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Purpose: Musculoskeletal disorders (MSDs) are common worldwide and gender differences exist in terms of prevalence and disability. MSDs are a leading cause of sick leave and physical work exposures. To assess the association between physical exposures assessed by the gender-specific CONSTANCES Job-Exposure Matrix (JEM) and musculoskeletal pain in six areas: neck pain, shoulder pain, elbow/arm pain, hand/wrist pain, low back pain, knee/leg pain; and to compare the results with those obtained using the non-gendered CONSTANCES JEM and with individual self-report exposures., Methods: We included 48,736 male and 63,326 female workers from the CONSTANCES cohort (France). The association between 27 physical exposures and musculoskeletal self-reported pain in six body areas was assessed using logistic regression. We conducted the analysis with three types of exposures: (1) individual self-reported exposures; (2) gender-specific CONSTANCES JEM; (3) non-gendered CONSTANCES JEM, and adjusted for age and Body Mass Index (BMI). Analyses were stratified by gender., Results: The associations to the gender-specific and non-gendered JEM were similar. The odds ratios using individual self-reported exposures were comparable to the JEM-based associations, with the exceptions of the exposures 'change tasks', 'rest eyes' and 'reach behind'. In some comparisons, there were differences in the direction and/or significance of effects between genders (regardless of whether the JEM used was gender-specific or not)., Conclusion: The gender-specific and non-gendered JEMs gave similar results, hence, developing physical work exposures JEMs that are gender-specific may not be essential. However, when predicting musculoskeletal pain, it seems relevant to stratify the analysis by gender., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study aimed to construct and evaluate a gender-specific job exposure matrix (JEM) for 27 physical work exposures, based on self-report., Methods: We constructed a JEM using questionnaire data on current physical exposures from 29 381 male and 35 900 female asymptomatic workers aged 18-69 years in the French CONSTANCES cohort study. We excluded workers with musculoskeletal pain to reduce potential reporting bias. We grouped 27 self-reported physical exposures using the French national job codes and stratified by gender. We compared individual and group-based exposures using the performance indicators Cohen's kappa (κ), sensitivity, specificity, and area under the receiver operating curve (AUC)., Results: JEM validation showed fair-to-moderate agreement (κ 0.21-0.60) for most physical exposures for both genders except for 'reach behind' (poor), 'bend neck' (poor), 'finger pinch' (poor), standing' (good), 'use computer screen' (good), and 'use keyboard or scanner' (good). We found the highest AUC for 'standing' (men 0.85/ women 0.87), 'kneel/squat' (men 0.80/women 0.81), 'use computer screen' (men/women 0.81), and 'use keyboard or scanner' (men 0.82/ women 0.84). The AUC was <0.60 for only three exposures: 'bend neck' (men 0.58/women 0.57), 'finger pinch' (men 0.56/ women 0.55), and 'reach behind' (men 0.54/ women 0.51)., Conclusion: The constructed JEM validation measures were comparable for men and women for all exposures. Further research will examine the predictive ability of this gender-specific JEM for musculoskeletal disorders and the relevance of gender-stratification in this process, knowing accuracy of each exposure.

Objectives: Musculoskeletal disorders (MSDs) are a leading cause of disability and sick leave among workers. Although MSDs are associated with physical exposures, there are gender differences in the prevalence and related disability. This study aimed to compare self-reported physical work exposures by gender for people within the same occupational group., Methods: We used cross-sectional data from 65 281 asymptomatic workers aged 18-69 years from the CONSTANCES cohort study (France). We compared 27 physical exposures between men and women in the same occupational groups ('Profession et Categorie Sociale' group) using Mann-Whitney U tests., Results: Men and women performing the same job often reported different levels of exposure. 38 of 365 occupational groups had a gender difference in reported exposure for 10 or more of 27 physical exposures, with men reporting higher exposures in 79% of these jobs. Women reported higher exposures in nursing and other healthcare professions. The probability that a random man had an exposure value higher than a random woman varied widely, from 8% to 92%, and was highly dependent on occupational groups and the specific exposure., Conclusions: Men and women working in the same jobs reported different physical exposures for some jobs and some exposures. Further research should further define and explore these reported differences to improve prevention and research., Competing Interests: Competing interests: Authors are paid by their institution, AD and MF is also paid as editor of the Archives des Maladies professionnelles et de l’Environnement (Elsevier). AD and FW supported by TEC-TOP Grant, AD received other funds for research outside of work (Mat-O-Covid, Soignances)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Question: What is the impact of BMI on uncomplicated pregnancies and healthy births in women who did or did not have medically assisted reproduction (MAR, i.e. ART or hormonal stimulation without manipulation of eggs or embryos) in the Flanders region (Belgium)?, Summary Answer: Women with a higher BMI who use MAR are at the highest risk of pregnancy and birth complications., What We Know Already: Medically assisted reproduction (MAR) is used increasingly worldwide and is associated with increased risk of adverse perinatal outcomes. Obesity is also increasing globally and obese women are more likely to seek MAR since obesity is associated with infertility. When obese women undergo MAR, the risk of adverse outcomes may be enhanced but it is not clear to what extent., Study Design, Size, Duration: We conducted a registry-based study using the data from the Study Centre for Perinatal epidemiology database for years 2009-2015, region of Flanders, Belgium. This included 428 336 women., Participants/materials, Setting, Methods: The average age was 30.0 years (SD 4.78), 194 061 (45.31%) were nulliparous, and 6.3% (n = 26 971) conceived with MAR. We examined the association of BMI and MAR with the following composite primary outcomes: 'uncomplicated pregnancy and birth' and 'healthy baby'. We conducted Poisson regression and adjusted for maternal age, parity, gestational weight gain, smoking and previous caesarean section., Main Results and the Role of Chance: In our study, 36.80% (n = 157 623) of women had an uncomplicated pregnancy and birth according to the definition used. The predicted probability of having an uncomplicated pregnancy and birth for women with a BMI of 25 kg/m2 who conceived spontaneously was 0.33 (0.32 to 0.35), while it was 0.28 (0.24 to 0.32) for women who used hormonal stimulation and 0.26 (0.22 to 0.29) for women who used IVF/ICSI. This probability reduced with increasing BMI category for both MAR and non-MAR users. For women with a BMI of 30 kg/m2, the predicted probability of having an uncomplicated pregnancy and birth was 0.28 (0.26 to 0.30) for women who conceived spontaneously, and 0.22 (0.16 to 0.29) and 0.20 (0.14 to 0.26) for women who used hormonal stimulation only or IVF/ICSI, respectively. The predicted probability of having a healthy baby for women with a BMI of 25 kg/m2 who conceived spontaneously was 0.92 (0.91 to 0.93), 0.89 (0.87 to 0.92) for women who used hormonal stimulation only and 0.85 (0.84 to 0.87) for women who used IVF/ICSI., Limitations, Reasons for Caution: The database did not include data on socio-economic status, pre-pregnancy morbidities and paternal BMI. Subsequently, we could not adjust for these factors in the analysis., Wider Implications of the Findings: Obese women who use MAR are at the highest risk of pregnancy and birth complications. This increase in interventions also has cost and resource implications which is relevant for funding policies. Weight loss interventions prior to MAR seem plausible but their (cost-) effectiveness needs urgent investigation., Study Funding/competing Interest(s): F.W. received an Erasmus Plus training grant to visit A.B., L.A. and R.D. and conducted this study during this visit. The authors have no competing interest to declare., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study provides evidence- and consensus-based recommendations for the instruments to measure the five Pelvic Girdle Pain Core Outcome Set (PGP-COS): pain frequency, pain intensity/severity, function/disability/activity limitation, health-related quality of life and fear avoidance. Studies evaluating measurement properties of instruments measuring any PGP-COS outcome in women with PGP were identified through a systematic search of MEDLINE, EMBASE and PEDro databases (inception-July 2021). The methodological quality of studies and quality of measurement properties were evaluated using the COnsensus-based Standards for the selection of health status Measurement Instruments (COSMIN) checklist. Quality criteria and the synthesized evidence were graded using the modified grading of recommendations, assessment, development, and evaluation (GRADE) approach. A consensus meeting with PGP stakeholders was then held to establish recommendations, based on the evidence, for the instruments that should be used to measure the PGP-COS. Ten instruments were identified from 17 studies. No instrument showed high quality evidence for all measurement properties and/or measured all PGP-COS outcomes. Based on current evidence and consensus, the Pelvic Girdle Questionnaire (PGQ), the Short Form-8 (SF-8) and the Fear Avoidance Beliefs Questionnaire (FABQ) are recommended for measuring the PGP-COS. Future research should establish additional measurement properties of instruments and to substantiate these recommendations., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction and Hypothesis: Considerable proportions of pregnant and postpartum women experience urinary incontinence, but to our knowledge, there are no national data on the preventative and treatment services available in Ireland's 19 maternity hospitals., Methods: Ethical approval was granted. A national benchmarking survey on the range and type of services on prevention and treatment of urinary incontinence during pregnancy and postpartum was developed. Directors of Midwifery and Nursing in each hospital identified midwives and women's health physiotherapists to complete the survey. Data were analysed descriptively, and results presented as proportions., Results: Responses were received from 17 hospitals. Women were asked about urinary incontinence during their first booking visit in 6 hospitals, during all antenatal visits in 2 and the onus was on women self-reporting symptoms in 9. Pelvic floor muscle exercises were taught in antenatal classes in 14 hospitals and management of urinary incontinence in 9. In hospital postpartum, midwives in 13 hospitals asked women about urinary incontinence. All women were seen by a physiotherapist in 7 hospitals and only those who were referred in 6. Women could access the hospital's physiotherapy services up to 6 weeks postpartum in 3 hospitals, up to 6 months or 1 year in 5 and beyond 1 year in 6., Conclusions: Geographical inequity exists in the services offered to pregnant and postpartum women nationally. This indicates that many pregnant and postpartum women, both continent and incontinent, cannot avail themselves of preventative and treatment services within the maternity hospital system and points to the need to review, reconfigure and resource services., (© 2022. The International Urogynecological Association.)

Background: Women's experiences of pregnancy, birth and motherhood extend beyond healthcare provision and the immediate postpartum. Women's social, cultural and political environments shape the positive or negative effects of their experiences through this transition. However, there is limited research concerning the factors that women identify as being protective or promotive of maternal well-being in the perinatal period and motherhood transition., Objective: To explore women's views on the factors within healthcare, social, cultural, organizational, environmental and political domains that do or can work well in creating positive perinatal experiences., Design, Setting and Participants: A qualitative descriptive study with embedded public and participant involvement (PPI). Participants were 24 women who were maternity care service users giving birth in Ireland., Results: Three themes were developed. The first theme, 'tone of care', related to women's interactions with and attitudes of healthcare professionals in setting the tone for the care they experienced. The second theme, 'postpartum presence and support', concerned the professional postpartum supports and services that women found beneficial in the motherhood transition. The final theme, 'flexibility for new families' addresses social and organizational issues around parents returning to paid employment., Discussion and Conclusion: Women suggested multiple avenues for promoting positive perinatal experiences for women giving birth in Ireland, which may be implemented at healthcare and policy levels. Women identified that maternal health education focuses on supporting informed decision-making processes as a positive and worry-alleviating resource. Additionally, women valued being met by healthcare professionals who regard women as the decision makers in their care experience. Exchanges in which healthcare professionals validate and encourage women in their mothering role and actively involve their partners as caregivers left lasting positive impressions. Extended and professional postpartum support was a common issue, and phone lines or drop-in clinics were suggested as invaluable and affirming assets where women could access personalized support with healthcare professionals who had the knowledge and skills to genuinely approach women's concerns. Social and organizational considerations involved supporting parents to balance their responsibilities as new or growing families in the return to work., Public or Patient Contribution: Maternity care service users were involved in the interviews and manuscript preparation., (© 2022 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Women's postpartum health is a public health issue that has lifelong consequences. Timely recognition and treatment of physical and mental health issues can have positive health consequences while lack of access to effective treatments or health care services can lead to long-term health problems. To advance knowledge of priority health symptoms and trajectories of postpartum recovery from women's health perspectives, we share findings from the Maternal health And Maternal Morbidity in Ireland (MAMMI) study. Data from 3047 first-time mothers recruited to a longitudinal maternal health study in Ireland from 2012 to 2017 reveal the trajectories of maternal health and health problems experienced up to 12 months postpartum. Morbidities explored include urinary incontinence, pelvic girdle pain, and sexual and mental health issues. Viewed together, and over time, the scale and persistent nature of many physical and mental health problems become apparent, yet considerable proportions of women were not asked directly about health problems by health care professionals. When women do not know what is and is not normal postpartum, they may suffer in silence and the consequence is that health problems/issues that are preventable, and treatable, are likely to become chronic. To make positive contributions to women's health, maternity care systems must be truly woman-centered and structured in ways that place emphasis on women's own health needs. In systems where women's voices and concerns are acknowledged and central, women are likely to thrive and flourish in motherhood., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Many studies on women's maternity care experiences reveal recurring issues that are poor or less than optimal. Women's opinions on the maternal health-related issues that matter most to them are essential if care and services are to be improved., Aims: To identify the maternal health-related issues that matter most to women in Ireland, based on their own experiences of maternity care, services and motherhood., Methods: A qualitative exploratory study with 24 women. Following university ethical approval, audio-recorded one-to-one telephone interviews were conducted and thematically analysed., Findings: We identified two themes, each with four subthemes, connected to a central concept of the invisible woman. Pendulum of care, and subthemes Inconsistent services, All about the baby, Induced anxiety and Information seesaw, illustrated the extremes of care and services that women experienced. Magnitude of motherhood, and subthemes Weight of responsibility, Real-time reassurance, Change of identity and Growth into advocacy, depicted the intensity of their new role while transitioning to motherhood., Discussion: Findings articulate the issues that mattered most to women in Ireland as they transitioned to motherhood. Some women identified specific research topics/areas, but all of the issues identified can be translated into researchable topics that seek to improve local care and service provision., Conclusion: Given the recurring nature of women's less than satisfactory experiences of aspects of maternity care in many countries, it is likely that conducting research on issues that matters most to women will have the greatest impact on their health, wellbeing and lives as they transition to motherhood., (Copyright © 2021 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Aims: To systematically review the literature on possible associations between parity and urinary incontinence (UI) during pregnancy and in the first year postpartum., Methods: We searched the databases Pubmed, CINAHL, Embase, the Cochrane Library, PsycINFO, MIDIRS, ClinicalTrials.gov (inception-18 April 2020). One reviewer screened all titles. Two reviewers independently selected studies by abstract and full text. Risk of bias was assessed using the Quality In Prognosis Studies tool. Findings were synthesised in meta-analysis or narratively. We assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation Working Group approach adopted for prognostic studies., Results: We identified 16 643 records and 39 were included. Thirty studies examined UI during pregnancy and 12 examined UI postpartum. Multiparity was associated with UI at any point in the last pregnancy (odds ratio [OR]: 1.59 [1.26-2.00], 5 studies, 1565 participants) and in the third trimester when measured by ICIQ-SF (OR: 2.67 [1.53-4.67], 4 studies, 1150 participants), but not when studies measured the UI point prevalence (OR: 2.48 [0.91-6.79], 4 studies, 52 976 participants), or if they measured the prevalence at one point in any trimester (OR: 1.09 (0.60-1.95), 3 studies, 872 participants). At 3 months postpartum, UI was associated with multiparity (OR: 2.03 [1.35-3.06], 4 studies, 6781 participants)., Conclusions: Increased parity was associated with UI in the first year postpartum, but studies on UI during pregnancy had conflicting results. The evidence was (very) uncertain. Future studies should use comparable definitions and further explore UI sub-types., (© 2021 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Aim: This systematic review aims to identify disease-specific and generic quality of life (QoL) outcome measurement instruments used in populations of women with urinary incontinence (UI) and to determine the most psychometrically robust and appropriate disease-specific and generic tools for measuring the quality of life in this population., Methods: A systematic search was conducted of PubMed, Embase, SCIELO, and CINAHL databases for studies evaluating measurement properties of QoL instruments in women with UI. The methodological quality of studies and the quality of measurement properties were evaluated using the COnsensus-based Standards for the selection of health status Measurement INtruments (COSMIN) checklist and quality criteria. Overall, evidence for measurement properties was graded using the modified grading of recommendations, assessment, development & evaluation approach., Results: A total of 73 studies were included, and 27 specific and 6 generic instruments were identified. The Incontinence QoL questionnaire (IQoL) had the highest overall psychometric quality for English-speaking populations and was the most widely translated tool. Evidence for generic QoL tools in this population is limited. Few studies evaluated measurement error or cross-cultural validity., Conclusion: The IQoL is the most psychometrically robust disease-specific tool for use in this population. More research is needed to determine the most psychometrically robust generic tool. Future studies should also evaluate measurement error and cross-cultural validity as evidence for these properties is particularly lacking., (© 2021 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

There is a high level of medication usage among people with intellectual disability due to the presence of significant morbidity and co-morbidities. This review sought to explore medication management and administration in intellectual disability settings, identifying frameworks for practice, analysing whether collaborative practice led to better outcomes, identifying key processes associated with practice, locating tools to support practice and describing metrics for outcome measurement. A systematic review was conducted with analysis of 64 sources which remained following screening and appraisal. Limited evidence was identified with some insight into the processes underpinning medication management and administration. No assessment tools were found, but two potential outcome measures, adherence and errors, were noted. The paucity of guidelines and frameworks is concerning as this is a complex area of practice. There is a need for further practice development and research to be undertaken that takes note of the unique issues that can present in intellectual disability settings.

Background: Inconsistent reporting of outcomes in clinical trials of women with Pelvic Girdle Pain (PGP) hinders comparison of findings and the reliability of evidence synthesis. A core outcome set (COS) can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials on the condition. The aim of this study was to develop a consensus-based COS for evaluating the effectiveness of interventions in PGP during pregnancy and postpartum for use in research and clinical practice., Methods: A systematic review of previous studies on PGP and semi-structured interviews with women were undertaken to identify all outcomes that were reported in prior studies and that are relevant to those experiencing the condition. Key stakeholders (clinicians, researchers, service providers/policy makers and individuals with PGP) then rated the importance of these outcomes for including in a preliminary PGP-COS using a 3-round Delphi study. The final COS was agreed at a face-to-face consensus meeting., Results: Consensus was achieved on five outcomes for inclusion in the final PGP-COS. All outcomes are grouped under the "life impact" domain and include: pain frequency, pain intensity/severity, function/disability/activity limitation, health-related quality of life and fear avoidance., Conclusion: This study identified a COS for evaluating the effectiveness of interventions in pregnancy-related and postpartum-related PGP in research and clinical settings. It is advocated that all trials, other non-randomised studies and clinicians in this area use this COS by reporting these outcomes as a minimum. This will ensure the reporting of meaningful outcomes and will enable the findings of future studies to be compared and combined. Future work will determine how to measure the outcomes of the PGP-COS., Core Outcome Set Registration: This PGP-COS was registered with COMET (Core Outcome Measures for Effectiveness Trials) in January 2017 (http://www.comet-initiative.org/studies/details/958)., Competing Interests: The authors have declared that no competing interests exist.

Background: Many women experience perineal pain after childbirth, especially after having sustained perineal trauma. Perineal pain-management strategies are an important part of postnatal care. Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly-used type of medication in the management of postpartum pain, and their effectiveness and safety should be assessed. This is an update of a review first published in 2016., Objectives: To determine the effectiveness of a single dose of an oral NSAID for relief of acute perineal pain in the early postpartum period., Search Methods: For this update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (9 December 2019), OpenSIGLE and ProQuest Dissertations and Theses (28 February 2020), and reference lists of retrieved studies., Selection Criteria: Randomised controlled trials (RCTs) assessing a single dose of a NSAID versus a single dose of placebo, paracetamol or another NSAID for women with perineal pain in the early postpartum period. We excluded quasi-RCTs and cross-over trials. We included papers in abstract format only if they had sufficient information to determine that they met the review's prespecified inclusion criteria., Data Collection and Analysis: Two review authors (FW and VS) independently assessed all identified papers for inclusion and risks of bias, resolving any discrepancies through discussion. Two review authors independently conducted data extraction, including calculations of pain relief scores, and checked it for accuracy. We assessed the certainty of the evidence using the GRADE approach., Main Results: We included 35 studies examining 16 different NSAIDs and involving 5136 women (none were breastfeeding). Studies were published between 1967 and 2013. Risk of bias due to random sequence generation, allocation concealment and blinding of outcome assessors was generally unclearly to poorly reported, but participants and caregivers were blinded, and outcome data were generally complete. We downgraded the certainty of evidence due to risk of bias, suspected publication bias, and imprecision for small numbers of participants. NSAID versus placebo Compared to women who receive a placebo, more women who receive a single-dose NSAID may achieve adequate pain relief at four hours (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23; 10 studies, 1573 women; low-certainty evidence) and at six hours (RR 1.92, 95% CI 1.69 to 2.17; 17 studies, 2079 women; very low-certainty evidence), although we are less certain about the effects at six hours. At four hours after administration, women who receive a NSAID are probably less likely to need additional analgesia compared to women who receive placebo (RR 0.39, 95% CI 0.26 to 0.58; 4 studies, 486 women; moderate-certainty evidence) and may be less likely to need additional analgesia at six hours after initial administration, although the evidence was less certain at six hours (RR 0.32, 95% CI 0.26 to 0.40; 10 studies, 1012 women; very low-certainty evidence). One study reported that no adverse events were observed at four hours post-administration (90 women). There may be little or no difference in maternal adverse effects between NSAIDs and placebo at six hours post-administration (RR 1.38, 95% CI 0.71 to 2.70; 13 studies, 1388 women; low-certainty evidence). Fourteen maternal adverse effects were reported in the NSAID group (drowsiness (5), abdominal discomfort (2), weakness (1), dizziness (2), headache (2), moderate epigastralgia (1), not specified (1)) and eight in the placebo group (drowsiness (2), light-headedness (1), nausea (1), backache (1), dizziness (1), epigastric pain (1), not specified (1)), although not all studies assessed adverse effects. Neonatal adverse effects were not assessed in any of the studies. NSAID versus paracetamol NSAIDs may lead to more women achieving adequate pain relief at four hours, compared with paracetamol (RR 1.54, 95% CI 1.07 to 2.22; 3 studies, 342 women; low-certainty evidence). We are uncertain if there is any difference in adequate pain relief between NSAIDs and paracetamol at six hours post-administration (RR 1.82, 95% CI 0.61 to 5.47; 2 studies, 99 women; very low-certainty evidence) or in the need for additional analgesia at four hours (RR 0.55, 95% CI 0.27 to 1.13; 1 study, 73 women; very low-certainty evidence). NSAIDs may reduce the risk of requiring additional analgesia at six hours compared with paracetamol (RR 0.28, 95% CI 0.12 to 0.67; 1 study, 59 women; low-certainty evidence). One study reported that no maternal adverse effects were observed at four hours post-administration (210 women). Six hours post-administration, we are uncertain if there is any difference between groups in the number of maternal adverse effects (RR 0.74, 95% CI 0.27 to 2.08; 3 studies, 300 women; very low-certainty evidence), with one case of pruritis in the NSAID group and one case of sleepiness in the paracetamol group. Neonatal adverse effects were not assessed in any of the included studies. Comparisons of different NSAIDs or doses did not demonstrate any differences in effectiveness for any primary outcome measures; however, few data were available on some NSAIDs. None of the included studies reported on any of this review's secondary outcomes., Authors' Conclusions: In women who are not breastfeeding and who sustained perineal trauma, NSAIDs (compared to placebo or paracetamol) may provide greater pain relief for acute postpartum perineal pain and fewer women need additional analgesia, but uncertainty remains, as the evidence is rated as low- or very low-certainty. The risk of bias was unclear for many studies, adverse effects were often not assessed and breastfeeding women were not included. While this review provides some indication of the likely effect, there is uncertainty in our conclusions. The main reasons for downgrading were the inclusion of studies at high risk of bias and inconsistency in the findings of individual studies. Future studies could examine NSAIDs' adverse effects, including neonatal effects and the compatibility of NSAIDs with breastfeeding, and could assess other secondary outcomes. Future research could consider women with and without perineal trauma, including perineal tears. High-quality studies could be conducted to further assess the efficacy of NSAIDs versus paracetamol and the efficacy of multimodal treatments., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: As the development of core outcome sets (COS) increases, guidance for developing and reporting high-quality COS continues to evolve; however, a number of methodological uncertainties still remain. The objectives of this study were: (1) to explore the impact of including patient interviews in developing a COS, (2) to examine the impact of using a 5-point versus a 9-point rating scale during Delphi consensus methods on outcome selection and (3) to inform and contribute to COS development methodology by advancing the evidence base on COS development techniques., Methods: Semi-structured patient interviews and a nested randomised controlled parallel group trial as part of the Pelvic Girdle Pain Core Outcome Set project (PGP-COS). Patient interviews, as an adjunct to a systematic review of outcomes reported in previous studies, were undertaken to identify preliminary outcomes for including in a Delphi consensus survey. In the Delphi survey, participants were randomised (1:1) to a 5-point or 9-point rating scale for rating the importance of the list of preliminary outcomes., Results: Four of the eight patient interview derived outcomes were included in the preliminary COS, however, none of these outcomes were included in the final PGP-COS. The 5-point rating scale resulted in twice as many outcomes reaching consensus after the 3-round Delphi survey compared to the 9-point scale. Consensus on all five outcomes included in the final PGP-COS was achieved by participants allocated the 5-point rating scale, whereas consensus on four of these was achieved by those using the 9-point scale., Conclusions: Using patient interviews to identify preliminary outcomes as an adjunct to conducting a systematic review of outcomes measured in the literature did not appear to influence outcome selection in developing the COS in this study. The use of different rating scales in a Delphi survey, however, did appear to impact on outcome selection. The 5-point scale demonstrated greater congruency than the 9-point scale with the outcomes included in the final PGP-COS. Future research to substantiate our findings and to explore the impact of other rating scales on outcome selection during COS development, however, is warranted.

Background: Pregnancy-related Pelvic Girdle Pain (PPGP) is a common complaint. The aetiology remains unclear and reports on risk factors for PPGP provide conflicting accounts. The aim of this scoping review was to map the body of literature on risk factors for experiencing PPGP., Methods: We searched the databases PubMed, Embase, CINAHL, PsycINFO, MIDIRS, and ClinicalTrial.gov (3 August 2020). We selected studies with two reviewers independently. Observational studies assessing risk factors for PPGP were included. Studies examining specific diagnostic tests or interventions were excluded., Results: We identified 5090 records from databases and 1077 from ClinicalTrial.gov. Twenty-four records met the inclusion criteria. A total of 148 factors were examined of which only 14 factors were examined in more than one study. Factors that were positively associated with PPGP included a history of low back or pelvic girdle pain, being overweight/obese, already having a child, younger age, lower educational level, no pre-pregnancy exercise, physically demanding work, previous back trauma/disease, progestin-intrauterine device use, stress, depression and anxiety., Conclusions: A large number of factors have been examined as potential risk factors for PPGP, but there is a lack of repetition to be able to draw stronger conclusions and pool studies in systematic reviews. Factors that have been examined in more than five studies include age, body mass index, parity and smoking. We suggest a systematic review be conducted to assess the role of these factors further in the development of PPGP.

Caesarean section (CS) rates throughout Europe have risen significantly over the last two decades. As well as being an important clinical issue, these changes in mode of birth may have substantial resource implications. Policy initiatives to curb this rise have had to contend with the multiplier effect of women who had a CS for their first birth having a greater likelihood of requiring one during subsequent births, thus making it difficult to decrease CS rates in the short term. Our study examines the long-term resource implications of reducing CS rates among first-time mothers, as well as improving rates of vaginal birth after caesarean section (VBAC), among an annual cohort of women over the course of their most active childbearing years (18 to 44 years) in two public health systems in Europe. We found that the economic benefit of improvements in these two outcomes is considerable, with the net present value of the savings associated with a five-percentage-point change in nulliparous CS rates and VBAC rates being €1.1million and £9.8million per annual cohort of 18-year-olds in Ireland and England/Wales, respectively. Reductions in CS rates among first-time mothers are associated with a greater payoff than comparable increases in VBAC rates. The net present value of achieving CS rates comparable to those currently observed in the best performing Scandinavian countries was €3.5M and £23.0M per annual cohort in Ireland and England/Wales, respectively., Competing Interests: The authors have declared that no competing interests exist.

Maternity care in Ireland is provided through a mixture of free public and fee-based private or semi-private services. We examined factors associated with choice of care pathway among nulliparous women and how this influences the care they receive and their experience of childbirth using data from a prospective cohort study. Complete data were available for 1,789 women on choice of care pathway and birth outcomes, and for 1,336 women on birth experience. Maternal age (marginal effect [ME] 1.6 percentage points [ppts], p < 0.01), socioeconomic status (ME 0.5ppts, p < 0.01) and being born in Ireland (ME 10.3ppts, p < 0.01) were all positively associated with choosing private care, but level of risk in early pregnancy did not influence this decision. Intervention rates in public and semi-private care were comparable, but women in private care were more likely to receive epidural anaesthesia (odds ratio [OR] 1.65, p < 0.01) and give birth by caesarean section (ratio of relative risks [RRR] 1.98, p < 0.01). Private care was also associated with longer hospital stays (28 % longer, p < 0.01). Increased risk was negatively correlated with birth experience in public and semi-private care, but not in private care. Policies promoting the allocation of maternity care resources by level of risk, along with the standardisation of clinical practice across care pathways, could reduce rates of obstetric intervention and address risk-based disparities in birth experience outcomes., (Copyright © 2020. Published by Elsevier B.V.)

Aim: To estimate the economic burden of common health problems associated with pregnancy and childbirth, such as incontinence, mental health problems, or gestational diabetes, excluding acute complications of labour or birth, or severe acute adverse maternal outcomes., Methods: Searches for relevant studies were carried out to November 2019 in Medline, Embase, CINAHL, PsycINFO and EconLit databases. After initial screening, all results were reviewed for inclusion by two authors. An adapted version of a previously developed checklist for cost-of-illness studies was used for quality appraisal. All costs were converted to 2018 Euro using national consumer price indices and purchasing power parity conversion factors., Results: Thirty-eight relevant studies were identified, some of which reported incremental costs for more than one health problem (16 gestational diabetes, 13 overweight/obesity, 8 mental health, 4 hypertensive disorders, 2 nausea and vomiting, 2 epilepsy, 1 intimate partner violence). A high level of heterogeneity was observed in both the methods used, and the incremental cost estimates obtained for each morbidity. Average incremental costs tended to be higher in studies that modelled a hypothetical cohort of women using data from a range of sources (compared to analyses of primary data), and in studies set in the United States. No studies that examined the economic burden of some common pregnancy-related morbidities, such as incontinence, pelvic girdle pain, or sexual health problems, were identified., Conclusion: Our findings indicate that maternal morbidity is associated with significant costs to health systems and society, but large gaps remain in the evidence base for the economic burden of some common health problems associated with pregnancy and childbirth. More research is needed to examine the economic burden of a range of common maternal health problems, and future research should adopt consistent methodological approaches to ensure comparability of results., Competing Interests: The authors have declared that no competing interests exist.

Background: Pelvic girdle pain is a common problem during pregnancy and postpartum with significant personal and societal impact and costs. Studies examining the effectiveness of interventions for pelvic girdle pain measure different outcomes, making it difficult to pool data in meta-analysis in a meaningful and interpretable way to increase the certainty of effect measures. A consensus-based core outcome set for pelvic girdle pain can address this issue. As a first step in developing a core outcome set, it is essential to systematically examine the outcomes measured in existing studies., Objective: The objective of this systematic review was to identify, examine and compare what outcomes are measured and reported, and how outcomes are measured, in intervention studies and systematic reviews of interventions for pelvic girdle pain and for lumbopelvic pain (which includes pelvic girdle pain)., Methods: We searched PubMed, Cochrane Library, PEDro and Embase from inception to the 11th May 2018. Two reviewers independently selected studies by title/abstract and by full text screening. Disagreement was resolved through discussion. Outcomes reported and their outcome measurement instruments were extracted and recorded by two reviewers independently. We assessed the quality of reporting with two independent reviewers. The outcomes were grouped into core domains using the OMERACT filter 2.0 framework., Results: A total of 107 studies were included, including 33 studies on pelvic girdle pain and 74 studies on lumbopelvic pain. Forty-six outcomes were reported across all studies, with the highest amount (26/46) in the 'life impact' domain. 'Pain' was the most commonly reported outcome in both pelvic girdle pain and lumbopelvic pain studies. Studies used different instruments to measure the same outcomes, particularly for the outcomes pain, function, disability and quality of life., Conclusions: A wide variety of outcomes and outcome measurements are used in studies on pelvic girdle pain and lumbopelvic pain. The findings of this review will be included in a Delphi survey to reach consensus on a pelvic girdle pain - core outcome set. This core outcome set will allow for more effective comparison between future studies on pelvic girdle pain, allowing for more effective translation of findings to clinical practice., Supplementary Information: Supplementary information accompanies this paper at 10.1186/s12998-019-0279-2., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

The Ca 2+ /Mn 2+ transport ATPases 1a and 2 (SPCA1a/2) are closely related to the sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) and are implicated in breast cancer and Hailey-Hailey skin disease. Here, we purified the human SPCA1a/2 isoforms from a yeast recombinant expression system and compared their biochemical properties after reconstitution. We observed that the purified SPCA1a displays a lower Ca 2+ affinity and slightly lower Mn 2+ affinity than SPCA2. Remarkably, the turnover rates of SPCA1a in the presence of Mn 2+ and SPCA2 incubated with Ca 2+ and Mn 2+ were comparable, whereas the turnover rate of SPCA1a in Ca 2+ was 2-fold higher. Moreover, we noted an unusual biphasic activation curve for the SPCA1a ATPase and autophosphorylation activity, not observed with SPCA2. We also found that the biphasic pattern and low apparent ion affinity of SPCA1a critically depends on ATP concentration. We further show that the specific properties of SPCA1a at least partially depend on an N-terminal EF-hand-like motif, which is present only in the SPCA1a isoform and absent in SPCA2. This motif binds Ca 2+ , and its mutation lowered the Ca 2+ turnover rate relative to that of Mn 2+ , increased substrate affinity, and reduced the level of biphasic activation of SPCA1a. A biochemical analysis indicated that Ca 2+ binding to the N-terminal EF-hand-like motif promotes the activity of SPCA1a by facilitating autophosphorylation. We propose that this regulation may be physiologically relevant in cells with a high Ca 2+ load, such as mammary gland cells during lactation, or in cells with a low ATP content, such as keratinocytes., (© 2019 Chen et al.)

Background: Systematic reviews of randomised trials guide policy and healthcare decisions. Yet, we observed that some reviews judge randomised trials as high or unclear risk of bias (ROB) for sequence generation, potentially introducing bias. However, to date, the extent of this issue has not been well examined. We evaluated the consistency in the ROB assessment for sequence generation of randomised trials in Cochrane and non-Cochrane reviews, and explored the reviewers' judgement of the quality of evidence for the related outcomes., Methods: Cochrane intervention reviews (01/01/2017-31/03/2017) were retrieved from the Cochrane Database of Systematic Reviews. We also searched for systematic reviews in ten general medical journals with highest impact factors (01/01/2016-31/03/2017). We examined the proportion of reviews that rated the sequence generation domain as high, low or unclear risk of selection bias. For reviews that had rated any randomised trials as high or unclear risk of bias, we examined the proportion that had assessed the quality of evidence., Results: Overall, 100 systematic reviews were included in our analysis. We evaluated 64 Cochrane reviews which comprised of 984 randomised trials; 0.8% (n = 8) and 52.2% (n = 514) were rated as high and unclear ROB for sequence generation respectively. We further evaluated 36 non-Cochrane reviews which comprised of 1376 trials; 5.8% (n = 80) and 39.6% (n = 545) were rated as high and unclear ROB respectively. Ninety percent (n = 10) of non-Cochrane reviews which rated randomised trials as high ROB for sequence generation did not report an underlying reason. All Cochrane reviews assessed the quality of evidence (GRADE). For the non-Cochrane reviews, only just over half had assessed the quality of evidence., Conclusion: Systematic reviews of interventions frequently rate randomised trials as high or unclear ROB for sequence generation. In general, Cochrane reviews were more transparent than non-Cochrane reviews in ROB and quality of evidence assessment. The scientific community should more strongly promote consistent ROB assessment for sequence generation to minimise selection bias and support transparent quality of evidence assessment. Consistency ensures that appropriate conclusions are drawn from the data.

Background: Pelvic Girdle Pain (PGP) is an important cause of disability and economic cost worldwide. There is a need for effective preventative and management strategies. Emerging studies measure a variety of outcomes rendering synthesis and translation to clinical practice difficult. A Core Outcome Set (COS) can address this problem by ensuring that data are relevant, useful and usable for making well-informed healthcare choices. The aim of this study is to develop a consensus-based PGP-COS, including agreement on methods (e.g. instruments) for measuring the construct outcomes in the COS for use in research and clinical practice. Furthermore, as there is uncertainty as to whether incorporating stakeholder interviews in addition to conducting a systematic review to determine an initial list of outcomes for the Delphi survey, or, whether using different rating scales in a Delphi survey impacts on the final COS, we propose to embed two methodological studies within the PGP-COS development process to address these questions., Methods: The PGP-COS study will include five phases: (1) A systematic review of the literature and semi-structured interviews with 15 patients (three countries) to form the initial list of outcomes for the Delphi survey; (2) A 3-round Delphi including patients, clinicians, researchers and service providers; (3) A systematic review of methods for measuring the outcomes in the preliminary PGP-COS identified in the Delphi survey; (4) A face-to-face consensus meeting to agree on the final PGP-COS and methods for measuring the COS; (5) Global dissemination. To address the methodological questions, we will assess the number and type of outcomes, in the final PGP-COS, that were exclusively derived from the interviews. Secondly, we will randomise Delphi survey participants to either a 5-point or 9-point importance rating scale, and examine potential differences in 'important' ratings between the groups., Discussion: There is currently no COS for measuring/monitoring PGP in trials and clinical practice. A PGP-COS will ensure that relevant outcomes are measured using appropriate measurement instruments for patients with PGP globally., Core Outcome Set Registration: This PGP-COS was registered with COMET (Core Outcome Measures for Effectiveness Trials) in January 2017 ( http://www.comet-initiative.org/studies/details/958 ).

Background: Pregnancy-related Pelvic Girdle Pain (PPGP) is a very common complaint. Although many women recover after a birth, about a third continue to have symptoms three months postpartum and 8.5% of women still have persistent symptoms two years afterwards. Knowledge of prognostic factors may help understand the course of PPGP and inform management., Objectives: To determine the prognostic factors for PPGP by systematically reviewing the literature., Design: Systematic review., Methods: We searched PubMed, Embase, CINAHL, PsycINFO, MIDIRS, and ClinicalTrial.gov (15 April 2017) with no filters. Only studies reported in English were included. Two review authors independently selected studies. Any factors that might affect the course of PPGP up to one year postpartum were of interest. We excluded interventions and diagnostic studies. We conducted double independent data extraction, risk of bias and quality of evidence (GRADE) assessment., Findings: We identified 4374 citations of which three studies were included in our analysis. Previous low back pain, pain in three to four pelvic locations, and being overweight/obese made recovery 12 weeks postpartum less likely. Six months postpartum, Pelvic Girdle Syndrome (PGS) was more likely to persist in women who used crutches or had severe pain in three pelvic locations during pregnancy, had other pain conditions, a younger age of menarche, previous low back pain or a high co-morbidity index, were obese, or experienced emotional distress during pregnancy. For women who used crutches during pregnancy, an instrumental birth or caesarean section was associated with persistent PGS. However, the quality of evidence (GRADE) was low to very low for all factors, hence, findings are uncertain., Key Conclusions: The limited number of studies and lack of replication prevents us from drawing definitive conclusions., Implications for Practice: Potentially modifiable factors during pregnancy seem to impact the prognosis of PPGP postpartum., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease is a common, preventable and treatable disease. Exercise training programmes (ETPs) improve symptoms, health-related quality of life (HRQoL) and exercise capacity, but the optimal setting is unknown. In this review, we compared the effects of ETPs in different settings on HRQoL and exercise capacity. We searched (5 July 2016) the Cochrane Airways Group Specialised Register, ClinicalTrials.gov and World Health Organization trials portal. We selected studies, extracted data and assessed risk of bias with two independent reviewers. We calculated mean differences (MD) with 95% CI. We assessed the quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Ten trials (934 participants) were included. Hospital (outpatient) and home-based ETPs (seven trials) were equally effective at improving HRQoL on the Chronic Respiratory Questionnaire (CRQ) (dyspnoea: MD -0.09, 95% CI: -0.28 to 0.10; fatigue: MD -0.00, 95% CI: -0.18 to 0.17; emotional: MD 0.10, 95% CI: -0.24 to 0.45; and mastery: MD -0.02, 95% CI: -0.28 to 0.25; moderate quality) and on the St George's Respiratory Questionnaire (SGRQ) (MD -0.82, 95% CI: -7.47 to 5.83, low quality). Hospital (outpatient) and community-based ETPs (three trials) were equally effective at improving HRQoL (CRQ dyspnoea: MD 0.29, 95% CI: -0.05 to 0.62, moderate quality; fatigue: MD -0.02, 95% CI: -1.09 to 1.05, low quality; emotional: MD 0.10, 95% CI: -0.40 to 0.59, moderate quality; and mastery: MD -0.08, 95% CI: -0.45 to 0.28, moderate quality). There was no difference in exercise capacity. There was low to moderate evidence that outpatient and home-based ETPs are equally effective. See related Editorial., (© 2017 Asian Pacific Society of Respirology.)

Background: Changes to physiological parameters precede deterioration of ill patients. Early warning and track and trigger systems (TTS) use routine physiological measurements with pre-specified thresholds to identify deteriorating patients and trigger appropriate and timely escalation of care. Patients presenting to the emergency department (ED) are undiagnosed, undifferentiated and of varying acuity, yet the effectiveness and cost-effectiveness of using early warning systems and TTS in this setting is unclear. We aimed to systematically review the evidence on the use, development/validation, clinical effectiveness and cost-effectiveness of physiologically based early warning systems and TTS for the detection of deterioration in adult patients presenting to EDs., Methods: We searched for any study design in scientific databases and grey literature resources up to March 2016. Two reviewers independently screened results and conducted quality assessment. One reviewer extracted data with independent verification of 50% by a second reviewer. Only information available in English was included. Due to the heterogeneity of reporting across studies, results were synthesised narratively and in evidence tables., Results: We identified 6397 citations of which 47 studies and 1 clinical trial registration were included. Although early warning systems are increasingly used in EDs, compliance varies. One non-randomised controlled trial found that using an early warning system in the ED may lead to a change in patient management but may not reduce adverse events; however, this is uncertain, considering the very low quality of evidence. Twenty-eight different early warning systems were developed/validated in 36 studies. There is relatively good evidence on the predictive ability of certain early warning systems on mortality and ICU/hospital admission. No health economic data were identified., Conclusions: Early warning systems seem to predict adverse outcomes in adult patients of varying acuity presenting to the ED but there is a lack of high quality comparative studies to examine the effect of using early warning systems on patient outcomes. Such studies should include health economics assessments.

The Golgi/secretory pathway Ca 2+ /Mn 2+ -transport ATPase (SPCA1a) is implicated in breast cancer and Hailey-Hailey disease. Here, we purified recombinant human SPCA1a from Saccharomyces cerevisiae and measured Ca 2+ -dependent ATPase activity following reconstitution in proteoliposomes. The purified SPCA1a displays a higher apparent Ca 2+ affinity and a lower maximal turnover rate than the purified sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA1a). The lipids cholesteryl hemisuccinate, linoleamide/oleamide, and phosphatidylethanolamine inhibit and phosphatidic acid and sphingomyelin enhance SPCA1a activity. Moreover, SPCA1a is blocked by micromolar concentrations of the commonly used SERCA1a inhibitors thapsigargin (Tg), cyclopiazonic acid, and 2,5-di- tert -butylhydroquinone. Because tissue-specific targeting of SERCA2b by Tg analogues is considered for prostate cancer therapy, the inhibition of SPCA1a by Tg might represent an off-target risk. We assessed the structure-activity relationship (SAR) of Tg for SPCA1a by in silico modeling, site-directed mutagenesis, and measuring the potency of a series of Tg analogues. These indicate that Tg and the analogues are bound via the Tg scaffold but with lower affinity to the same homologous cavity as on the membrane surface of SERCA1a. The lower Tg affinity may depend on a more flexible binding cavity in SPCA1a, with low contributions of the Tg O-3, O-8, and O-10 chains to the binding energy. Conversely, the protein interaction of the Tg O-2 side chain with SPCA1a appears comparable with that of SERCA1a. These differences define a SAR of Tg for SPCA1a distinct from that of SERCA1a, indicating that Tg analogues with a higher specificity for SPCA1a can probably be developed., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Dysregulation of the Golgi/Secretory Pathway Ca 2+ transport ATPase SPCA2 is implicated in breast cancer. During lactation and in luminal breast cancer types, SPCA2 interacts with the plasma membrane Ca 2+ channel Orai1, promoting constitutive Ca 2+ influx, which is termed store independent Ca 2+ entry (SICE). The mechanism of SPCA2/Orai1 interaction depends on the N- and C-termini of SPCA2. These extensions may play a dual role in activating not only Orai1, but also Ca 2+ transport into the Golgi/secretory pathway, which we tested by investigating the impact of various SPCA2 N- and/or C-terminal truncations on SICE and Ca 2+ transport activity of SPCA2. C-terminal truncations impair SICE and SPCA2 activity, but also affect targeting, whereas N-terminal truncations affect targeting and inactivate SPCA2, but remarkably, SICE activation remains unaffected. Importantly, overexpression of SPCA2 increases the Ca 2+ content of non-ER stores, which depends on Orai1 and SPCA2 activity. Thus, Orai1-mediated Ca 2+ -influx and SPCA2-mediated Ca 2+ uptake activity into the Golgi/secretory pathway might be coupled possibly in a microdomain. This channel/pump complex may efficiently transfer Ca 2+ into the secretory pathway, which might play a role in SPCA2-expressing secretory cells, such as mammary gland during lactation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Many women experience perineal pain after childbirth, especially after having sustained perineal trauma. Perineal pain-management strategies are thus an important part of postnatal care. Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly used type of medication in the management of postpartum pain and their effectiveness and safety should be assessed., Objectives: To determine the effectiveness of a single dose of an oral NSAID for relief of acute perineal pain in the early postpartum period., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2016), OpenSIGLE, ProQuest Dissertations and Theses, the ISRCTN Registry and ClinicalTrials.gov (31 March 2016). We also reviewed reference lists of retrieved papers and contacted experts in the field., Selection Criteria: Randomised controlled trials (RCTs) assessing a single dose of a NSAID versus a single dose of placebo, paracetamol or another NSAID for women with perineal pain in the early postpartum period. Quasi-RCTs and cross-over trials were excluded., Data Collection and Analysis: Two review authors (FW and VS) independently assessed all identified papers for inclusion and risk of bias. Any discrepancies were resolved through discussion and consensus. Data extraction, including calculations of pain relief scores, was also conducted independently by two review authors and checked for accuracy., Main Results: We included 28 studies that examined 13 different NSAIDs and involved 4181 women (none of whom were breastfeeding). Studies were published between 1967 and 2013, with the majority published in the 1980s. Of the 4181 women involved in the studies, 2642 received a NSAID and 1539 received placebo or paracetamol. Risk of bias was generally unclear due to poor reporting, but in most studies the participants and personnel were blinded, outcome data were complete and the outcomes that were specified in the methods section were reported.None of the included studies reported on any of this review's secondary outcomes: prolonged hospitalisation or re-hospitalisation due to perineal pain; breastfeeding (fully or mixed) at discharge; breastfeeding (fully or mixed) at six weeks; perineal pain at six weeks; maternal views; postpartum depression; instrumental measures of disability due to perineal pain. NSAID versus placeboCompared to women who received a placebo, more women who received a single dose NSAID achieved adequate pain relief at four hours (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23, 10 studies, 1573 participants (low-quality evidence)) and adequate pain relief at six hours (RR 1.92, 95% CI 1.69 to 2.17, 17 studies, 2079 participants (very low-quality evidence)). Women who received a NSAID were also less likely to need additional analgesia compared to women who received placebo at four hours (RR 0.39, 95% CI 0.26 to 0.58, four studies, 486 participants (low-quality evidence)) and at six hours after initial administration (RR 0.32, 95% CI 0.26 to 0.40, 10 studies, 1012 participants (low-quality evidence)). Fourteen maternal adverse effects were reported in the NSAID group (drowsiness (5), abdominal discomfort (2), weakness (1), dizziness (2), headache (2), moderate epigastralgia (1), not specified (1)) and eight in the placebo group (drowsiness (2), light headed (1), nausea (1), backache (1), dizziness (1), epigastric pain (1), not specified (1)), although not all studies assessed adverse effects. There was no difference in overall maternal adverse effects between NSAIDs and placebo at six hours post-administration (RR 1.38, 95% CI 0.71 to 2.70, 13 studies, 1388 participants (very low-quality evidence)). One small study (with two treatment arms) assessed maternal adverse effects at four hours post-administration, but there were no maternal adverse effects observed (one study, 90 participants (low-quality evidence)). Neonatal adverse effects were not assessed in any of the included studies. NSAID versus paracetamolNSAIDs versus paracetamol were also more effective for adequate pain relief at four hours (RR 1.54, 95% CI 1.07 to 2.22, three studies, 342 participants) but not at six hours post-administration. There was no difference in the need for additional analgesia between the two groups at four hours (RR 0.55, 95% CI 0.27 to 1.13, one study, 73 participants), but women in the NSAID group were less likely to need any additional analgesia at six hours (RR 0.28, 95% CI 0.12 to 0.67, one study, 59 participants). No maternal adverse effects were reported four hours after drug administration (one study). Six hours post-administration, there was no difference between the groups in the number of maternal adverse effects (RR 0.74, 95% CI 0.27 to 2.08, three studies, 300 participants), with one case of pruritis in the NSAID group and one case of sleepiness in the paracetamol group. Neonatal adverse effects were not assessed in any of the included studies.Comparisons of different NSAIDs and different doses of the same NSAID did not demonstrate any differences in their effectiveness on any of the primary outcome measures; however, few data were available on some NSAIDs., Authors' Conclusions: In women who are not breastfeeding and who sustained perineal trauma, NSAIDs (compared to placebo) provide greater pain relief for acute postpartum perineal pain and fewer women need additional analgesia when treated with a NSAID. However, the risk of bias was unclear for many of the included studies, adverse effects were often not assessed and breastfeeding women were not included in the studies. The overall quality of the evidence (GRADE) was low with the evidence for all outcomes rated as low or very low. The main reasons for downgrading were inclusion of studies with high risk of bias and inconsistency of findings of individual studies.NSAIDs also appear to be more effective in providing relief for perineal pain than paracetamol, but few studies were included in this analysis.Future studies should examine NSAIDs' adverse effects profile including neonatal adverse effects and the compatibility of NSAIDs with breastfeeding, and assess other important secondary outcomes of this review. Moreover, studies mostly included women who had episiotomies. Future research should consider women with and without perineal trauma, including perineal tears. High-quality studies should be conducted to further assess the efficacy of NSAIDs versus paracetamol and the efficacy of multimodal treatments.

Objective: to explore the health-seeking behaviours of primiparous women with pelvic girdle pain persisting for more than three months post partum., Design: a descriptive qualitative design involving face-to-face semi-structured interviews following institutional ethical approval. Transcripts were analysed using thematic analysis., Setting: an urban hospital in Ireland., Participants: a purposive sample of 23 consenting first-time mothers with pelvic girdle pain persisting for at least three months post partum., Findings: 'they didn't ask, I didn't tell' was a key theme, which included emerging categories of a perceived lack of follow-up post partum, and feeling ignored by healthcare professionals. The theme 'Seeking advice and support' describes women's role of talking to others, and triggers and barriers to getting help. 'Coping strategies' was the third theme emerging from the interviews, whereby participants described different strategies they used to deal with their symptoms, although many expressed uncertainty about what to do or who to see., Conclusion and Implications for Practice: our findings show the importance of appropriate information and follow-up care for women with pelvic girdle pain and highlight barriers they encounter in seeking help. They also question the duration of postnatal care as participants felt that postnatal care was stopped too early. The findings may assist maternity care providers in addressing mothers' expectations and needs related to persistent pelvic girdle pain., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Pelvic girdle pain (PGP) is common during pregnancy and negatively affects women's lives. When PGP persists after the birth, the way it affects women's lives may change, particularly for first-time mothers as they adjust to motherhood, yet the experiences of women with persistent PGP remain largely unexplored., Objectives: The objective of this study was to explore primiparous women's experiences of persistent PGP and its impact on their lives postpartum, including caring for their infant and their parental role., Design: This was a descriptive qualitative study., Methods: Following institution ethical approval, 23 consenting primiparous women with PGP that had started during pregnancy and persisted for at least 3 months postpartum participated in individual interviews. These interviews were recorded, transcribed, and analyzed using thematic analysis., Results: Four themes emerged: (1) "Putting up with the pain: coping with everyday life," in which women put up with the pain but had to balance activities and were grateful for support from family and friends to face everyday challenges; (2) "I don't feel back to normal," in which women's feelings of physical limitations, frustration, and a negative impact on their mood were described; (3) "Unexpected," in which persistent symptoms were unexpected for women due to a lack of information given about PGP; and (4) "What next?," in which the future of women's symptoms was met with great uncertainty, and they expressed worry about having another baby., Conclusion: For first-time mothers, having persistent PGP postpartum affects their daily lives in many ways. These findings provide important information for health care providers, which will improve their understanding of these women's experiences, will enhance rapport, and can be used to provide information and address concerns to optimize maternity care during pregnancy and beyond., (© 2015 American Physical Therapy Association.)

ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor-Rakeb syndrome and Parkinson's disease (PD), providing protection against α-synuclein, Mn(2+), and Zn(2+) toxicity in various model systems. So far, the molecular function and regulation of ATP13A2 remains undetermined. Here, we demonstrate that ATP13A2 contains a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5)bisphosphate [PI(3,5)P2]. We further demonstrate that ATP13A2 accumulates in an inactive autophosphorylated state and that PA and PI(3,5)P2 stimulate the autophosphorylation of ATP13A2. In a cellular model of PD, only catalytically active ATP13A2 offers cellular protection against rotenone-induced mitochondrial stress, which relies on the availability of PA and PI(3,5)P2. Thus, the N-terminal binding of PA and PI(3,5)P2 emerges as a key to unlock the activity of ATP13A2, which may offer a therapeutic strategy to activate ATP13A2 and thereby reduce α-synuclein toxicity or mitochondrial stress in PD or related disorders.

Background: A core outcome set (COS) can address problems of outcome heterogeneity and outcome reporting bias in trials and systematic reviews, including Cochrane reviews, helping to reduce waste. One of the aims of the international Core Outcome Measures in Effectiveness Trials (COMET) Initiative is to link the development and use of COS with the outcomes specified and reported in Cochrane reviews, including the outcomes listed in the summary of findings (SoF) tables. As part of this work, an earlier exploratory survey of the outcomes of newly published 2007 and 2011 Cochrane reviews was performed. This survey examined the use of COS, the variety of specified outcomes, and outcome reporting in Cochrane reviews by Cochrane Review Group (CRG). To examine changes over time and to explore outcomes that were repeatedly specified over time in Cochrane reviews by CRG, we conducted a follow-up survey of outcomes in 2013 Cochrane reviews., Methods: A descriptive survey of outcomes in Cochrane reviews that were first published in 2013. Outcomes specified in the methods sections and reported in the results section of the Cochrane reviews were examined by CRG. We also explored the uptake of SoF tables, the number of outcomes included in these, and the quality of the evidence for the outcomes., Results: Across the 50 CRGs, 375 Cochrane reviews that included at least one study specified a total of 3142 outcomes. Of these outcomes, 32 % (1008) were not reported in the results section of these reviews. For 23 % (233) of these non-reported outcomes, we did not find any reason in the text of the review for this non-report. Fifty-seven percent (216/375) of reviews included a SoF table., Conclusions: The proportion of specified outcomes that were reported in Cochrane reviews had increased in 2013 (68 %) compared to 2007 (61 %) and 2011 (65 %). Importantly, 2013 Cochrane reviews that did not report specified outcomes were twice as likely to provide an explanation for why the outcome was not reported. There has been an increased uptake of SoF tables in Cochrane reviews. Outcomes that were repeatedly specified in Cochrane reviews by CRG in 2007, 2011, and 2013 may assist COS development.

We provide a detailed procedure to determine the Ca(2+)-dependent ATPase activity in COS or HEK293 cells overexpressing a Ca(2+) pump. The ATPase activity is determined by the Baginsky method, which allows measurement of the steady-state production of inorganic phosphate (Pi). We have adapted this widely applied method into a sensitive, fast, and semi-high-throughput protocol suitable for use in a 96-well plate format., (© 2014 Cold Spring Harbor Laboratory Press.)

The apparent Ca(2+) affinity of the isoforms of the sarco/endoplasmic reticulum Ca(2+) ATPase SERCA2 is controlled primarily by two proteins, phospholamban (PLB) and sarcolipin (SLN). The rate of ATP-driven Ca(2+) uptake into sarcoplasmic reticulum (SR)-derived vesicles can be monitored by a technique in which the net uptake of (45)Ca(2+) in the form of an intravesicular calcium oxalate precipitate is recorded. Here, we present details of a modification of such a protocol for determining the apparent Ca(2+) affinity of the Ca(2+) pump, and its control by various regulators, in crude homogenates of mouse heart., (© 2014 Cold Spring Harbor Laboratory Press.)

Sarco-/endoplasmic reticulum (SR/ER) Ca(2+) pumps (SERCAs) build up vital Ca(2+) gradients across the intracellular SR/ER membrane, helping to control cell function, proliferation, growth, differentiation, and death. We describe two techniques to measure the SERCA activity either in mammalian culture cells overexpressing SERCAs or in muscle tissue containing high levels of endogenous SERCAs. As Ca(2+) transport is tightly coupled to ATP hydrolysis, it is possible to determine the rate of Ca(2+)-dependent ATP hydrolysis and use it as a measure for SERCA activity or, in a second approach, to quantify ATP-stimulated uptake of radioactive (45)Ca(2+). Here, we first provide an overview of the mechanism of Ca(2+)-transport ATPases and show how this can be taken advantage of in protocols for measuring Ca(2+) pump activity., (© 2014 Cold Spring Harbor Laboratory Press.)

Excess Mn(2+) in humans causes a neurological disorder known as manganism, which shares symptoms with Parkinson's disease. However, the cellular mechanisms underlying Mn(2+) -neurotoxicity and the involvement of Mn(2+) -transporters in cellular homeostasis and repair are poorly understood and require further investigation. In this work, we have analyzed the effect of Mn(2+) on neurons and glia from mice in primary cultures. Mn(2+) overload compromised survival of both cell types, specifically affecting cellular integrity and Golgi organization, where the secretory pathway Ca(2+) /Mn(2+) -ATPase is localized. This ATP-driven Mn(2+) transporter might take part in Mn(2+) accumulation/detoxification at low loads of Mn(2+) , but its ATPase activity is inhibited at high concentration of Mn(2+) . Glial cells appear to be significantly more resistant to this toxicity than neurons and their presence in cocultures provided some protection to neurons against degeneration induced by Mn(2+) . Interestingly, the Mn(2+) toxicity was partially reversed upon Mn(2+) removal by wash out or by the addition of EDTA as a chelating agent, in particular in glial cells. These studies provide data on Mn(2+) neurotoxicity and may contribute to explore new therapeutic approaches for reducing Mn(2+) poisoning., (© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

The molecular mechanism underlying the characteristic high apparent Ca(2+) affinity of SERCA2b relative to SERCA1a and SERCA2a isoforms was studied. The C-terminal tail of SERCA2b consists of an 11th transmembrane helix (TM11) with an associated 11-amino acid luminal extension (LE). The effects of each of these parts and their interactions with the SERCA environment were examined by transient kinetic analysis of the partial reaction steps in the Ca(2+) transport cycle in mutant and chimeric Ca(2+)-ATPase constructs. Manipulations to the LE of SERCA2b markedly increased the rate of Ca(2+) dissociation from Ca(2)E1. Addition of the SERCA2b tail to SERCA1a slowed Ca(2+) dissociation, but only when the luminal L7/8 loop of SERCA1 was simultaneously replaced with that of SERCA2, thus suggesting that the LE interacts with L7/8 in Ca(2)E1. The interaction of LE with L7/8 is also important for the low rate of the Ca(2)E1P → E2P conformational transition. These findings can be rationalized in terms of stabilization of the Ca(2)E1 and Ca(2)E1P forms by docking of the LE near L7/8. By contrast, low rates of E2P dephosphorylation and E2 → E1 transition in SERCA2b depend critically on TM11, particularly in a SERCA2 environment, but do not at all depend on the LE or L7/8. This indicates that interaction of TM11 with SERCA2-specific sequence element(s) elsewhere in the structure is critical in the Ca(2+)-free E2/E2P states. Collectively these properties ensure a higher Ca(2+) affinity of SERCA2b relative to other SERCA isoforms, not only on the cytosolic side, but also on the luminal side.

Presenilin (PSEN) deficiency is accompanied by accumulation of endosomes and autophagosomes, likely caused by impaired endo-lysosomal fusion. Recently, Lee et al. (2010. Cell. doi: http://dx.doi.org/10.1016/j.cell.2010.05.008) attributed this phenomenon to PSEN1 enabling the transport of mature V0a1 subunits of the vacuolar ATPase (V-ATPase) to lysosomes. In their view, PSEN1 mediates the N-glycosylation of V0a1 in the endoplasmic reticulum (ER); consequently, PSEN deficiency prevents V0a1 glycosylation, compromising the delivery of unglycosylated V0a1 to lysosomes, ultimately impairing V-ATPase function and lysosomal acidification. We show here that N-glycosylation is not a prerequisite for proper targeting and function of this V-ATPase subunit both in vitro and in vivo in Drosophila melanogaster. We conclude that endo-lysosomal dysfunction in PSEN(-/-) cells is not a consequence of failed N-glycosylation of V0a1, or compromised lysosomal acidification. Instead, lysosomal calcium storage/release is significantly altered in PSEN(-/-) cells and neurons, thus providing an alternative hypothesis that accounts for the impaired lysosomal fusion capacity and accumulation of endomembranes that accompanies PSEN deficiency.

Manganese is a vital element and cofactor of many key enzymes, but it is toxic at high levels, causing pronounced disturbances in the mammalian brain. Magnetic resonance imaging (MRI) studies using manganese ions as a paramagnetic contrast agent are often limited by the neurotoxicity of Mn(2+) . In this work, we have explored a new in vivo model to study Mn(2+) uptake, distribution and neurotoxicity in mice by subcutaneous implantation of mini-osmotic pumps delivering MnCl(2) continuously for 21 days. Fractionated injections can reduce the toxicity; however, constant administration at very low doses using osmotic pumps caused a substantial effect on the T(1) contrast in MRI while reducing toxicity. Manganese-enhanced MRI documented fast but reversible Mn(2+) deposition largely in glomerular and mitral cell layers of the olfactory bulb, in the CA3 area of the hippocampus, and in the gray matter of the cerebellum. Mn(2+) accumulated as early as the first days after implantation, with a fast dispersal 9 days after stopping a 12-days Mn(2+) exposure. Prominent Mn(2+) accumulation was also seen in salivary glands and in the endocrine thyroid and posterior pituitary gland. These structures with enhanced Mn(2+) accumulation correlated well with those showing high expression of the secretory pathway Ca(2+) /Mn(2+) -ATPase (SPCA1), i.e. a transporter that could take part in Mn(2+) detoxification. Our new experimental model for continuous low-dosage administration of Mn(2+) is an easy alternative for enhancing Mn(2+) -based contrast in MEMRI studies, and might provide insight into the etiology of neuropathologies resulting from chronic Mn(2+) exposure in vivo., (Copyright © 2012 John Wiley & Sons, Ltd.)

Cardiomyocytes from failing hearts exhibit reduced levels of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA) and/or increased activity of the endogenous SERCA inhibitor phospholamban. The resulting reduction in the Ca(2+) affinity of SERCA impairs SR Ca(2+) cycling in this condition. We have previously investigated the physiological impact of increasing the Ca(2+) affinity of SERCA by substituting SERCA2a with the higher affinity SERCA2b pump. When phospholamban was also ablated, these double knockouts (DKO) exhibited a dramatic reduction in total SERCA levels, severe hypertrophy, and diastolic dysfunction. We presently examined the role of cardiomyocyte Ca(2+) homeostasis in both functional and structural remodeling in these hearts. Despite the low SERCA levels in DKO, we observed near-normal Ca(2+) homeostasis with rapid Ca(2+) reuptake even at high Ca(2+) loads and stimulation frequencies. Well-preserved global Ca(2+) homeostasis in DKO was paradoxically associated with marked activation of the Ca(2+)-dependent nuclear factor of activated T-cell-calcineurin pathway known to trigger hypertrophy. No activation of the MAP kinase signaling pathway was detected. These findings suggest that local changes in Ca(2+) homeostasis may play an important signaling role in DKO, perhaps due to reduced microdomain Ca(2+) buffering by SERCA2b. Furthermore, alterations in global Ca(2+) homeostasis can also not explain impaired in vivo diastolic function in DKO. Taken together, our results suggest that normalizing global cardiomyocyte Ca(2+) homeostasis does not necessarily protect against hypertrophy and heart failure development and that excessively increasing SERCA Ca(2+) affinity may be detrimental.

The housekeeping sarco(endo)plasmic reticulum Ca(2+) ATPase SERCA2b transports Ca(2+) across the endoplasmic reticulum membrane maintaining a vital Ca(2+) gradient. Compared with the muscle-specific isoforms SERCA2a and SERCA1a, SERCA2b houses an 11th transmembrane segment (TM11) and a short luminal extension (LE) at its C terminus (2b-tail). The 2b-tail imposes a 2-fold higher apparent Ca(2+) affinity and lower V(max). Previously, we assumed that LE is the sole functional region of the 2b-tail and that TM11 is a passive element providing an additional membrane passage. However, here we show that peptides corresponding to the TM11 region specifically modulate the activity of the homologous SERCA1a in co-reconstituted proteoliposomes and mimic the 2b-tail effect (i.e. lower V(max) and higher Ca(2+) affinity). Using truncated 2b-tail variants we document that TM11 regulates SERCA1a independently from LE, confirming that TM11 is a second, previously unrecognized functional region of the 2b-tail. A phylogenetic analysis further indicates that TM11 is the oldest and most conserved feature of the 2b-tail, found in the SERCA pump of all Bilateria, whereas LE is only present in Nematoda and vertebrates. Considering remarkable similarities with the Na(+),K(+)-ATPase α-β interaction, we now propose a model for interaction of TM11 with TM7 and TM10 in the anchoring subdomain of the Ca(2+) pump. This model involves a TM11-induced helix bending of TM7. In conclusion, more than just a passive structural feature, TM11 acts as a genuine regulator of Ca(2+) transport through interaction with the pump.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with proximal pulmonary artery obstruction and vascular remodeling. We hypothesized that pulmonary arterial smooth muscle (PASMC) and endothelial cells (PAEC) may actively contribute to remodeling of the proximal pulmonary vascular wall in CTEPH. Our present objective was to characterize PASMC and PAEC from large arteries of CTEPH patients and investigate their potential involvement in vascular remodeling., Methods: Primary cultures of proximal PAEC and PASMC from patients with CTEPH, with non-thromboembolic pulmonary hypertension (PH) and lung donors have been established. PAEC and PASMC have been characterized by immunofluorescence using specific markers. Expression of smooth muscle specific markers within the pulmonary vascular wall has been studied by immunofluorescence and Western blotting. Mitogenic activity and migratory capacity of PASMC and PAEC have been investigated in vitro., Results: PAEC express CD31 on their surface, von Willebrand factor in Weibel-Palade bodies and take up acetylated LDL. PASMC express various differentiation markers including α-smooth muscle actin (α-SMA), desmin and smooth muscle myosin heavy chain (SMMHC). In vascular tissue from CTEPH and non-thromboembolic PH patients, expression of α-SMA and desmin is down-regulated compared to lung donors; desmin expression is also down-regulated in vascular tissue from CTEPH compared to non-thromboembolic PH patients. A low proportion of α-SMA positive cells express desmin and SMMHC in the neointima of proximal pulmonary arteries from CTEPH patients. Serum-induced mitogenic activity of PAEC and PASMC, as well as migratory capacity of PASMC, were increased in CTEPH only., Conclusions: Modified proliferative and/or migratory responses of PASMC and PAEC in vitro, associated to a proliferative phenotype of PASMC suggest that PASMC and PAEC could contribute to proximal vascular remodeling in CTEPH.

Background: Fibromyalgia is a chronic syndrome with no cure. A thorough understanding of the illness experience is therefore key in the palliative care of patients with this condition. In search for supportive treatments fibromyalgia patients often attend a chiropractor or other manual therapist. Knowledge of the meaning and reality of living with this condition to the patient could be considered essential to any health care practitioner playing a role in the management. This study aimed to gain a better understanding of the subjective experience of fibromyalgia, focusing on the personal, occupational and social impact of the condition on patients' lives. This included exploring the patients' views about the future., Methods: This study employed descriptive phenomenology and adopted Husserl's concept of transcendental subjectivity or "bracketing". This qualitative study involved semi-structured interviews and was undertaken to obtain rich data that reflected the essence of the participants' experience. Participants consisted of six female volunteers, diagnosed with fibromyalgia by the University Hospital Gent, Belgium. Data were analysed using a thematic framework., Results: Fibromyalgia pervaded all aspects of life. Four main themes arose from data analysis, namely; the impact of fibromyalgia on patients' occupational and personal life, the impact on their future and aspects of social interaction. Nearly all participants had stopped working, giving rise to feelings of uselessness and loss of identity. Leisure activities were also greatly affected. Fibromyalgia was said to alter family bonds, some of which were reinforced, others were broken. The diagnosis was seen as a relief, marking an end to a period of uncertainty. Participants reported ambivalence in interaction. Despite some positive encounters, frustration arising from perceived incomprehension dominated. Consequently patients preferred not to share their experiences., Conclusions: The study revealed the negative impact of fibromyalgia on patients' lives as comprising of great complexity and individuality. Several implications for health care practitioners can be extrapolated, including the need of a more efficient diagnostic process and increased education about the fibromyalgia experience. Further studies are required to better clarify the multifaceted nature of living with the condition.

As a major Ca2+ pump in the sarcoplasmic reticulum of the cardiomyocyte, SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) controls the relaxation and contraction of the cardiomyocyte. It is meticulously regulated by adapting its expression levels and affinity for Ca2+ ions to the physiological demand of the heart. Dysregulation of the SERCA2a activity entails poor cardiomyocyte contractility, resulting in heart failure. Conversely, improving cardiac SERCA2a activity, e.g. by boosting its expression level or by increasing its affinity for Ca2+, is a promising strategy to rescue contractile dysfunction of the failing heart. The structures of the related SERCA1a Ca2+ pump and the Na+/K+-ATPase of the plasma membrane exposed the pumping mechanism and conserved domain architecture of these ion pumps. However, how the Ca2+ affinity of SERCA2a is regulated at the molecular level remained unclear. A structural and functional analysis of the closely related SERCA2b Ca2+ pump, i.e. the housekeeping Ca2+ pump found in the endoplasmic reticulum and the only SERCA isoform characterized by a high Ca2+ affinity, aimed to fill this gap. We demonstrated the existence of a novel and highly conserved site on the SERCA2 pump mediating Ca2+ affinity regulation by the unique C-terminus of SERCA2b (2b-tail). It differs from the earlier-described target site of the affinity regulator phospholamban. Targeting this novel site may provide a new approach to improve SERCA2a function in the failing heart. Strikingly, the intramembrane interaction site of the 2b-tail in SERCA2b shares sequence and structural homology with the binding site of the β-subunit on the α Na+/K+-ATPase. Thus P-type ATPases seem to have developed related mechanisms of regulation, and it is a future challenge for us to discover these general principles of P-type regulation.

The various splice variants of the three SERCA- and the two SPCA-pump genes in higher vertebrates encode P-type ATPases of the P(2A) group found respectively in the membranes of the endoplasmic reticulum and the secretory pathway. Of these, SERCA2b and SPCA1a represent the housekeeping isoforms. The SERCA2b form is characterized by a luminal carboxy terminus imposing a higher affinity for cytosolic Ca(2+) compared to the other SERCAs. This is mediated by intramembrane and luminal interactions of this extension with the pump. Other known affinity modulators like phospholamban and sarcolipin decrease the affinity for Ca(2+). The number of proteins reported to interact with SERCA is rapidly growing. Here, we limit the discussion to those for which the interaction site with the ATPase is specified: HAX-1, calumenin, histidine-rich Ca(2+)-binding protein, and indirectly calreticulin, calnexin, and ERp57. The role of the phylogenetically older and structurally simpler SPCAs as transporters of Ca(2+), but also of Mn(2+), is also addressed.

The ubiquitous sarco(endo)plasmic reticulum (SR/ER) Ca(2+) ATPase (SERCA2b) and secretory-pathway Ca(2+) ATPase (SPCA1a) belong both to the P(2A)-type ATPase subgroup of Ca(2+) transporters and play a crucial role in the Ca(2+) homeostasis of respectively the ER and Golgi apparatus. They are ubiquitously expressed, but their low abundance precludes purification for crystallization. We have developed a new strategy for purification of recombinant hSERCA2b and hSPCA1a that is based on overexpression in yeast followed by a two-step affinity chromatography method biasing towards properly folded protein. In a first step, these proteins were purified with the aid of an analogue of the SERCA inhibitor thapsigargin (Tg) coupled to a matrix. Wild-type (WT) hSERCA2b bound efficiently to the gel, but its elution was hampered by the high affinity of SERCA2b for Tg. Therefore, a mutant was generated carrying minor modifications in the Tg-binding site showing a lower affinity for Tg. In a second step, reactive dye chromatography was performed to further purify and concentrate the properly folded pumps and to exchange the detergent to one more suitable for crystallization. A similar strategy was successfully applied to purify WT SPCA1a. This study shows that it is possible to purify functionally active intracellular Ca(2+) ATPases using successive thapsigargin and reactive dye affinity chromatography for future structural studies. This article is part of a Special Issue entitled: 11th European Symposium on Calcium., (2011 Elsevier B.V. All rights reserved.)

The SERCA2a isoform of the sarco/endoplasmic reticulum Ca(2+) pumps is specifically expressed in the heart, whereas SERCA2b is the ubiquitously expressed variant. It has been shown previously that replacement of SERCA2a by SERCA2b in mice (SERCA2(b/b) mice) results in only a moderate functional impairment, whereas SERCA activity is decreased by a 40% lower SERCA protein expression and by increased inhibition by phospholamban. To find out whether the documented kinetic differences in SERCA2b relative to SERCA2a (i.e., a twofold higher apparent Ca(2+) affinity, but twofold lower maximal turnover rate) can explain these compensatory changes, we simulated Ca(2+) dynamics in mouse ventricular myocytes. The model shows that the relative Ca(2+) transport capacity of SERCA2a and SERCA2b depends on the SERCA concentration. The simulations point to a dominant effect of SERCA2b's higher Ca(2+) affinity over its lower maximal turnover rate. The results suggest that increased systolic and decreased diastolic Ca(2+) levels in unstimulated conditions could contribute to the downregulation of SERCA in SERCA2(b/b) mice. In stress conditions, Ca(2+) handling is less efficient by SERCA2b than by SERCA2a, which might contribute to the observed hypertrophy in SERCA2(b/b) mice. Altogether, SERCA2a might be a better compromise between performance in basal conditions and performance during β-adrenergic stress., (Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.)