSpA is shorter compared to the use of TNFi, with no specific study examining the CV risk. It is considered that IL-17A may have deleterious effect on the arterial wall and cardiac cells, with potentially pro-atherogenic properties . In the post hoc analysis from the RA, psoriasis and PsA development programs and observational studies, the incidence rates for deep vein thrombosis (DVT), pulmonary embolism (PE) and venous thromboembolism (VTE) were similar between tofacitinib doses (5 vs. 10 mg twice daily) but generally higher in patients with CV or VTE risk factors (Janus kinase inhibitors (JAKi)  are currently in development in axSpA, but upadacitinib has recently been approved for the treatment of axSpA. During the phase 3 clinical trials, there was no safety signal regarding CV events with JAKi in patients with axSpA . In a sy factors . HoweverThere is compelling evidence that there is an increased CV risk in axSpA, and that it represents a major comorbidity deserving specific attention. In a Swedish study comparing the CV events between AS, RA and the general population, the adjusted RR for stroke was equivalent between AS and RA  while there was a smaller increase for acute coronary syndrome in RA than in AS . For thromboembolic events, the risk was also less in AS compared to RA . SimilarSimilarly to RA, CV risk is increased in axSpA. This comorbidity is a reality for patients with axSpA and must be adequately evaluated. It is highly probable that the use of bDMARDs (TNFi and probably IL-17i) and specific treatment strategies, such as the treat-to-target paradigm should have a favorable impact on CV risk, and thus, disease prognosis. However, specific clinical studies examining this question are required. Overall, CV risk detection and management is an important aspect for patients with axSpA that deserves specific attention from physicians.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Exposure to biologics was associated with a higher incidence of MI  in the insured IBD population. Conclusions: An increased prevalence but not incidence of MI and no increased risk of stroke were identified in this population-based IBD cohort.Background: Chronic inflammatory diseases are linked to an increased risk of atherothrombotic events, but the risk associated with inflammatory bowel disease (IBD) is controversial. We therefore examined the risk of and risk factors for myocardial infarction (MI) and stroke in IBD patients. Methods: We used the public health administrative database from the Province of Quebec, Canada, to identify IBD patients newly diagnosed between 1996 and 2015. The incidence and prevalence of MI and stroke in IBD patients were compared to those for the Canadian population. Results: A cohort of 35,985 IBD patients was identified. The prevalence but not incidence rates of MI were higher in IBD patients  compared to the Canadian rates , while the prevalence and incidence rates of stroke were not significantly higher in the IBD patients . We identified age, female gender, hyperlipidemia, diabetes, and hypertension ( Inflammatory bowel diseases (IBDs) are chronic, progressive, and disabling conditions mainly affecting young adults. IBD substantially impacts patients’ physical health, social functioning, and quality of life, thus contributing to the high health–economic burden associated with the disease. While cardiovascular diseases (CVDs) remain the primary cause of mortality and an essential public health concern in the developed world, a diverse set of inflammatory conditions  has previously been linked with the progression of atherogenesis and, consequently, increased cardiovascular outcomes . HoweverWith respect to Canada, Bernstein et al. confirmed, in a national study that included an assessment of all hospitalizations across Canada, that both Crohn’s disease (CD) and ulcerative colitis (UC) are associated with a three- to four-fold increased risk for venous thrombosis including pulmonary embolism . HoweverA meta-analysis reported by Fumery et al.  showed nConsidering the limited and partly conflicting data, our aim was to evaluate the cardiovascular and cerebrovascular outcomes and their risk factors in a defined population-based inception IBD cohort using a health administrative database of the province of Quebec, Canada. We used the population-based inception IBD cohort using the health administrative database of the province of Quebec. A more detailed description is available in our previous publication . AdminisThe incidence and prevalence of stroke and MI were defined using ICD codes found in primary and secondary care visits or admissions .We used the following ICD codes for MI—(ICD-10) I21–I22 and (ICD-9) 410—and for ischemic heart disease (including MI), we used (ICD-10) I20–25 and (ICD-9) 410–414. In the case of stroke, we used (ICD-10) I63–64 and (ICD-9) 433–438; if the stroke included subarachnoid and intracerebral hemorrhage, then (ICD-10) I60–I64 and (ICD-9) 431–438 were used.This IBD cohort was compared to the available Canadian control population data (the rates were available for 2012–2013) ,10,11,12The STROBE statement checklist is available online as We characterized an IBD cohort (UC and CD) and a non-IBD cohort adjusted for age and gender from the RAMQ administrative database. We obtained the incidence rate (IR) and prevalence odds ratio (OR) for the IBD population for each of the following: ischemic heart disease (IHD), myocardial infarction (MI), cardiovascular disease, and stroke. We compared the IR and OR obtained to those for a non-IBD cohort adjusted for age and gender, and available census data . In addition, we performed a sub-analysis in all IBD patients and UC versus CD patients. We performed an age-related subgroup analysis according to the two categories of <40- and ≥40-year-old patients and another according to gender . Finally, we compared the incidence and prevalence of both outcomes in the IBD cohort with the Canadian population data.The risk factors  were collected and calculated in the total cohort as well as in the insured cohort, including information regarding medical therapy. The data were analyzed in both the total population  and in a sensitivity analysis; we also assessed the importance of risk factors in the insured population, meaning in patients with public insurance coverage . Data on private drug dispensation were not available.In that analysis, the prevalence was defined as having had any outcome prior to 1 January 2014. We used that date to obtain data that were comparable to the Canadian rates. Incidence was defined using a subgroup of the IBD cohort that survived with no outcome at least 2 years after cohort entry. This ensured that the cases were incident. The outcome could occur any time after that. The person-time for incidence analysis was computed from cohort entry plus two years, until the end of the study. We put no restriction on a calendar year for the incidence analysis. p-values to compare between the IBD cohort outcome rates and Canadian rates. For the prevalence analysis, the rates were computed by dividing the total number of patients with an outcome, as defined above, by the total number of persons at risk. The rates were compared with Canadian rates using a Chi-square test for proportions. For the incidence analysis, we fitted a Poisson regression model for the number of outcomes, using the person-time as an offset. The only variable in the model consisted of an indicator of the IBD cohort or Canadian rates. The rates were computed for 100 person-years; we obtained The prevalence and the incidence analyses were further stratified by IBD type (CD/UC), by gender, and by age (<40/≥40 years old).In the comorbidity analysis, the prevalence for an outcome was defined as having had an outcome at any time, either before cohort entry or during follow-up, with no restriction on calendar year, while we defined incidence using a two-year buffer period where patients had to have at least 2 full years without the outcome. For the incidence analysis, the person-time was computed from the maximum date between cohort entry and 1 January 1998  to the end of the study, as we excluded any patient with outcomes that occurred before 1 January 1998—these patients not having a 2-year outcome-free buffer.p-value < 0.01) were kept and added to a multivariate model along with age and gender. For all the models and for each variable included, the odds ratio, 95% CIs, and p-values were computed. For the Poisson model, the outcome rate for 1000 person-years was fitted, first adjusting for age, gender, and every comorbidity one at a time . Each of the significant comorbidity variables  was subsequently added to a multivariate Poisson regression model along with age and gender. For all the models and for each variable included, the incidence rate ratios, 95% Cis, and p-values were computed.The prevalent and incident outcomes were modelled using a logistic regression model and a Poisson model, respectively. For the prevalent outcomes, we first fitted logistic regressions adjusted for age and gender along with one comorbidity of interest . In the univariate analysis, any of the 3 comorbidities that presented a significant coefficient  for both the prevalence and incidence analyses. The maximal therapeutic step was used as a proxy for disease activity and severity. The therapeutic groups were separated into three categories: 5-aminosalicylic acid (5-ASA), immunosuppressants (ISs)/corticosteroids, and biologics. The incident rate ratio (IRR) for each cardiovascular outcome  was obtained for each group/category in time-varying analyses. The study was approved by the McGill University Health Centre institutional review board and ethics committee . The research protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and local regulations. A total of 35,985 newly diagnosed IBD patients were identified between 1996 and 2015 in the RAMQ database, with 10,915 in the insured cohort .The majority of the patients had Crohn’s disease (57.3%), were female (53.9%), and were diagnosed over the age of 40 years (58.2%).In the insured subgroup, a higher proportion of the patients were diagnosed over 40 years (64.7%), were female (55.3%), and had Crohn’s disease (57.6%). The maximum therapeutic step before either myocardial infarction or stroke was nearly the same for 5-ASA, 15.7%/15.7%, and for biologics, 12.8%/12.9%. The majority of the patients used immunosuppressive drugs or steroids. Considering the major comorbidities, we found that 9.5% of the IBD patient had diabetes, 24.9% had hypertension, and 24.5% had hyperlipidemia.Analyzing the whole patient population, the 35,985 newly diagnosed IBD patients, and the non-IBD cohort adjusted for age and gender from the RAMQ administrative database showed that the prevalence but not incidence rates of MI were higher in IBD  compared to the background Canadian rates . Meanwhile, the prevalence and incidence rates of stroke were not significantly higher in IBD  vs. the Canadian population . p < 0.001 for each) as risk factors for developing MI and stroke in both CD and UC in the logistic-regression-based prevalence models  in the insured IBD population in the time-varying model . Thus, the therapeutic step can be regarded as a disease-severity marker in administrative databases.The major finding of the present study is an increased prevalence but not incidence of MI in this population-based IBD cohort from the province of Quebec. No increased risk of stroke was identified in this cohort of patients. The risk factors for both MI and stroke in IBD patients included age, female gender, hyperlipidemia, and hypertension. Exposure to biological therapy was associated with a tendency for a higher incidence rate ratio for MI in IBD ) versus in UC (SIR: 0.96 (0.92–1.01)). However, the risk increased in parallel with an increasing number of risk factors. However, the data on the CVD risk in IBD are partly conflictive. An early meta-analysis by Dorn et al. analyzed 4532 CD and 9533 UC patients’ data and showed no increased CVD mortality rates  and for UC of 0.9 (95% CI: 0.8–1.0)) [–1.34) veOne of the aims of the present study was to study the relative importance of the conventional CVD risk factors in IBD patients. Thus, we aimed to identify if the conventional risk factors assessed in this study (no data on smoking were available) were more prevalent in IBD patients with MI or stroke outcomes, but we did not directly compare the prevalence of CVD risk factors with that in non-IBD controls or the general population.p < 0.001 for each) were the significant risk factors for developing MI in IBD and both CD and UC. Of note, the prevalence of traditional CV risk factors was not more common, although it was numerically lower in patients with IBD compared to that reported in the general population  in other studies [In the present study, older age, female gender, hyperlipidemia, hypertension, and diabetes . In the IBD group, female gender was associated with stroke prevalence but not with incidence. Hyperlipidemia was associated in IBD, CD, and UC with stroke prevalence but not incidence.Nevertheless, the risk factors for developing stroke in the overall IBD group, the insured IBD group, and the CD or UC population were age, diabetes, and hypertension  in the time-dependent model.Disease activity has been linked to cardiovascular outcomes, and this may represent an independent risk factor as shown in the French IBD population . These dThe strength of this study stems from the large, well-characterized, population-based IBD cohort and methodology from the provincial administrative database for the Province of Quebec (1996–2015). We used well-defined administrative criteria to identify IBD patients as well as outcomes and risk factors. We evaluated both the incidence and prevalence of outcomes in IBD and performed a subgroup analysis for CD and UC as well as assessing the comorbidities and risk factors. There are some limitations to our cohort. No data on smoking status could be obtained. In addition, the Quebec drug plan for biologics therapy is two-fold, with public RAMQ or private insurance coverage; the latter was not captured in our data set. Of note, 41.8% of prescribed drug spending is paid for by provincial healthcare plans across Canada . To decrIn conclusion, in this original, long-term, population-based, observational study from Quebec, Canada, we used a sophisticated statistical approach and have demonstrated that the prevalence but not incidence rates of MI were higher in IBD compared to the Canadian background population. By contrast, we did not uncover a higher prevalence or incidence of stroke in IBD. In addition, we identified older age, female gender, hyperlipidemia, diabetes, and hypertension as risk factors for developing MI in IBD, CD, and UC. Finally, in the insured IBD population, the exposure to biological therapy was associated with a tendency toward a higher incidence rate ratio for MI in IBD, further confirming that therapeutic steps can be regarded as a disease-severity marker in administrative databases.


Introduction: Few studies in the literature discuss the benefits of compliance with sepsis bundles in hospitals in low- and middle-income countries, where resources are limited and mortality is high.Methods: This is a retrospective cohort study conducted at a public hospital in a low-income region in Brazil. We evaluated whether completion of a sepsis bundle is associated with reduced in-hospital mortality for sepsis, severe sepsis, and septic shock, as well as prevention of septic shock and organ dysfunction. Bundle compliance required the completion of three items: (1) obtaining blood count and culture, arterial or venous blood gases, and arterial or venous lactate levels; (2) antibiotic infusion within the first hour of diagnosis; and (3) infusion of 10–20 ml/kg saline solution within the first hour of diagnosis.Results: A total of 548 children with sepsis, severe sepsis, or septic shock who were treated at the emergency room from February 2008 to August of 2016 were included in the study. Of those, 371 patients were included in the protocol group and had a lower median length of stay , fewer organ dysfunctions during hospitalization , and a lower probability of developing septic shock. According to a propensity score analysis, mortality was lower during the post-implementation period .Conclusions: A simple and low-cost protocol was feasible and yielded good results at a general hospital in a low-income region in Brazil. Protocol use resulted in decreased mortality and progression of dysfunctions and was associated with a reduced probability of developing septic shock. Sepsis prognosis depends greatly on time of diagnosis and treatment , 2. SepsAccording to Tan et al., children with severe sepsis in developing countries are four times as likely to die than those in developed countries . MoreoveHere, we hypothesized that the complete application of sepsis bundles in a Brazilian hospital would result in reduced in-hospital mortality, a lower incidence of septic shock, and fewer cases of organ dysfunction during hospitalization.In this article we aimed to evaluate whether completion of a sepsis bundle would result in: (1) reduced in-hospital mortality for sepsis, severe sepsis, and septic shock; and (2) prevention of septic shock and organ dysfunction.In this retrospective cohort study, we compared septic patients whose emergency room care adhered to a sepsis bundle protocol with patients whose treatment did not. We analyzed mortality, probability of septic shock, and organ dysfunction during hospitalization.We used data collected from 2008 to August of 2016 in the database of the Quality Department and Medical and Statistics Archive Service of Hospital Dr. Moysés Deutsch—M'Boi Mirim (HMMD), in São Paulo, Brazil, a 300-bed general public hospital in a low-income area that serves a population of 650,000. HMMD was inaugurated in April of 2008.Here, we defined sepsis, severe sepsis, septic shock, and organ dysfunction based on the criteria established by the International Pediatric Sepsis Consensus Conference of 2005 (IPSCC) , and treth Edition) discharge codes (August 2008 to December 2014): A.41 (Septicemia), R.57 (Shock), or A.39 (Meningococcemia). We then excluded medical records that did not meet IPSCC criteria.During the pre-implementation period, we included patients that received one of the following ICD-10 , we included (1) patients included in the sepsis protocol; and (2) patients with ICD-10 discharge codes A.41, R.57, or A.39 who were not included in the protocol and met IPSCC criteria.Bundle compliance to the sepsis protocol required the completion of three items: (1) obtaining blood count and culture, arterial or venous blood gases, and arterial or venous lactate levels; (2) antibiotic infusion within the first hour of diagnosis; and (3) infusion of 10–20 ml/kg saline solution within the first hour of diagnosis.Blood cultures were collected after rigorous antisepsis with 70% alcohol, applied 3–4 times on the skin; 1–3 ml blood samples were placed in a Bac tec® flask (PEDS PLUS/F).“Time Zero” was the time of hospital admission, and all times were recorded relative to time zero.We define a chronic condition as any medical condition that persists for at least 12 months and that requires specialist follow-up . Our popWe excluded patients who developed sepsis, severe sepsis, or septic shock in the Pediatric Intensive Care Unit, Neonatal Intensive Care Unit or Ward, and patients transferred from other services with sepsis, severe sepsis, or septic shock.The pediatric sepsis protocol was initiated at the HMMD pediatric emergency unit in February 2015. The protocol consisted of screening patients who presented with a history of fever or hypothermia at triage or first medical care with one of the following signs: tachycardia, tachypnea, hypotension, altered tissue perfusion, respiratory discomfort, oxygen saturation <92%, altered consciousness, or oliguria.The medical chart was electronic, but the system could not alert if there were vital sign alterations. To facilitate the process, we placed a banner at each treatment location that showed the normal range of vital signs for different age groups. Then team could recognize the alterations of vital signs and star the protocol.Whenever a protocol was opened, the triage nurse or physician at first medical care filled out a form. Author DNMM reviewed all forms with the help of a pediatric nurse. Next, they reviewed all patients with discharge codes ICD 10 A.41, ICD 10 R.57, and ICD 10 A.39 to identify patients with sepsis, severe sepsis, or septic shock who did not receive the protocol.Patients from the pre-intervention period and those who were not treated according to protocol in the post-intervention period were grouped together in the “no protocol” group.The variable times of fluid and antibiotic administration were categorized into: 1 h (0–60 min); 2 h (61–120 min); 3 h (121–180 min); 4 h (181–240 min); 5 h (241–300 min), and more than 5 h (more than 301 min).To assess the association between death by septic shock and other variables in the patient's profile, we adjusted a Poisson regression model to consider the total length of hospital stay as the patient's follow-up time –13.To obtain multiple models of the factors associated with septic shock and death, variables were selected following a stepwise process in both directions .We used an adjusted Poisson regression model to measure growing sepsis protocol compliance.We also estimated generalized mixed effects linear models to compare patients' clinical condition at the time of admission vs. hospital discharge (T0 and T1). The models considered the effect of the moment, protocol compliance and the interaction between the two factors. For septic shock, we used a logistic model with binomial distribution, and for the number of dysfunctions, we used a Poisson distribution with logarithmic connection. Confidence intervals were constructed using 1,000 simulations.Matching packages, and global significance was set at 5%  of the Municipal Health Department of São Paulo and Hospital Israelita Albert Einstein under protocols CAAE 55237316.3.0000.0086 and 55237316.3.3001.0071. The ERC of the Municipal Health Department of São Paulo usually asks researchers to obtain informed consent in retrospective studies. Because the study covered a long period of time, the ERC dispensed consent for parents who could not be reached and for those who did not attend the meeting.At the beginning of the study, patients' parents received an invitation to participate in a meeting in which author DNMM explained what sepsis is, how to recognize clinical signs in children, and the study's significance. Afterwards, DNMM asked parents' consent to authorize chart analysis. During protocol implementation, DNMM also trained health professionals of the HMMD Health Network to disseminate knowledge about sepsis and to work toward earlier diagnosis and treatment.p-values <0.001). All organ dysfunctions were significant risk factors for death, as well as the number of organ dysfunctions upon hospitalization and the number of new dysfunctions . The presence of chronic disease and admission for septic shock were also risk factors for mortality .During the post implementation period, 10 patients had septic shock. Four of these patients were not included in the protocol and all of them died. The remaining six patients were included in the protocol and three of them died. Among the six patients included in the protocol, two had five organ failures and one patient had four organ failures within the first 6 h of treatment.p < 0.001].Between the pre- and post-implementation periods, overall mortality decreased from 15.4 to 2.75% [RR 95%IC 0.13 ; p-value was set at <0.001. The number needed to treat (NNT) with the protocol to prevent septic shock was 12 and the NNT with the protocol to prevent death was 8.Mortality was also assessed using the propensity score, matching age, gender, presence of chronic disease and number of dysfunctions between the pre- and post-implementation periods. The Protocol usage increased the number of sepsis diagnoses. Patients included in the pediatric sepsis protocol experienced reduced mortality and fewer new organ dysfunctions, which was mostly associated with a lower probability of developing septic shock. In septic patients with organ failures at admission, we did not observe reduced mortality.Our study contributes to information regarding protocol usage in low-and middle-income countries. The implementation of a simple low-cost protocol was feasible and helped in the diagnosis of sepsis cases. Further, adherence increased over time.According to Kortz et al., there are many challenges to data collection in resource-limited settings, such as a lack of research infrastructure, incomplete documentation, severe personnel shortages, inadequate funding, and technical difficulties performing follow-up . Even wiOne of our aims was to elaborate a low-cost protocol. We chose lactate as a bundle item because blood levels are a good marker of tissue hypoperfusion, septic shock adverse outcomes, and treatment improvement –22.In the no-protocol group, there were fewer cases of sepsis and severe sepsis, which may be partly explained by the use of the ICD for screening. Balamuth et al. showed that different ICD screening methodologies differently influence prevalence and mortality data . Other aBecause the Emergency Department initially applied the sepsis protocol to critically ill patients, many patients without sepsis and with signs of dysfunction due to other diseases  were included at the beginning of protocol implementation. No patient experienced adverse events due to protocol treatment. The inclusion of no sepsis patients was also observed by Kortz et al. after implementing the sepsis protocol in Bangladesh. Those authors reported that provider awareness increased and that there may have been a post-protocol diagnosis bias, with more children diagnosed with sepsis not meeting sepsis criteria. This may have also happened in our study .p < 0.05). Following the New York sepsis care mandate, Evans et al. observed that mortality decreased among patients who received all three elements of a bundle within an hour, which included blood culture, antibiotics, and a 20 ml/kg isotonic fluid bolus  data and observed that the prevalence of septic shock within the first 24 h of pediatric ICU admission and sepsis-related mortality was significantly higher in public hospitals relative to private hospitals. The authors attributed this difference to greater disease severity and a larger proportion of patients with prior comorbidities and septic shock on admission in public hospitals  protocols that restrict fluid administration; (2) protocols that do not consider laboratory exams as part of the protocol bundle; (3) barriers to adopting and implementing sepsis protocols, and (4) the development of efficient sepsis protocols designed especially for limited resource settings and specific populations.In our study, a simple low-cost protocol was feasible and yielded good results at a general hospital in a low-income region in Brazil. The protocol helped diagnose sepsis at earlier stages, which helped avoid further complications. Protocol use resulted in decreased mortality and progression of dysfunctions, which was associated with a reduced probability of developing septic shock.10.17632/hj2j3drw3v.3 Description: Completion of sepsis bundle is associated with reduction in in-hospital mortality, in probability of septic shock development, and in organ dysfunctions on hospitalization.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: doi: The studies involving human participants were reviewed and approved by the Ethics and Research Committee of the Municipal Health Department of São Paulo and Hospital Israelita Albert Einstein under protocols CAAE 55237316.3.0000.0086 and 55237316.3.3001.0071. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.DM, JC, and ET designed the study. DM collected the data and wrote the manuscript. AM conducted the statistical analysis and helped with methods. ET, AM, and JC reviewed and corrected the paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


LAeq of 42–45 dB(A). Noise annoyance ratings were collected after each scenario. Annoyance was found to vary with the macro-temporal pattern: It decreased with increasing total duration of quiet periods. Further, shorter but more regular breaks were somewhat less annoying than longer but irregular breaks. Since Stroop task performance did not systematically vary with different noise scenarios, differences in annoyance are not moderated by experiencing worsened performance but can be attributed to differences in the macro-temporal pattern of road traffic noise.Noise annoyance is usually estimated based on time-averaged noise metrics. However, such metrics ignore other potentially important acoustic characteristics, in particular the macro-temporal pattern of sounds as constituted by quiet periods (noise breaks). Little is known to date about its effect on noise annoyance and cognitive performance, e.g., during work. This study investigated how the macro-temporal pattern of road traffic noise affects short-term noise annoyance and cognitive performance in an attention-based task. In two laboratory experiments, participants worked on the Stroop task, in which performance relies predominantly on attentional functions, while being exposed to different road traffic noise scenarios. These were systematically varied in macro-temporal pattern regarding break duration and distribution , and played back with moderate  LAeq), the day-night level (Ldn), or the day-evening-night level (Lden) )LAeq of 42–45 dB(A) were chosen, which are representative values for an office environment. The daytime limit value (impact threshold) for road traffic noise of 60 dB outdoors in residential zones according to Swiss legislation [LAeq. Likewise, a road traffic noise Lden of 53 dB according to the recommendation of WHO [LAeq of ~51 dB(A) [In the present study, the participants conducted a visually presented cognitive task, while road traffic noise scenarios were played back. The participants’ primary focus was thus on the cognitive task and not on the noise scenarios. However, at the end of each noise scenario, the participants rated their noise annoyance. As laboratory setup, an office environment was chosen where an open window was simulated from which the road traffic noise would enter the office . To thatislation  and a soislation ,53 appro51 dB(A) , and a sThe experiments were approved by the ethics committee of Empa . They followed general guidelines such as ,56 and wCognitive performance was tested using different versions of the Stroop task. Details on the Stroop task are given, e.g., in . In its Performance in the Stroop task relies on attentional functions, namely, selective attention and inhibitory functions, so that it should be sensitive to attentional capture induced by transitions from a quiet period to road traffic noise or vice versa. As working on a large amount of look-alike items for prolonged time periods might become too tiresome, different versions of the Stroop task were used in the present study. Two versions of the Stroop task were identified in a pilot experiment to this study (details see ) as suffShape test variant A: oval, square, and triangle cf. Shape test variant B: circle, rectangular, and starColour test variant A: green, orange, and purple cf. Colour test variant B: blue, yellow, and redIn addition to the above two versions of the Stroop Tasks, two variants each were used to keep the task to be processed sufficiently diverse:The different versions/variants of the Stroop task were implemented in a listening test program in the Python-based PsychoPy software environment . The indN), Relative Quiet Time (RQT), Intermittency Ratio (IR), Centre of Mass Time (CMT), A-weighted and FAST-time weighted maximum sound pressure level (LAFmax), and Quiet Time Distribution (QTD). The indicators were all calculated from the road traffic noise scenarios (see below) in MATLAB Version 2019a .The following indicators were used to quantify the macro-temporal pattern of the road traffic noise situations: Number of events (N): Since this study used isolated car pass-by events mixed to prepare the scenarios (see below), the number of events, as well as the logarithm log(N) as sometimes used to predict annoyance , in eacTquiet) to total duration of a scenario (Tscenario) [Tquiet is calculated as the sum of all  quiet periods and divided by Tscenario asRelative Quiet Time (RQT): Based on suggestions by , RQT is cenario) . To thatIR, %): IR is a measure for the eventfulness of a noise scenario [LAeq,T,Events is calculated from contributions of events exceeding a given threshold K. In contrast to other descriptors working with thresholds, the latter is not constant, but defined dynamically relative to the LAeq of the scenarios usingC is a constant offset, set to 3 dB. IR ranges from 0–100%. An IR larger than 50% indicates that more than half of the total sound energy is due to distinct pass-by events. In situations where all events clearly emerge from background noise , IR gets close to 100%, while constant road traffic as observed from a receiver not too close to a motorway yields only small IR values. Note that while a high IR is a precondition for noise breaks (large RQT) to occur, it does not allow studying the effect of QTD .Intermittency Ratio (scenario . It exprit is the duration of the Centre of Mass Time (CMT): CMT is an indicator for quiet periods which penalizes the fragmentation of quiet periods and rewards their clustering and thus increases with longer quiet time periods . It is cQuiet Time Distribution (QTD): QTD is a categorical variable for the nature of noise breaks. Here, it discriminates between regular and irregular temporal distribution of the breaks as well as between different durations of the irregular noise breaks.In experiment 1, the individual and combined effects of the independent macro-temporal pattern indicators RQT and QTD on noise annoyance and cognitive performance in the Stroop task were investigated.Road traffic noise scenarios (WAVE PCM format) were prepared in MATLAB Version 2019a  from stereo recordings with a Jecklin disk setup made within a previous study , of indiLAF), an average duration of 10 s was chosen for the excerpts. However, to obtain realistic sound scenarios, three excerpts, of 9, 10, and 11 s length, were cut from each signal. One of these three excerpts per event was randomly chosen for the preparation of a scenario. The excerpts were gated with raised-cosine ramps of 2 s. They were further highpass and lowpass filtered at 52 Hz and 10 kHz, respectively, to consider the limits of the loudspeaker at low frequencies and inherent recording noise at high frequencies. In total, seven scenarios, each lasting 4.5 min, were prepared for experiment 1. Additionally, two 30 s long road traffic noise scenarios were created for the participant’s familiarization period with the noise and the cognitive task at the beginning of the experimental session.Road traffic noise scenarios were created from excerpts of the individual car pass-by events by mixing them together sequentially (and sometimes slightly overlapping) in time. After careful inspection of the audio files  at the window (measured 50 cm away from and in front of the loudspeaker) and of 44.5 dB(A) at the participant’s ear level at the desk. As the number of car pass-by events varied between scenarios, the LAeq of the individual pass-by events had to be adjusted. rs) [LAF,max generally decreases with increasing number of events to obtain the same overall LAeq for all scenarios, a few events of scenarios S5 and S6 (each encompassing 15 events) had a similar LAF,max as the events of S3 and S4 (each encompassing 10 events), so that the LAF,max were almost identical for those four scenarios , 44.3% (15 events), 62.9% (10 events), and 81.5% (5 events). Further, two types of QTD were used for the quiet periods: either a regular distribution (referred to as “regular” in the following account) or a combination of short quiet periods and two longer (1-min) quiet periods (referred to as “irregular”). While the situation with 0.0% RQT served as a reference without quiet periods, the three levels of RQT  were combined with the two QTD types, . All road traffic noise scenarios had the same ted. rs)  for the cenarios . N, RQT,dicators , but wasdicators . Thus, w QTD cf. .LAeq of 30 dB(A), which was a combination of filtered pink noise  and sound from a low-level running office air conditioning system. The additional loudspeaker was located at the wall in front of and above the participant, at the same height as the running low-level office air-conditioning system, so that both sounds were received from roughly same direction and combined to one background sound source. The background sound helped masking possible low-level sounds from outside the office environment, which was not an isolated listening booth. In addition, a sign was put up during the experiments in the corridor outside the office, asking passers-by to be silent. Thus, sounds from outside the office were minimized. With the played-back background sound being constant and ~15 dB lower than the actual road traffic noise scenarios, both sound sources (sound outside the office and background sound) are negligible as a source of bias for the annoyance ratings. Also, even if the background sound within the mock office would have somewhat affected the participants’ perception and/or performance, this is something that would also be present in a real office environment.Note that in addition to these road traffic noise scenarios, the participants were exposed to a constant background sound with an The experiments were conducted in single sessions in English. To ensure sufficient understanding of the experimental tasks, one requirement for study participation was to have good self-reported English language skills. In addition, after task instruction the participants could ask the experimenter in case of ambiguities.Participants first answered questions about their hearing status, vision, and well-being for inclusion and exclusion criteria, which were (i) self-reported normal hearing (not hearing impaired), (ii) self-reported normal or corrected-to-normal vision (but not colour blind), (iii) legal age (18 years or older) and (iv) feeling well (not further specified). Thereafter, they read instructions on the road traffic noise scenarios, the cognitive task and the test program. To familiarize them with the two versions of the Stroop task, the two short road traffic noise scenarios were used: Participants worked on trials of the colour version of the Stroop task during the first short scenario and of the shape version during the second one. Then, data collection in the actual listening experiment started. During each noise scenario, the participant worked on trials of one version of the Stroop task for the first 135 s and then of the other version for the second 135 s. Congruent and incongruent trials were presented in random order. An overall mixing ratio of approximately 50% each was secured by the program increasing the probability of drawing either the congruent or incongruent trials after 60% of a noise scenario’s duration. Participants were asked to respond to the semantics of the colour word (colour version) or the shape of the geometric form (shape version) as fast and as accurately as possible. Immediately after the participant’s response (without any time delay), the next trial started automatically. There was only a break in Stroop tasks between the noise scenarios, when no sound was played back. The participants did the Stroop task self-paced, which resulted in a different number of trials per participant and noise scenario, depending on how fast they worked on the tasks.The sequence of the two Stroop versions was randomized for each noise scenario, as was the sequence of the noise scenarios. After each noise scenario, participants answered the following question, which was adapted from the ICBEN noise annoyance question ,61: “WhaAfter a break of 30 s the next noise scenario started. The total experiment lasted approximately 50 min, with the actual unfocussed listening test taking around 35 min.The participants were mostly recruited within Empa, via internal online advertisement or direct verbal recruitment. Twenty-four persons , aged between 19 and 63 years (median of 28.5 years), participated in experiment 1. This number of participants lies well within the range of 16–32 participants proposed in  to obtaiAnnoyance: In total 168 annoyance ratings were obtained .Performance: Task completion was self-paced, i.e., each participant had an individual pace in completing the tasks. This resulted in different amounts of worked-out trials per noise scenario and participant. On average, 208 trials in the Stroop task were worked-out, ranging from 85–265 trials per participant and traffic noise scenario, meaning that the slowest participant completed 82 trials during one specific noise scenario, and the fastest participant 262 trials during one specific noise scenario. In sum, a total of 34,911 individual responses  were available and processed as follows.Reaction times : Each trial not correctly worked-out counted as an error. As usual in analysis of RTs, error trials were removed from the data set, as cognitive mechanisms might have been different from those involved in successful task processing. In a second step, long RTs  were removed, as again other mechanisms might have played a role . In total, 3000 individual responses  (9.1%) were removed. In a last step, the remaining 31,911 individual responses were averaged per participant and road traffic noise scenario separately for congruent and for incongruent trials to obtain mean RTs .Error rate : In a first step, individual colour and shape task versions/variants cf.  per partThe data was statistically analysed, separately for annoyance on the one hand, and RT and ER as measures of cognitive performance on the other hand. To that aim, linear mixed-effects models were established . These rs [r, the latter assuming a linear relation) of the annoyance ratings with the continuous indicators for the temporal pattern. Both correlation analyses reveal the same insights, although correlation with Spearman’s rs is less strong than with Pearson’s r. Annoyance increased with increasing N (more events) and CMT , but decreased with increasing RQT , IR  and LAF,max . As the acoustical indicators are closely correlated to either CMT or QTD  or to QTD (model MQDT). The first model, MRQT, reveals the dependence of annoyance on the continuous variables RQT and playback number (PN). This model takes into account all noise scenarios, S0–S6.Linear mixed-effects modelling analysis confirmed these observations and significant differences between regular and irregular QTD cf. b,c. HereAnnoy is the dependent variable annoyance, μ denotes the overall grand mean, β1 and β2 are regression coefficients for the continuous variables RQT and PN, respectively, of the seven scenarios (S0–S6), u is the participants’ random intercept (k = 1–24), and the error term ε is the random deviation between observed and expected values of Annoy. RQT shows that annoyance significantly decreases by 1.4 units on the 11-point scale when RQT increases from 0–81% (cf. In Equation (5), –81% cf. a, and siQDT, reveals how annoyance is linked to QTD. In this model, only six scenarios, S1–S6, are taken into account, since no level of QTD is applicable for S0 with RQT of 0%  of the six scenarios (S1–S6), and the other variables have the same notation as in Equation (5). QTD, annoyance is significantly higher for longer, irregular than for shorter, regular breaks, but the difference of ~0.7 points on the 11-point scale is moderate (cf. RQT).In Equation (6), rate cf. b. Furthep < 0.001), with incongruent trials  being answered 31 ms (or 5%) slower than congruent trials , as usual in the Stroop paradigm. Furthermore, the Stroop effect was also found for ERs (p < 0.05), with more errors been made in incongruent trials  than in congruent trials . Consequently, the effects of the different road traffic noise scenarios on RTs and ERs were analysed separately for congruent and incongruent trials in the following.Performance data was first checked for the Stroop effect with a simple model considering congruency as the sole fixed effect. In fact, the Stroop effect was found for both, RTs and ERs: Overall, the effect of congruency was highly significant for RTs (RT: p = 0.29) and congruent trials (p = 0.65)  for both incongruent and congruent trials (details not shown). While the effect of QTD was significant, it was quite small  cf. a, but wip’s > 0.30 for RQT, p’s > 0.26 for QTD, p’s > 0.23 for playback number).ER: In both incongruent and congruent trials, ER varied neither with RQT nor with QTD nor with playback number (not shown), as also confirmed by mixed-effects model analysis  (Three road traffic noise scenarios (WAVE PCM format) were again prepared in MATLAB Version 2019a , in the same way and from the same recordings as in experiment 1. Furthermore, participants were also exposed to the same constant background sound at an 30 dB(A) . Each ofLAF,max of the individual car pass-by events, but differed with respect to QTD. Three levels of QTD were used: regular quiet periods, a combination of short quiet periods and six 1-min quiet periods, or two 3-min quiet periods (“irregular”). Each noise scenario contained 25 car pass-by events. The scenarios had an LAeq of 51 dB(A) at the window (measured 50 cm away from and in front of the loudspeaker) and of 41.5 dB(A) at participant’s ear level at the desk. N, and LAF,max were the same for S1–S3 and IR varied only little , aged between 26 and 61 years (median of 33.0 years) participated in experiment 2. All participants fulfilled the requirements for participation  were obtained.Performance: Since task completion was self-paced, different amounts of worked-out trials resulted per participant and road traffic noise scenario. On average, 452 trials in the Stroop tasks were worked-out, ranging from 301–593 trials per participant and noise scenario. In total, 33,915 individual responses  were available and processed analogously as in experiment 1 , removinAs in experiment 1, the data was statistically analysed with linear mixed-effects models, separately for annoyance, RT and ER. As fixed effects, QTD as well as the playback number were used, and as random effects the participants (simple random intercept). The statistical analysis was again performed with IBM SPSS Version 25 using the procedure MIXED.QDT, but with τQTD with 3 levels, i = 1–3, for regular and irregular with 1-min or 3-min breaks), revealed that the overall association of annoyance with QTD was not significant (p = 0.13). In fact, only the annoyance to the 3-min and 1-min irregular breaks was in tendency different by ~0.6 units on the 11-point scale .In line with these observations, linear mixed-effects model analysis , using tp < 0.001), due to prolonged RTs and higher ERs during incongruent compared to congruent trials. Overall, incongruent trials  were answered 31 ms (or 5%) slower than congruent trials , and more errors were made in incongruent  than in congruent trials . Consequently, the effects on RTs and ERs were analysed separately for congruent and incongruent trials.As in experiment 1, the performance data was first checked for the Stroop effect with a simple model considering congruency as the sole fixed effect. For both RT and ER a highly significant effect of congruency was given (RT: p < 0.02) and playback number (p < 0.001) (details not shown). While the effect of QTD was significant, it was again small . RTs decreased with playback number increasing from 1–3 by some 100 and 90 ms for incongruent and congruent stimuli, respectively.These observations and significant differences between long irregular and short irregular/regular QTD were confirmed by linear mixed-effects model analysis, which showed that RTs were significantly associated with QTD .ER: In both congruent and incongruent trials, ER was neither associated with QTD nor playback number, which was also confirmed by mixed-effects model analysis (LAeq of ~45 dB(A) (experiment 1) and ~42 dB(A) (experiment 2), as might be expected in an office environment, affected short-term noise annoyance and cognitive performance in the Stroop task. A range of indicators for the macro-temporal pattern of the scenarios, including relative quiet time (RQT) and quiet time distribution (QTD), were quantified.This study performed two unfocussed laboratory listening experiments to study how the macro-temporal pattern of different road traffic noise scenarios with rather low IR (positively correlated with RQT) shows a negative correlation with annoyance, confirming the findings of [IR, one should keep in mind that with the exception of the reference scenario S0, all scenarios were highly intermittent , the clustering of car pass-by events after prolonged quiet times (irregular QTD), giving a more distinct temporal pattern, was more annoying to the participants than the shorter but regular events. Thus, to optimize QTD in order to minimize annoyance, providing a smooth traffic flow without too many interruptions, e.g., by reducing traffic lights, might be beneficial. In line with this thought, a laboratory study found that at high traffic densities, road traffic noise at a roundabout was perceived as less unpleasant than at crossroads with traffic lights [LAeq.The experiments confirmed that quiet periods affect annoyance, revealing that annoyance ratings decreased with increasing RQT, at least up to some 60% . This isdings of . In intetent cf. , with IRc lights . RQT, inLAeq of ~42–45 dB(A), the effects were moderate only, changing annoyance by 1.4 units on the 11-point scale for a RQT increase from 0–81%, and 0.5–0.7 units for longer irregular compared to shorter quiet times (QTD).The present results on QTD contrast the conclusions of previous studies that suggest a minimal duration of one  or threeLAeq of 42–45 dB(A)) is in line with a recent laboratory study that found the link between subjective disturbance and road traffic noise with an LAeq of 35–41 dB(A) to be quite weak [Overall, the moderate association of annoyance with relatively low-level road traffic noise  in terms of transitions from noisy to quiet periods (and back) diverting the attentional focus away from the task at hand to measure an effect on performance in the Stroop task when considering all trials worked out. However, the analysis of performance data could not be limited to those trials of the Stroop task that were performed at the time of, or shortly after, the salient changes in the road traffic noise scenarios. This was because the processing of the Stroop trials was self-paced in the present experiments, so that the relevant individual trials in the cognitive task could not be identified. In contrast, the above-mentioned laboratory study  found trNevertheless, the typical Stroop effect was found in both experiments. That is, RTs were prolonged and ERs were increased for incongruent items, in which two dimensions of the visual stimulus did not match, compared to congruent items. This indicates that the participants seriously worked on the given cognitive task, and that our study in fact comprised unfocused listening experiments to investigate annoyance. Since performance in the Stroop task versions used here hardly changed during the different road traffic noise scenarios and, moreover, did not change systematically between the two experiments, differences in annoyance ratings can be assumed to not be moderated or even caused by performance effects . Instead, the observed annoyance effects can be indeed attributed to the differing macro-temporal pattern of road traffic noise. In that context, it would be interesting to study the effects on noise annoyance in situations where also performance in (possible more difficult) cognitive tasks is affected by the macro-temporal pattern of road traffic noise.A particular asset of the current study is that both, noise annoyance and cognitive performance, were mutually studied in two experiments to evaluate potential effects of road traffic noise comprehensively. While similar studies are available for background speech and music ,40,41, sThe study also faces certain limitations. As is generally true for laboratory studies, the ecological validity is limited due to the laboratory setting and the rather limited number of participants. Further, inferring from short-term noise annoyance in the laboratory to long-term annoyance in the field still needs to be verified , and inLAeq, which is a decisive factor for road traffic noise annoyance  annoyance. These limitations could be addressed and improved in future studies , would be beneficial. Besides, varying the e e.g., ,68) woul woulLAeqdies cf. .Our experiment revealed that, for moderate sound exposure in an office environment, the macro-temporal pattern of road traffic noise affects annoyance. This was true although participants were not actively listening to the noise but were working on a cognitive task, and even though performance on that task was not systematically affected by the noise. Future research might test whether the association of the macro-temporal pattern of the road traffic noise scenarios with annoyance is different if participants actively listen to them . This could be studied in a focussed listening experiment, where only the sound to be subjectively evaluated is presented, without any cognitive task to be performed. Besides, follow-up experiments focusing more on the effects of road traffic noise scenarios on attentional functions might be set-up in such a way that the relevant trials in the cognitive task at the time of, or shortly after, the salient changes in the noise scenarios can be identified . Then one could test more sensitively than in our experiments whether the transitions from traffic noise to quiet periods and back, and/or irregular breaks as unanticipated changes in the auditory background cause attentional capture.LAeq = 55–60 dB(A)). Such experiments could help further filling the gap in knowledge on the links between annoyance, performance and macro-temporal pattern of environmental sounds.In the experiments presented here, the levels were as one might well find them in an office environment. However, people are also exposed to traffic noise in street cafés, on balconies and in front gardens, where the sound levels can be significantly higher. Also there, people spend longer time periods and concentrate on certain cognitive tasks, if they have to or wish to. Consequently, further unfocussed listening experiments similar to the experiments presented here would be desirable to study the effect of macro-temporal pattern on annoyance and cognitive performance under substantially higher sound exposure (e.g., In unfocussed laboratory listening experiments, the associations of annoyance and cognitive performance with the macro-temporal pattern of relatively low-level road traffic noise situations were investigated in a mock office environment. In line with literature, annoyance decreased with increasing total duration of quiet periods. Also the distribution of the quiet times affected annoyance. Shorter but more regular breaks were found to be less annoying than longer but irregular breaks of identical total duration; a minimal necessary duration of noise breaks as proposed in literature could thus not be confirmed. Cognitive performance in an attention-based task, in contrast, did not systematically vary with the macro-temporal pattern of the situations. Thus, while the macro-temporal pattern of road traffic noise situations with moderate sound exposure seems playing a minor role for cognitive performance, it may still be important for annoyance of office staff.