The impact of irritant challenge on the skin barrier and myeloid resident immune cells in post-menopausal women is modulated by hormone replacement therapy.

BACKGROUND: Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. Therefore, we examined how menopause and HRT affect skin barrier and immune cell composition in post-menopausal women following irritant challenge. METHODS: Two cohorts of post-menopausal women were recruited to the study, one untreated (HRT-; n = 10; mean age 56.5 yrs [range 48-63 yrs]) and the other receiving HRT (n = 8; mean age 54 yrs [range 48-63 yrs]). Skin irritation was induced by applying 1.25% topical Sodium Lauryl Sulfate (SLS) to occluded buttock skin for 48 hours. Clinical assessment was conducted after 24 hours, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. RESULTS: Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in trans-epidermal water loss (p<0.05), filaggrin deposition and keratin-10-positive cell layers (p<0.01) was observed in individuals receiving HRT compared to the HRT- group. Following SLS challenge in individuals taking HRT, a significant (p<0.01) reduction of CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans' cells (LCs). Significantly fewer migrating LCs were observed in those not receiving HRT (p<0.01). Furthermore, the number of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (p<0.05) higher in those taking HRT following SLS challenge. CONCLUSION: Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased keratin-10-positive epidermal cell layers. Following challenge, HRT users exhibited elevated counts of LCs, inflammatory DCs, and macrophages in the dermis. These may render skin both, more prone to inflammation and more capable of resolving it, while also promoting skin repair.

Social connectedness and supported self-management of early medication abortion in the UK: experiences from the COVID-19 pandemic and learning for the future.

Medication abortion has been established globally as safe and effective. This modality has increased accessibility and the opportunity to centre individual autonomy at the heart of abortion care, by facilitating self-managed abortion. Previous research has shown how self-managed abortion is beneficial in myriad settings ranging from problematic to (relatively) unproblematic contexts of access. In this paper we explore the relationship between self-management and sources of support (including health professionals, family, and friends); as well as considering issues of reproductive control and autonomy. Drawing on qualitative, experience-centred interviews, we utilise the concept of social connectedness to examine how supported self-managed abortion was experienced in the United Kingdom during the COVID-19 pandemic. Overall, self-management was welcomed, with participants speaking positively about managing their own abortion at home. However, a sense of connectedness was crucial in helping participants deal with difficult experiences; and functioned to support individual autonomy in self-care. This paper is the first to examine factors of connection, support, and isolation, as experienced by those undergoing self-managed abortion in the UK in detail. Our research suggests a continued need to advocate for high quality support for self-managed abortion, as well as for choice of abortion method, to support patient-centered care.

SOX9 maintains reserve stem cells and preserves radioresistance in mouse small intestine.

BACKGROUND & AIMS: Reserve intestinal stem cells (rISCs) are quiescent/slowly cycling under homeostatic conditions, allowing for their identification with label-retention assays. rISCs mediate epithelial regeneration after tissue damage by converting to actively proliferating stem cells (aISCs) that self renew and demonstrate multipotency, which are defining properties of stem cells. Little is known about the genetic mechanisms that regulate the production and maintenance of rISCs. High expression levels of the transcription factor Sox9 (Sox9(high)) are associated with rISCs. This study investigates the role of SOX9 in regulating the rISC state. METHODS: We used fluorescence-activated cell sorting to isolate cells defined as aISCs (Lgr5(high)) and rISCs (Sox9(high)) from Lgr5(EGFP) and Sox9(EGFP) reporter mice. Expression of additional markers associated with active and reserve ISCs were assessed in Lgr5(high) and Sox9(high) populations by single-cell gene expression analyses. We used label-retention assays to identify whether Sox9(high) cells were label-retatining cells (LRCs). Lineage-tracing experiments were performed in Sox9-CreERT2 mice to measure the stem cell capacities and radioresistance of Sox9-expressing cells. Conditional SOX9 knockout mice and inducible-conditional SOX9 knockout mice were used to determine whether SOX9 was required to maintain LRCs and rISC function. RESULTS: Lgr5(high) and a subset of crypt-based Sox9(high) cells co-express markers of aISC and rISC (Lgr5, Bmi1, Lrig1, and Hopx). LRCs express high levels of Sox9 and are lost in SOX9-knockout mice. SOX9 is required for epithelial regeneration after high-dose irradiation. Crypts from SOX9-knockout mice have increased sensitivity to radiation, compared with control mice, which could not be attributed to impaired cell-cycle arrest or DNA repair. CONCLUSIONS: SOX9 limits proliferation in LRCs and imparts radiation resistance to rISCs in mice.

Foregrounding pain in self-managed early medication abortion: a qualitative study.

OBJECTIVE: To explore experiences of pain in the context of early medical abortion (EMA) in the UK and to guide best practice around anticipatory guidance on pain. METHODS: From late 2020 to early 2021, we recruited individuals from across the UK who had undergone abortion during the COVID-19 pandemic to participate in in-depth, semi-structured telephone interviews. A storytelling approach was used and data were analysed thematically using NVivo 12 software. RESULTS: Focused coding and thematic analysis addressed accounts of pain, which were prominent in many interviews. We constructed the following subthemes: expected pain is manageable for some; the problem with unexpected pain; pain (co)produces fear; and problematising 'period-like pain'. The key issue which our analysis draws out is that while EMA pain experience might vary, for some it may be much worse than anticipated. Moreover, the common trope of likening it to 'period pain' can be misleading and a source of additional uncertainty at a potentially already challenging time. CONCLUSIONS: For some individuals, pain experienced in EMA will be severe and/or worse than expected. Insufficient preparation for pain can result in extremely negative experiences of EMA. Alongside development of improved analgesia, improvements should be made to anticipatory guidance on pain, particularly for those self-manging EMA at home. Framings of 'period-like pain' do not clarify expectations and should be avoided.

Young women's experiences of side-effects from contraceptive implants: a challenge to bodily control.

In the UK, long-acting reversible contraceptives have been welcomed by sexual health policy-makers and many practitioners as a particularly effective way of preventing unintended pregnancy, especially teenage conception. However, little is known about women's individual experiences of these forms of contraception beyond limited data on retention rates and reasons for discontinuation. The main aims of this research were to gain a fuller understanding of why some young women have their implants removed, and what may help them maintain this method of contraception if they wish to do so. The contraceptive choices of 20 young women (aged 16-22) who had chosen the implant, and later discontinued it, were examined. They had experienced unacceptable side effects that they attributed to the implant, and interpreted as a threat to their bodily control, which they were not prepared to tolerate. These feelings were exacerbated if they then encountered delays after requesting removal. Although they remained concerned to avoid unintended pregnancy, they generally moved to a less reliable form of contraception following implant removal and felt discouraged from trying other long-acting contraception. We suggest that principles of contraceptive choice should include facilitating the discontinuation of unsatisfactory methods; implant removal should therefore be readily available when requested, regardless of the length of time the implant has been in place. Long-acting forms of contraception do not suit all women, and will not obviate the need for other forms of reproductive control, including legal abortion.

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy.

The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production.

Suppressor of cytokine signaling-2 gene disruption promotes Apc(Min/+) tumorigenesis and activator protein-1 activation.

Epigenetic in vitro and in vivo studies suggest that suppressor of cytokine signaling-2 (SOCS2) may normally limit tumorigenesis in the intestine; however, this theory has not been directly tested. We hypothesized that SOCS2 deficiency promotes spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Therefore, we quantified tumor number, size, and load in the small intestine and colon using SOCS2(+/+)/Apc(Min/+), SOCS2(+/-)/Apc(Min/+), and SOCS2(-/-)/Apc(Min/+) mice and assayed hematocrit as an indirect marker of disease severity. Biochemical and histological assays were used to assess mechanisms. Heterozygous and homozygous disruption of SOCS2 alleles promoted 166 and 441% increases in tumor load in the small intestine, respectively, accelerated development of colon tumors, and caused severe anemia. SOCS2 deletion promoted significant increases in intestinal insulin-like growth factor-I mRNA but did not affect plasma insulin-like growth factor-I. Western blots and immunohistochemical analysis demonstrated that tumor and nontumor intestinal tissue of SOCS2(-/-)/Apc(Min/+) mice had increased serine 727 phosphorylation of signal transducer and activator of transcription 3 compared with SOCS2(+/+)/Apc(Min/+) mice. Moreover, electromobility shift assays showed that SOCS2 deletion did not alter signal transducer and activator of transcription 3 DNA binding. However, tumors and small intestine from SOCS2(-/-)/Apc(Min/+) showed dramatic increases in activator protein-1 (AP-1) DNA binding, and SOCS2 overexpression in vitro reduced levels of AP-1. These studies indicate that SOCS2 deletion promotes the spontaneous development of intestinal tumors driven by mutations in the adenomatous polyposis coli/beta-catenin pathway and activates AP-1. Therefore, reduced expression or epigenetic silencing of SOCS2 may serve as a useful biomarker for colorectal cancer risk.

Young women's fertility knowledge: partial knowledge and implications for contraceptive risk-taking.

BACKGROUND: There is a lack of research on young women's fertility knowledge and awareness. This has implications for contraceptive risk-taking, including the use of emergency hormonal contraception (EHC). By drawing on two research studies, this article shows how greater fertility knowledge could benefit young women in terms of pregnancy prevention. METHODS: We draw on two qualitative research studies ('fertility study' and 'abortion study') resulting in a composite sample of 46 interviews with women aged 16-24 years. Focused secondary analysis was undertaken looking specifically at fertility knowledge in relation to contraceptive behaviour. FINDINGS: A lack of accurate knowledge about the menstrual cycle was evident in two ways. Young women drew conclusions about their invulnerability to pregnancy if previous unprotected sexual intercourse (UPSI) had not resulted in pregnancy. Additionally, although participants were aware of EHC, there was no awareness of when it might fail other than after a certain time limit. CONCLUSIONS: Young women would benefit from a more nuanced understanding of fertility. Episodes of UPSI that do not result in pregnancy can encourage a belief that 'it won't happen to me', and this has implications for taking chances with contraception. Partial knowledge about the effectiveness of EHC may also lead to unintended pregnancy. Calculating the number of hours following UPSI generates overreliance on what is only one of the factors determining the effectiveness of EHC. Information regarding the link between EHC and failure rates near the day of ovulation needs to be more widely publicised.

Presence of PPE proteins in Mycobacterium avium subsp. paratuberculosis isolates and their immunogenicity in cattle.

Johne's disease or paratuberculosis in cattle is caused by Mycobacterium avium subsp. paratuberculosis (MAP). Although the stages of infection have been well described, very few virulence factors of MAP have been studied in detail. We aimed to study the localization and immunogenicity of members of the polymorphic PPE protein family which is unique to Mycobacteria and has been linked to virulence in Mycobacterium tuberculosis (Mtb). The presence of PPE proteins in the cell wall was investigated by enzymatic digest of surface exposed proteins of live MAP bacteria and analysis by LC-MS/MS. Polyclonal antisera were generated against a recombinant fragment of one PPE protein and a synthetic peptide of the other to confirm their surface exposure. Sera from naturally infected cows were investigated for the presence of specific antibodies against the recombinant PPE protein. Two PPE proteins, Map3420c and Map1506, were detected by mass spectrometry and confirmed to be surface exposed on live MAP cells by immunohistochemistry. The sera from naturally infected animals contained specific antibodies against recombinantly expressed Map3420c as demonstrated by western blotting. These findings show the in vitro expression of two PPE proteins. Additionally the surface exposure and immunogenicity of PPE proteins of MAP was demonstrated.

Circadian rhythms in skin and other elastic tissues.

Circadian rhythms are daily oscillations that, in mammals, are driven by both a master clock, located in the brain, and peripheral clocks in cells and tissues. Approximately 10% of the transcriptome, including extracellular matrix components, is estimated to be under circadian control. Whilst it has been established that certain collagens and extracellular matrix proteases are diurnally regulated (for example in tendon, cartilage and intervertebral disc) the role played by circadian rhythms in mediating elastic fiber homeostasis is poorly understood. Skin, arteries and lungs are dynamic, resilient, elastic fiber-rich organs and tissues. In skin, circadian rhythms influence cell migration and proliferation, wound healing and susceptibility of the tissues to damage (from protease activity, oxidative stress and ultraviolet radiation). In the cardiovascular system, blood pressure and heart rate also follow age-dependent circadian rhythms whilst the lungs exhibit diurnal variations in immune response. In order to better understand these processes it will be necessary to characterise diurnal changes in extracellular matrix biology. In particular, given the sensitivity of peripheral clocks to external factors, the timed delivery of interventions (chronotherapy) has the potential to significantly improve the efficacy of treatments designed to repair and regenerate damaged cutaneous, vascular and pulmonary tissues.

Lysophosphatidic acid decreases the nuclear localization and cellular abundance of the p53 tumor suppressor in A549 lung carcinoma cells.

Lysophosphatidic acid (LPA) is a bioactive lipid that promotes cancer cell proliferation and motility through activation of cell surface G protein-coupled receptors. Here, we provide the first evidence that LPA reduces the cellular abundance of the tumor suppressor p53 in A549 lung carcinoma cells, which express endogenous LPA receptors. The LPA effect depends on increased proteasomal degradation of p53 and it results in a corresponding decrease in p53-mediated transcription. Inhibition of phosphatidylinositol 3-kinase protected cells from the LPA-induced reduction of p53, which implicates this signaling pathway in the mechanism of LPA-induced loss of p53. LPA partially protected A549 cells from actinomycin D induction of both apoptosis and increased p53 abundance. Expression of LPA(1), LPA(2), and LPA(3) receptors in HepG2 hepatoma cells, which normally do not respond to LPA, also decreased p53 expression and p53-dependent transcription. In contrast, neither inactive LPA(1) (R124A) nor another G(i)-coupled receptor, the M(2) muscarinic acetylcholine receptor, reduced p53-dependent transcription in HepG2 cells. These results identify p53 as a target of LPA action and provide a new dimension for understanding how LPA stimulates cancer cell division, protects against apoptosis, and thereby promotes tumor progression.

Provider-based barriers to provision of intrauterine contraception in general practice.

OBJECTIVES: Intrauterine contraception (IUC) is highly effective, safe and long-lasting, but is not a popular method of contraception among British women. This study examined barriers to the uptake of IUC in general practice in England. METHOD: A sequential mixed-method approach to explore the views of practitioners regarding the provision of IUC. We e-surveyed 208 practitioners from 69 practices in a region of England and subsequently interviewed 14 practitioners from eight practices. RESULTS: Just under half of general practitioners (GPs) (46.8%; 58/124), and only 8.2% (4/49) of nurses reported being trained to fit IUC. Lack of knowledge of IUC was a barrier to fitting, and also to recommending IUC, especially by practitioners who were not trained to fit. There was discordance between reported knowledge of eligibility for IUC and the likelihood of recommending IUC. Respondents were less likely to recommend IUC to young, nulliparous women, women who had experienced a previous ectopic pregnancy, a recent sexually transmitted infection (STI), or an abnormal cervical smear. The qualitative data indicate that risk aversion and limited training, together with practitioners' assessments that women are uninterested, may lead to IUC being precluded as a suitable method. CONCLUSIONS: Increased practitioner education, for those not trained to fit IUC, may remove a barrier to the uptake of IUC in general practice. More research is required on the discordance between the practitioners' views on the characteristics of women considered suitable for IUC, and the criteria set out in the UK Medical Eligibility Criteria (UKMEC) guidelines.

"I think maybe 10 years seems a bit long." Beliefs and attitudes of women who had never used intrauterine contraception.

AIM: To explore, in a general practice setting, the concerns, beliefs and attitudes about intrauterine contraception (IUC) reported by women, who had never used the methods. METHODS: We used a sequential mixed-method (QUAL/quant) approach. A pragmatic, self-selecting sample of 30 women, aged 18-46 years, who had never used IUC), was recruited through seven general practices in South East England. Themes arising from qualitative interviews were used to construct a quantitative survey, completed by a pragmatic sample of 1195 women, aged 18-49 years, attending 32 general practices in the same region, between February and August 2015. RESULTS: Qualitative themes were concerns about the long-acting nature of IUC, concerns about body boundaries, and informal knowledge of IUC, especially 'friend of a friend' stories. Women were not sure if the devices can be removed before their full 5- or 10-year duration of use, and felt that these timeframes did not fit with their reproductive intentions. Quantitative survey data showed that the most commonly endorsed concerns among never-users were painful fitting (55.8%), unpleasant removal of the device (60.1%), and concern about having a device 'inside me' (60.2%). CONCLUSIONS: To facilitate fully informed contraceptive choice, information provided to women considering IUC should be tailored to more fully address the concerns expressed by never-users, particularly around the details of insertion and removal, and concerns about the adverse, long-term effects of the device. Women need to be reassured that IUC can be removed and fertility restored at any time following insertion. TRIAL REGISTRATION: Trial registration NIHR CRN portfolio; 15912.

'Repeat abortion', a phrase to be avoided? Qualitative insights into labelling and stigma.

BACKGROUND: In recent years there has been growing international interest in identifying risk factors associated with 'repeat abortion', and developing public health initiatives that might reduce the rate. This article draws on a research study looking at young women's abortion experience in England and Wales. The study was commissioned with a specific focus on women who had undergone more than one abortion. We examine what may influence women's post-abortion reproductive behaviour, in addition to exploring abortion-related stigma, in the light of participants' own narratives. STUDY DESIGN: Mixed-methods research study: a quantitative survey of 430 women aged 16-24 years, and in-depth qualitative interviews with 36 women who had undergone one or more abortions. This article focuses on the qualitative data from two subsets of young women: those we interviewed twice (n=17) and those who had experienced more than one unintended/unwanted pregnancy (n=15). RESULTS: The qualitative research findings demonstrate the complexity of women's contraceptive histories and reproductive lives, and thus the inherent difficulty of establishing causal patterns for more than one abortion, beyond the obvious observation that contraception was not used, or not used effectively. Women who had experienced more than one abortion did, however, express intensified abortion shame. CONCLUSIONS: This article argues that categorising women who have an abortion in different ways depending on previous episodes is not helpful. It may also be damaging, and generate increased stigma, for women who have more than one abortion.

Neutrophils Infiltrate the Spinal Cord Parenchyma of Rats with Experimental Diabetic Neuropathy.

Spinal glial cell activation and cytokine secretion have been implicated in the etiology of neuropathic pain in a number of experimental models, including diabetic neuropathy. In this study, streptozotocin- (STZ-) induced diabetic rats were either untreated or treated with gabapentin (50 mg/kg/day by gavage for 2 weeks, from 6 weeks after STZ). At 8 weeks after STZ, hypersensitivity was confirmed in the untreated diabetic rats as a reduced response threshold to touch, whilst mechanical thresholds in gabapentin-treated diabetic rats were no different from controls. Diabetes-associated thermal hypersensitivity was also ameliorated by gabapentin. We performed a cytokine profiling array in lumbar spinal cord samples from control and diabetic rats. This revealed an increase in L-selectin, an adhesion molecule important for neutrophil transmigration, in the spinal cord of diabetic rats but not diabetic rats treated with gabapentin. Furthermore, we found an increase in the number of neutrophils present in the parenchyma of the spinal cord, which was again ameliorated in gabapentin-treated diabetic rats. Therefore, we suggest that dysregulated spinal L-selectin and neutrophil infiltration into the spinal cord could contribute to the pathogenesis of painful diabetic neuropathy.

Introduction of novel 3D-printed superficial applicators for high-dose-rate skin brachytherapy.

PURPOSE: Custom-made surface mold applicators often allow more flexibility when carrying out skin brachytherapy, particularly for small treatment areas with high surface obliquity. They can, however, be difficult to manufacture, particularly if there is a lack of experience in superficial high-dose-rate brachytherapy techniques or with limited resources. METHODS AND MATERIALS: We present a novel method of manufacturing superficial brachytherapy applicators utilizing three-dimensional (3D)-printing techniques. We describe the treatment planning process and the process of applicator manufacture. RESULTS: The treatment planning process, with the introduction of a pre-plan, allows for an "ideal" catheter arrangement within an applicator to be determined, exploiting varying catheter orientations, heights, and curvatures if required. The pre-plan arrangement is then 3D printed to the exact specifications of the pre-plan applicator design. This results in improved target volume coverage and improved sparing of organs at risk. CONCLUSIONS: Using a pre-plan technique for ideal catheter placement followed by automated 3D-printed applicator manufacture has greatly improved the entire process of superficial high-dose-rate brachytherapy treatment. We are able to design and manufacture flexible, well-fitting, superior quality applicators resulting in a more efficient and improved patient pathway and patient experience.

Dietary nitrate supplementation increases acute mountain sickness severity and sense of effort during hypoxic exercise.

Dietary nitrate supplementation enhances sea level performance and may ameliorate hypoxemia at high altitude. However, nitrate may exacerbate acute mountain sickness (AMS), specifically headache. This study investigated the effect of nitrate supplementation on AMS symptoms and exercise responses with 6-h hypoxia. Twenty recreationally active men [age, 22 ± 4 yr, maximal oxygen consumption (V̇o2max), 51 ± 6 ml·min-1·kg-1, means ± SD] completed this randomized double-blinded placebo-controlled crossover study. Twelve participants were classified as AMS- on the basis of Environmental Symptoms Questionnaire [Acute Cerebral Mountain Sickness score (AMS-C)] <0.7 in both trials, and five participants were classified as AMS+ on the basis of AMS-C ≥0.7 on placebo. Five days of nitrate supplementation (70-ml beetroot juice containing ~6.4 mmol nitrate daily) increased plasma NO metabolites by 182 µM compared with placebo but did not reduce AMS or improve exercise performance. After 4-h hypoxia [inspired O2 fraction ([Formula: see text]) = 0.124], nitrate increased AMS-C and headache severity (visual analog scale; whole sample ∆10 [1, 20] mm, mean difference [95% confidence interval]; P = 0.03) compared with placebo. In addition, after 5-h hypoxia, nitrate increased sense of effort during submaximal exercise (∆7 [-1, 14]; P = 0.07). In AMS-, nitrate did not alter headache or sense of effort. In contrast, in AMS+, nitrate increased headache severity (∆26 [-3, 56] mm; P = 0.07), sense of effort (∆14 [1, 28]; P = 0.04), oxygen consumption, ventilation, and mean arterial pressure during submaximal exercise. On the next day, in a separate acute hypoxic exercise test ([Formula: see text] = 0.141), nitrate did not improve time to exhaustion at 80% hypoxic V̇o2max In conclusion, dietary nitrate increases AMS and sense of effort during exercise, particularly in those who experience AMS. Dietary nitrate is therefore not recommended as an AMS prophylactic or ergogenic aid in nonacclimatized individuals at altitude.NEW & NOTEWORTHY This is the first study to identify that the popular dietary nitrate supplement (beetroot) does not reduce acute mountain sickness (AMS) or improve exercise performance during 6-h hypoxia. The consumption of nitrate in those susceptible to AMS exacerbates AMS symptoms (headache) and sense of effort and raises oxygen cost, ventilation, and blood pressure during walking exercise in 6-h hypoxia. These data question the suitability of nitrate supplementation during altitude travel in nonacclimatized people.

MEDEX2015: Greater Sea-Level Fitness Is Associated with Lower Sense of Effort During Himalayan Trekking Without Worse Acute Mountain Sickness.

Rossetti, Gabriella M.K., Jamie H. Macdonald, Matthew Smith, Anna R. Jackson, Nigel Callender, Hannah K. Newcombe, Heather M. Storey, Sebastian Willis, Jojanneke van den Beukel, Jonathan Woodward, James Pollard, Benjamin Wood, Victoria Newton, Jana Virian, Owen Haswell, and Samuel J. Oliver. MEDEX2015: Greater sea-level fitness is associated with lower sense of effort during Himalayan trekking without worse acute mountain sickness. High Alt Med Biol. 18:152-162, 2017.-This study examined the complex relationships of fitness and hypoxic sensitivity with submaximal exercise responses and acute mountain sickness (AMS) at altitude. Determining these relationships is necessary before fitness or hypoxic sensitivity tests can be recommended to appraise individuals' readiness for altitude. Forty-four trekkers (26 men; 18 women; 20-67 years) completed a loaded walking test and a fitness questionnaire in normoxia to measure and estimate sea-level maximal aerobic capacity (maximum oxygen consumption [[Formula: see text]O2max]), respectively. Participants also completed a hypoxic exercise test to determine hypoxic sensitivity (cardiac, ventilatory, and arterial oxygen saturation responses to acute hypoxia, fraction of inspired oxygen [Fio2] = 0.112). One month later, all participants completed a 3-week trek to 5085 m with the same ascent profile. On ascent to 5085 m, ratings of perceived exertion (RPEascent), fatigue by Brunel Mood Scale, and AMS were recorded daily. At 5085 m, RPE during a fixed workload step test (RPEfixed) and step rate during perceptually regulated exercise (STEPRPE35) were recorded. Greater sea-level [Formula: see text]O2max was associated with, and predicted, lower sense of effort (RPEascent; r = -0.43; p < 0.001; RPEfixed; r = -0.69; p < 0.001) and higher step rate (STEPRPE35; r = 0.62; p < 0.01), but not worse AMS (r = 0.13; p = 0.4) or arterial oxygen desaturation (r = 0.07; p = 0.7). Lower RPEascent was also associated with better mood, including less fatigue (r = 0.57; p < 0.001). Hypoxic sensitivity was not associated with, and did not add to the prediction of submaximal exercise responses or AMS. In conclusion, participants with greater sea-level fitness reported less effort during simulated and actual trekking activities, had better mood (less fatigue), and chose a higher step rate during perceptually regulated exercise, but did not suffer from worse AMS or arterial oxygen desaturation. Simple sea-level fitness tests may be used to aid preparation for high-altitude travel.

Predictors of non-use of intrauterine contraception among women aged 18-49 years in a general practice setting in the UK.

OBJECTIVES: Our research examined the barriers to the uptake of intrauterine contraception (IUC) by women in a general practice (GP) setting in the UK. This study reports predictors of non-use of IUC in this context. DESIGN: We used a mixed method Qual/Quant approach in which the initial qualitative research provides a framework for subsequent larger quantitative surveys. Utilizing findings derived from 30 qualitative interviews, a quantitative survey was developed and distributed to a pragmatic sample of 1,195 women, aged 18-49 years, who were recruited through 32 participating GP practices in an area of England, UK. Outcome measures were percentage of attributes or responses in the sample and use or non-use of IUC. Results were analyzed using descriptive statistical analysis and binary logistic regression, using use/non-use as a binary response variable. RESULTS: Attitudinal variables, which were the strongest predictors of non-use of IUC, were an adverse opinion on long-acting aspect of IUC (odds ratio [OR]=8.34), disliking the thought of IUC inside the body (OR=3.138), concerns about IUC causing difficulties becoming pregnant in the future (OR=2.587), concerns about womb damage (OR=2.224), having heard adverse opinions about levonorgestrel-releasing intrauterine system (Mirena®) (OR=2.551), having an adverse opinion of having light, irregular periods (OR=2.382) and, having an adverse opinion of having no periods (OR=2.018). CONCLUSION: Concerns about the long-acting nature of IUC and persisting concerns about the safety of IUC may act as barriers to its use. Information for women, tailored to specifically address these concerns, is needed. IMPLICATIONS: Clinicians should provide more reassurance and information to potential users of IUC to increase their confidence about the possibility of removing IUC early or on request. They should also specifically seek to alleviate concerns about internal damage, damage to the womb, or damage to future fertility from using the methods.