Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

Formoterol is a long‐acting beta2‐adrenoceptor agonist (LABA) used for treatment of asthma and exercise‐induced bronchoconstriction. Formoterol is usually administered as a racemic (rac‐) mixture of (R,R)‐ and (S,S)‐enantiomers. While formoterol is restricted by the World Anti‐Doping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 μg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)‐formoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 μg inhaled dose of rac‐formoterol. Urine was collected over 24‐hours and analysed by enantioselective UPLC‐MS/MS assay. Total (free drug plus conjugated metabolite) median (min‐max) rac‐formoterol urine levels following inhalation were 1.96(1.05‐13.4) ng/mL, 1.67(0.16‐9.67) ng/mL, 0.45(0.16‐1.51) ng/mL, 0.61(0.33‐0.78) ng/mL, and 0.17(0.08‐1.06) ng/mL at 2, 4, 8, 12 and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)‐formoterol (around 30‐60% of total) compared to (S,S)‐formoterol (0‐30%). There was clear evidence of inter‐individual enantioselectivity observed in the ratios of (R,R):(S,S)‐formoterol, where (S,S)‐ was predominant in free formoterol, and (R,R)‐ predominant in the conjugated metabolite. In conclusion, rac‐formoterol delivered by inhalation exhibits enantioselective elimination in urine following single dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2‐agonist chiral switch products such as (R,R)‐formoterol, and total hydrolysed rac‐formoterol is warranted to account for inter‐individual differences in enantioselective glucuronidation

The Road to the Beijing Winter Olympics and Beyond: Opinions and Perspectives on Physiology and Innovation in Winter Sport

Open Access This article is licensed under a Creative Commons Attri bution 4.0 International License, which permits use, sharing, adapta tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/Beijing will host the 2022 Winter Olympics, and China strengthens research on various aspects to allow their athletes to compete successfully in winter sport. Simultaneously, Government-directed initiatives aim to increase public participation in recreational winter sport. These parallel developments allow research to advance knowledge and understanding of the physiological determinants of performance and health related to winter sport. Winter sport athletes often conduct a substantial amount of training with high volumes of low-to-moderate exercise intensity and lower volumes of high-intensity work. Moreover, much of the training occur at low ambient temperatures and winter sport athletes have high risk of developing asthma or asthma-related conditions, such as exercise-induced bronchoconstriction. The high training volumes require optimal nutrition with increased energy and dietary protein requirement to stimulate muscle protein synthesis response in the post-exercise period. Whether higher protein intake is required in the cold should be investigated. Cross-country skiing is performed mostly in Northern hemisphere with a strong cultural heritage and sporting tradition. It is expected that innovative initiatives on recruitment and training during the next few years will target to enhance performance of Chinese athletes in classical endurance-based winter sport. The innovation potential coupled with resourcing and population may be substantial with the potential for China to become a significant winter sport nation. This paper discusses the physiological aspects of endurance training and performance in winter sport highlighting areas where innovation may advance in athletic performance in cold environments. In addition, to ensure sustainable development of snow sport, a quality ski patrol and rescue system is recommended for the safety of increasing mass participation

Cardiological health in patients with schizophrenia. A prospective cohort study

INTRODUCTION: Patients with schizophrenia have a four-fold increased all-cause and a doubled cardiovascular mortality rate as compared to the general population. OBJECTIVES: The study overall investigates the point-prevalence and prospective changes in cardiovascular risk factors in patients with schizophrenia, with baseline demographics of participants presented here. METHODS: A prospective study of patients diagnosed with schizophrenia divided into two subpopulations consisting of newly diagnosed (≤2 years from baseline in study (group A)) or chronic (diagnosed ≥10 years from baseline in study (group B)). RESULTS: A total of 199 patients (57 diagnosed ≤2 years preceding baseline and 142 diagnosed ≥10 years ago) were included. Group A had been diagnosed for an average of 1.13±0.58 years and 21.19±7.62 years in group B. The majority (n=135 (67.8%)) were diagnosed with paranoid schizophrenia. At baseline PANSS total (median[Q1;Q3]) for group A was 61.0[51.0;76.0] and 60.0[48.0;76.0] for group B, with PANNS Positive being 17.0[13.0;20.0] and 15.0[12;19], PANSS Negative being 16.0[11.0;20.0] and 14.5[10.0;20.0], and PANSS General being 28.0[22.0;35.0] and30.0 [25.0;37.0], respectively. No difference in Clinical Global Impression was observed between groups ((median[Q1;Q3): 4.0[3.0;4.0] in both groups). Lastly, global assessment of function was similar between groups ((median[Q1;Q3): group A symptom: 38.5[37.0;46.0] and group B 41.0[37.0;52.0], and with function being 48.0[44.5;53.5] in group A and 45.5[41.0;53.0] in group B). CONCLUSIONS: Prospective studies investigating prevalence of and prospective changes in cardiovascular risk in patients with schizophrenia are essential to understand the increased all-cause and cardiovascular specific mortality. Demographic descriptions of participants are essential to estimate generalizability in different treatment settings. DISCLOSURE: No significant relationships

Abdominal examination during pregnancy may enhance relationships between midwife, mother and child : a qualitative study of pregnant women's experiences

Background: Abdominal examination is a routine procedure performed by midwives several times during pregnancy to monitor the growth and well-being of the baby. Literature and instructions regarding abdominal examination focus on the technical performance, with limited attention paid to the women’s experience of the examination or the bonding-related aspects between the mother and baby. The aim of the study was to explore how pregnant women experience the abdominal examination and how the examination affects maternal–fetal attachment. Methods: Participant observation and semi-structured interviews with 10 pregnant women. We used thematic analysis to identify themes across the empirical material. Results: We identified the following four central themes: an essential examination, the baby becomes real, the importance of being involved and different senses provide different experiences. These themes describe how the women regarded the abdominal examination as an essential part of the midwifery consultation and considered it the occasion when the baby became real and tangible. Being prepared and involved before and during the examination were pivotal for how the examination was experienced by the women. The abdominal examination was crucial to the pregnant women because it provided them with important sensory aspects that were not obtained from ultrasound examination. Conclusion: The abdominal examination is regarded as essential in midwifery consultations and has the potential for supporting a woman’s bodily sensation of her baby, which is reinforced by the midwife’s manual palpation. Touch can be a way for a pregnant woman to become acquainted with her unborn child, which provides midwives a profound potential to facilitate the process of maternal–fetal attachment

Altered surface-based brain morphometry in type 1 diabetes and neuropathic pain

This study explored surface brain morphometry in type 1 diabetes including focus on painful diabetic peripheral neuropathy (DPN). Brain MRI was obtained from 56 individuals with diabetes (18 without DPN, 19 with painless DPN, 19 with painful DPN) and 20 healthy controls. Cortical thickness, sulcus depth, and gyrification were analysed globally and regionally in each group and in the combined diabetes group. Associations with clinical characteristics and pain were assessed. Globally, cortical thickness was reduced in the combined diabetes group and in painful DPN compared to healthy controls. No differences in sulcus depth and gyrification were found. Several regions, including the middle frontal gyrus showed reduced cortical thickness in the combined diabetes- and painful DPN group. The postcentral gyrus exhibited reduced cortical thickness in painful DPN compared to healthy controls, and reduced sulcus depth compared to painless DPN correlating with higher pain intensity. Cortical thinning manifested across the brain cortex in diabetes, especially for painful DPN. Altered postcentral gyrus morphometry may be associated with neuropathic pain. Assessing cortical morphometry may be critical for comprehending central neuropathy and the manifestation of painful DPN in diabetes.</p

Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake

Skeletal muscle glucose uptake, essential for metabolic health, is regulated by both insulin and exercise. Using phosphoproteomics, we analyze skeletal muscle from healthy individuals following acute exercise or insulin stimulation, generating a valuable dataset. We identify 71 phosphosites on 55 proteins regulated by both stimuli in the same direction, suggesting a convergence of exercise and insulin signaling pathways. Among these, the vesicle-associated protein, REPS1, is highly phosphorylated at Ser709 in response to both stimuli. We identify p90 ribosomal S6 kinase (RSK) to be a key upstream kinase of REPS1 S709 phosphorylation and that the RSK-REPS1 signaling axis is involved in insulin-stimulated glucose uptake. Insulin-induced REPS1 Ser709 phosphorylation is closely linked to muscle and whole-body insulin sensitivity and is impaired in insulin-resistant mice and humans. These findings highlight REPS1 as a convergence point for insulin and exercise signaling, presenting a potential therapeutic target for treating individuals with insulin resistance.</p