Nicotine promotes e-cigarette vapour-induced lung inflammation and structural alterations.

BACKGROUND: Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear. RESULTS: In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations (e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8 months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8 cells·mL-1; control: 37.0±21.1 cells·mL-1; NF ECV: 198.6±94.9 cells·mL-1) and in lung tissue (ECV: 25.7±3.3 cells·mm-3; control: 4.8±1.1 cells·mm-3; NF ECV: 14.1±2.2 cells·mm-3). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function (e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV. CONCLUSIONS: NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations.

Decreased plasma levels of the brain-derived neurotrophic factor correlate with right heart congestion in pulmonary arterial hypertension.

Background: The brain-derived neurotrophic factor (BDNF) may promote development of pulmonary hypertension and right ventricular (RV) failure. However, BDNF plasma levels were decreased in patients with left ventricular (LV) failure. Therefore, we investigated BDNF plasma levels in pulmonary hypertension patients and the role of BDNF in mouse models of pulmonary hypertension and isolated RV failure. Methods: BDNF plasma levels were correlated to pulmonary hypertension in two patient cohorts, including either post- and pre-capillary pulmonary hypertension patients (first cohort) or only pre-capillary pulmonary hypertension patients (second cohort). In the second cohort, RV dimensions and load-independent function were determined by imaging and pressure-volume catheter measurements, respectively. For induction of isolated RV pressure overload, heterozygous Bdnf knockout (Bdnf+/- ) mice were subjected to pulmonary arterial banding (PAB). For induction of pulmonary hypertension, mice with inducible knockout of BDNF in smooth muscle cells (Bdnf/Smmhc knockout) were exposed to chronic hypoxia. Results: Plasma BDNF levels were decreased in patients with pulmonary hypertension. Following adjustment for covariables, BDNF levels negatively correlated in both cohorts with central venous pressure. In the second cohort, BDNF levels additionally negatively correlated with RV dilatation. In animal models, BDNF downregulation attenuated RV dilatation in Bdnf+ /- mice after PAB or hypoxic Bdnf/Smmhc knockout mice, although they developed pulmonary hypertension to a similar extent. Conclusions: Similar to LV failure, circulating levels of BDNF were decreased in pulmonary hypertension patients, and low BDNF levels were associated with right heart congestion. Decreased BDNF levels did not worsen RV dilatation in animal models, and thus, may be the consequence, but not the cause of RV dilatation.

Digital platforms: Perceived criteria of success, importance of work design, occupational safety and health for present and prospective digital platforms.

BACKGROUND: Digital platforms have found their way into all our lives: they are discussed in political, economic, scientific and public fields worldwide. Platform-based work is also on the rise in the German labour market, not only in institutionalised work, but also in start-ups and spin-offs. OBJECTIVES: The article describes the results of an analysis aimed at identifying perceptions of new and already known major success factors on market entry and market penetration regarding occupational safety and health (OSH) and work design. METHODS: A total of 31 semi-standardised interviews were conducted with 39 people. First, perceived success factors in general were examined with the comparative analysis. Surprisingly, OSH/work design factors did not emerge as perceived success factors. For this reason, a in-depth analysis was performed in a secondary analysis with the structured content analysis. RESULTS: Identified perceived success factors were user orientation, scalability, network effects, niche occupation. The in-depth secondary analysis with focus on OSH/work design showed that the interviewees are aware of the topic of OSH/work design, but did not consider it to be important to economic success. CONCLUSIONS: The identified success factors may not seem surprising. What is surprising, however, is the role played by OSH/work design. Solutions must be developed that sensitize working persons in the platform sector to the topic of OSH/work design. A two-step process may be useful: First, uniform regulations and laws must be anchored in the platform architecture. Second, various measures and training courses can be designed to inform and raise awareness.

SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMCs) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVECs). On reexposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, the authors aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature. METHODS: After microarray analysis, the authors assessed the role of SPARC (secreted protein acidic and rich in cysteine) in PH using lung tissue from idiopathic pulmonary arterial hypertension (IPAH) patients, as well as from chronically hypoxic mice. In vitro studies were conducted in primary human PASMCs and PMVECs. In vivo function of SPARC was proven in chronic hypoxia-induced PH in mice by using an adeno-associated virus-mediated Sparc knockdown approach. RESULTS: C57BL/6J mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent reexposure to normoxia for different time points. Microarray analysis of the pulmonary vascular compartment after laser microdissection identified Sparc as one of the genes downregulated at all reoxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in IPAH, although SPARC plasma levels were not elevated in PH. TGF-ß1 (transforming growth factor ß1) or HIF2A (hypoxia-inducible factor 2A) signaling pathways induced SPARC expression in human PASMCs. In loss of function studies, SPARC silencing enhanced apoptosis and reduced proliferation. In gain of function studies, elevated SPARC levels induced PASMCs, but not PMVECs, proliferation. Coculture and conditioned medium experiments revealed that PMVECs-secreted SPARC acts as a paracrine factor triggering PASMCs proliferation. Contrary to the authors' expectations, in vivo congenital Sparc knockout mice were not protected from hypoxia-induced PH, most probably because of counter-regulatory proproliferative signaling. However, adeno-associated virus-mediated Sparc knockdown in adult mice significantly improved hemodynamic and cardiac function in PH mice. CONCLUSIONS: This study provides evidence for the involvement of SPARC in the pathogenesis of human PH and chronic hypoxia-induced PH in mice, most likely by affecting vascular cell function.

Being moved by listening to unfamiliar sad music induces reward-related hormonal changes in empathic listeners.

Many people enjoy sad music, and the appeal for tragedy is widespread among the consumers of film and literature. The underlying mechanisms of such aesthetic experiences are not well understood. We tested whether pleasure induced by sad, unfamiliar instrumental music is explained with a homeostatic or a reward theory, each of which is associated with opposite patterns of changes in the key hormones. Sixty-two women listened to sad music (or nothing) while serum was collected for subsequent measurement of prolactin (PRL) and oxytocin (OT) and stress marker (cortisol and adrenocorticotropic hormone) concentrations. Two groups of participants were recruited on the basis of low and high trait empathy. In the high empathy group, PRL and OT levels were significantly lower with music compared with no music. And compared to the low empathy group, the high empathy individuals reported an increase of positive mood and higher ratings of being moved with music. None of the stress markers showed any changes across the conditions or the groups. These hormonal changes, inconsistent with the homeostatic theory proposed by Huron, exhibit a pattern expected of general reward. Our findings illuminate how unfamiliar and low arousal music may give rise to pleasurable experiences.

The Relationship Between Individual Coping and the Need to Have and Seek Health Information Among Older Adults: Exploratory Mixed Methods Study.

BACKGROUND: The need to have and seek information shapes the context of computing systems. When it comes to health, individual coping influences human behavior. Therefore, the relationship between individual coping and the need to have and seek health information plays a crucial role in the development of digital health systems. OBJECTIVE: This study aims to examine the relationship between individual coping and the need to have and seek health information among older adults. METHODS: Questionnaires and semistructured interviews investigated the health information need (HIN) and health information-seeking behavior (HISB) in relation to the individual coping strategies of 26 older Germans. RESULTS: The mean age of the interviewed group was 71 years (SD 7). Quantitatively, a trend was found for a negative correlation between the avoidance-oriented coping and HIN (rs=-0.37895; bias-corrected and accelerated bootstrap 95% BCa CI -0.730 to 0.092; P=.05). The qualitative results supported this finding. For some participants, information and exchange was part of dealing with their health situation, whereas others wanted to learn as little as possible to avoid a decline in their health status. The older adults acquired, collected, and exchanged paper-based health data to augment clinical information sources and support information exchange with professionals. CONCLUSIONS: Individual coping strategies are relevant for the design of digital health systems. They can support older adults in coping with their health situation, although it remains unclear how systems must be designed for people with an avoidance coping strategy to achieve the same acceptance.

Response Priming with Horizontally and Vertically Moving Primes: A Comparison of German, Malaysian, and Japanese Subjects.

Response priming refers to the finding that a prime preceding a target influences the response to the target. With German subjects, horizontally moving dots as primes, and static arrows as targets, there are typically faster responses to compatible (i.e., prime and target are associated with the same response) as compared to incompatible targets (i.e., positive compatibility effect, PCE) with short stimulus onset asynchronies (SOAs). In contrast, with longer SOAs, subjects respond faster to incompatible as compared to compatible targets (i.e., negative compatibility effect, NCE). In the present study, we extended the evidence by adding vertically oriented materials. Furthermore, we tested subjects from Malaysia and Japan, where the vertical orientation is more present in daily life, and compared them to German subjects to investigate whether the amount of experience with one orientation influences the compatibility effects on this orientation. Overall, we found pronounced PCEs in the short SOA (i.e., 150 ms) but only reduced PCEs in the longer SOAs (i.e., 350, 550, and 750 ms) across all countries and orientations. There were no differences between the German and Malaysian samples, but the Japanese sample showed larger PCEs in the longer SOAs compared to both other samples. Furthermore, we found larger PCEs for horizontal than vertical materials in the short SOA and larger PCEs for vertical than horizontal materials in the longer SOAs. We discuss our findings in light of theories and findings on compatibility effects as well as attentional mechanisms.

AMICAI: A Method Based on Risk Analysis to Integrate Responsible Research and Innovation into the Work of Research and Innovation Practitioners.

The integration of ethics into the day-to-day work of research and innovation (R&I) is an important but difficult challenge. However, with the Aachen method for identification, classification and risk analysis of innovation-based problems (AMICAI) an approach from an engineering perspective is presented that enables the integration of ethical, legal and social implications into the day-to-day work of R&I practitioners. AMICAI appears in particular capable of providing a procedural guidance for R&I practitioners based on a method established in engineering science, breaking down the object of consideration into partial aspects and prioritizing the innovation-based problems in dependence of potential risk. This enables the user to apply AMICAI continuously during all stages of the research and development (R&D) process and to analyze and choose between certain sociotechnical alternatives. In this way, problems that affect ethical, legal, and social aspects can be understood, reflected and considered in the mostly technically focused R&D process. The paper gives a general guidance about AMICAI by describing principles and assumptions, providing the steps of analysis and application aids, giving an example application, explaining the necessary adjustments of AMICAI compared to the methodical basis of failure mode, effects, and criticality analysis and discussing the advantages and limits. AMICAI's simple applications can stimulate interdisciplinary cooperation in the R&D process and be a starting point for the development of an "open RRI risk analysis platform" allowing society to evaluate innovation-based problems.

Survey-based personas for a target-group-specific consideration of elderly end users of information and communication systems in the German health-care sector.

BACKGROUND: In many countries, including Germany, older people are increasing in numbers, while fewer caregivers are available. A way to address the problem is to develop new medical assistance and monitoring systems that are operated by the elderly on their own, e.g. in-home aftercare systems. OBJECTIVE: The development of a set of eight data-based personas in terms of a best practice approach is presented. METHOD: "Personas" are an integral method of the user-centered design approach. They address the problem of incomplete knowledge of individual user behaviour by introducing archetypal user groups. Thus, personas can be used at an early stage of development to raise the awareness of developers to the needs, skills, and abilities of the elderly. Personas are also a cost-effective method and quickly and easily accessible. In order to guarantee representativeness the development of personas needs to occur based on a robust data set of a certain user group. RESULTS: This article presents the data-driven development of eight personas. The applied data set results from a nationwide questionnaire study on the elderly's use of information and communication technology, out of elderly people in Germany. The results will be presented in terms of best practice. CONCLUSION: To conclude, survey-based personas of older end users can play an important role in the research and development of innovative devices. APPLICATION: The personas presented in this paper can be used in research and development to raise awareness of the needs and demands of end users.

Predicting technology usage by health information need of older adults: Implications for eHealth technology.

BACKGROUND: Information and communication technology increasingly addresses the information needs patients have regarding their personal health. While an understanding of older adults' needs is crucial for developing successful eHealth technology, user research results hardly apply to different systems. OBJECTIVE: The present study aims at: (1) describing and analysing the context of digital health systems in a general manner, (2) investigating if information need of older adults influences their technology usage to show the relevance of the concept for a general context analysis and (3) testing which demographic variables intervene with their health information need. METHODS: Survey data from a longitudinal study with older adults (N = 551) were reported descriptively. After showing a significant relationship during chi-square tests, we quantified the ones between general health information need and technology usage, as well as between general health information need and the demographic variables age, education, chronic diseases and gender by means of (multiple) linear regression models. RESULTS: We predicted older adults' technology usage based on their health information need. The results confirmed this relationship. Higher information need led to a more frequent usage of apps installed on the tablet personal computer (PC), to a frequent use of smartwatches and to the possession of a computer or laptop. Users' education has a higher impact on health information need than amount of chronic diseases, gender and age. CONCLUSIONS: Information need emerged as a useful object for investigation of context and user requirement analysis across different systems: it predicted technology usage so that design recommendations derived from the descriptive gained in importance.

Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension.

Increased mitochondrial reactive oxygen species (ROS), particularly superoxide have been suggested to mediate hypoxic pulmonary vasoconstriction (HPV), chronic hypoxia-induced pulmonary hypertension (PH) and right ventricular (RV) remodelling.We determined ROS in acute, chronic hypoxia and investigated the effect of the mitochondria-targeted antioxidant MitoQ under these conditions.The effect of MitoQ or its inactive carrier substance, decyltriphenylphosphonium (TPP+), on acute HPV (1% O2 for 10 minutes) was investigated in isolated blood-free perfused mouse lungs. Mice exposed for 4 weeks to chronic hypoxia (10% O2) or after banding of the main pulmonary artery (PAB) were treated with MitoQ or TPP+ (50 mg/kg/day).Total cellular superoxide and mitochondrial ROS levels were increased in pulmonary artery smooth muscle cells (PASMC), but decreased in pulmonary fibroblasts in acute hypoxia. MitoQ significantly inhibited HPV and acute hypoxia-induced rise in superoxide concentration. ROS was decreased in PASMC, while it increased in the RV after chronic hypoxia. Correspondingly, MitoQ did not affect the development of chronic hypoxia-induced PH, but attenuated RV remodelling after chronic hypoxia as well as after PAB.Increased mitochondrial ROS of PASMC mediate acute HPV, but not chronic hypoxia-induced PH. MitoQ may be beneficial under conditions of exaggerated acute HPV.

Prevalence of Health App Use Among Older Adults in Germany: National Survey.

BACKGROUND: Health apps are increasingly becoming an integral part of health care. Especially in older adults, the self-management of chronic diseases by health apps might become an integral part of health care services. OBJECTIVE: The aim of this explorative study was to investigate the prevalence of health app use and related demographic factors, as well as health status among older adults in Germany. METHODS: A nationwide postal survey was conducted. Of the 5000 individuals contacted, a total of 576 participants completed this survey. On the basis of their self-indicated assignment to one of the three predefined user groups (health app users, general app users, and nonusers of apps), participants answered various questions regarding app and health app use, including frequency of use and number of installed apps, demographic factors, and health status. RESULTS: In total, 16.5% (95/576) used health apps, whereas 37.5% (216/576) indicated only using general apps, and 46.0% (265/576) reported using no apps at all. The number of installed health apps was most frequently reported as between 1 and 5 apps per participant, which were usually used on a weekly basis. The most frequently cited type of health apps were exercise-related ones. Individuals using health apps were found to be younger (MeanmHealth 66.6, SD 4.7) and to have a higher level of technical readiness compared with general app users and nonusers of apps (adjusted odds ratio, AOR=4.02 [95% CI 2.23-7.25] for technical readiness, and AOR=0.905 [95% CI 0.85-0.97] for age). The most frequently mentioned sources of information about apps within the group of health and general app users were family and friends. Identified barriers against the use of health apps were a lack of trust, data privacy concerns, and fear of misdiagnosis. CONCLUSIONS: Health apps are already used by older adults in Germany. The main type of apps used are exercise-related ones. Barriers to and incentives for the use of health apps and associations with health status and users' demographics were revealed.

An integrative review of the enjoyment of sadness associated with music.

The recent surge of interest towards the paradoxical pleasure produced by sad music has generated a handful of theories and an array of empirical explorations on the topic. However, none of these have attempted to weigh the existing evidence in a systematic fashion. The present work puts forward an integrative framework laid out over three levels of explanation - biological, psycho-social, and cultural - to compare and integrate the existing findings in a meaningful way. First, we review the evidence pertinent to experiences of pleasure associated with sad music from the fields of neuroscience, psychophysiology, and endocrinology. Then, the psychological and interpersonal mechanisms underlying the recognition and induction of sadness in the context of music are combined with putative explanations ranging from social surrogacy and nostalgia to feelings of being moved. Finally, we address the cultural aspects of the paradox - the extent to which it is embedded in the Western notion of music as an aesthetic, contemplative object - by synthesising findings from history, ethnography, and empirical studies. Furthermore, we complement these explanations by considering the particularly significant meanings that sadness portrayed in art can evoke in some perceivers. Our central claim is that one cannot attribute the enjoyment of sadness fully to any one of these levels, but to a chain of functionalities afforded by each level. Each explanatory level has several putative explanations and its own shift towards positive valence, but none of them deliver the full transformation from a highly negative experience to a fully enjoyable experience alone. The current evidence within this framework ranges from weak to non-existent at the biological level, moderate at the psychological level, and suggestive at the cultural level. We propose a series of focussed topics for future investigation that would allow to deconstruct the drivers and constraints of the processes leading to pleasurable music-related sadness.

Quantifying patient adherence during active orthodontic treatment with removable appliances using microelectronic wear-time documentation.

OBJECTIVES: The aim of this study was to quantify the wear times of removable appliances during active orthodontic treatment. MATERIALS AND METHODS: The wear times of 141 orthodontic patients treated with active removable appliances in different locations were documented over a period of 3 months using an incorporated microsensor. Gender, age, treatment location, health insurance status, and type of device were evaluated with respect to wear time. Significant associations between wear times and patient factors were calculated using non-parametric tests. RESULTS: The median daily wear time was 9.7 hours/day for the entire cohort, far less than the 15 hours/day prescribed. Younger patients wore their appliances for longer than older patients (7-9 years 12.1 hours/day, 10-12 years 9.8 hours/day, and 13-15 years 8.5 hours/day; P < 0.0001). The median wear time for females (10.6 hours/day) was 1.4 hours/day longer than males (9.3 hours/day; P = 0.017). Patients treated at different locations wore their devices with a difference of up to 5.0 hours/day. Privately insured patients had significantly longer median wear times than statutorily insured patients. No significant difference in wear time was noted according to device type. CONCLUSIONS: The daily wear time of removable appliances during the active phase of orthodontic therapy can be routinely quantified using integrated microelectronic sensors. The relationship between orthodontist and patient seems to play a key role in patient adherence. Wear-time documentation provides the basis for more individualized wear-time recommendations for patients with removable appliances. This could result in a more efficient, shorter, and less painful orthodontic therapy.

Negative BOLD signal changes in ipsilateral primary somatosensory cortex are associated with perfusion decreases and behavioral evidence for functional inhibition.

We used functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to study the negative blood oxygenation level dependent (BOLD) signal and its underlying blood flow changes in healthy human subjects. This was combined with psychophysiological measurements to test that the negative BOLD signal is associated with functional inhibition. Electrical stimulation of the median nerve at 7 Hz evoked robust negative BOLD signals in the primary somatosensory cortex (SI) ipsilateral to stimulation, and positive BOLD signals in contralateral SI. The negative BOLD signal in ipsilateral SI was accompanied by commensurate decreases in relative regional cerebral blood flow (rCBF). Conjunction analysis of the fMRI and PET data revealed a region in the ipsilateral postcentral gyrus showing overlap of negative BOLD signals and relative rCBF decreases. The current perception threshold (CPT) at the ipsilateral finger during concomitant stimulation of the contralateral median nerve increased significantly, suggesting augmented functional inhibition. Since the CPT in the ipsilateral hallux did not significantly change in response to median nerve stimulation, it is more likely that the CPT-increase for the finger is due to functional inhibition (Kastrup et al., 2008) than to changes in selective attention. In conclusion, our data provide evidence that stimulus-induced reductions in relative rCBF may underlie the negative BOLD signal, which in turn may reflect increments in functional inhibition.

Poleward range expansion without a southern contraction in the ground beetle Agonum viridicupreum (Coleoptera, Carabidae).

We investigated the extent of poleward shifts in the distribution range of Agonum viridicupreum due to climate change in the western Palaearctic. Species' records were obtained from extensive literature sources as well as from collections, and consistent amateur entomologists' recordings. Within the general geographic range of the species, we analyzed in detail two parts of both, the northern and southern distribution range boundaries: (1 and 2) north-western Germany (leading or high-latitude edge), (3) Israel and (4) southern Italy (rear or low-latitude edge). Temporal changes in the occurrence data of the species indicated a northward shift of the leading edge of a minimum of 100 km within the last 50 to 100 years. In contrast, according to the data gathered, the rear edge has not changed during the last decades. Further studies are needed in order to fully understand the underlying mechanisms of the different behaviour of leading and rear range edges of Agonum viridicupreum in the current context of global change. Despite our incomplete understanding, chronosequences of the occurrence of the given species have the potential to optimize climate niche modelling to predict trends in the distribution range in the future.

Gender- and menstrual phase dependent regulation of inflammatory gene expression in response to aerobic exercise.

The immunological reaction to exercise has been investigated with increasing intensity in the last 10-20 years, with most human studies performed in male subjects. Recently, gender-specific aspects have received growing attention, but studies carefully monitoring the influence of gender including the menstrual cycle, are rare. Here, we report gene expression patterns in response to a run at 93% of the individual anaerobic threshold of 9 women with regular menstrual cycles and no use of oral contraceptives who ran both at day 10 (follicular phase, F) and at day 25 (luteal phase, L) of their cycle. 12 male subjects (M) served as controls. The mRNA was pooled group wise and processed on a gene expression microarray encompassing 789 genes, including major genes of the inflammatory and anti-inflammatory reaction. The differences of gene expression between time points to (before run) and t1 (after run) were analyzed. Females in L showed a higher extent of regulation than females in F or men. Among those genes which were up-regulated above 1.5 fold change (log2) pro-inflammatory genes were significantly enriched (p = 0.033, after Bonferroni correction) in L, while this was not the case in F or M. Conversely, women in L showed a strong trend towards downregulation of anti-inflammatory genes. Some prominent genes like IL6 (coding for interleukin-6), and IL1RN (also termed IL1RA, coding for interleukin-1 receptor antagonist) were clearly regulated in opposite directions in L as opposed to F and M. In conclusion, women in L showed a distinctly different pattern of gene regulation in response to exercise, compared with women in F or M. The overall direction of gene expression changes of women in L is clearly pro-inflammatory. This finding accentuates a need for careful consideration of the female cyclic phase when investigating women in exercise immunology studies. Our results may also have implications relevant to other forms of stress in females.