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Dysmenorrhea: a public health challenge demanding urgent attention

The mHealth clinical decision-making tools for maternal and perinatal health care in Sub-Saharan Africa: A systematic review

Introduction mobile Health (mHealth) refers to use of mobile wireless technologies for health. The potential for mHealth to enhance healthcare delivery is supported by near-universal availability of mobile phones and their expanding coverage in low- and middle-income countries. This systematic review analyses the available evidence on mHealth clinical decision-making tools in maternal and perinatal health, and whether they lead to improved maternal and perinatal health outcomes in Sub-Saharan Africa (SSA). Methods Eligibility criteria: Studies conducted in SSA describing mHealth tools piloted or used for clinical decision-making in maternal or perinatal healthcare. Exclusion criteria included mHealth tools used outside of maternal and perinatal healthcare, publications lacking sufficient detail (where information couldn’t be obtained through contacting authors), articles where tools were used on a laptop or desktop computer, and articles not published in English. Data sources: PubMed, CINAHL, EMBASE, Global Health, and Web of Science were searched for relevant articles following a predetermined search strategy with no date restrictions. A limited grey literature search was conducted. Risk of bias: We assessed the quality of included studies using the Cochrane Risk of bias 2 tool, Newcastle- Ottawa scale and COREQ. This comprehensive approach ensured a rigorous evaluation of bias and validity in our systematic review. Data extraction and synthesis: Two independent reviewers screened articles and extracted data. Results 1119 records were screened, and 36 articles met the inclusion criteria. Fifteen mHealth tools were identified across 11 SSA countries. Conclusion mHealth tools for clinical decision-making in maternal and perinatal care were found to be feasible, usable, and acceptable. They demonstrated adequate user satisfaction, and some demonstrated improvement of pregnancy outcomes. However, technologies lack scalability, with only one scaled up nationally, and few tools interacted with existing health information systems or had plans for sustainability. This review will help establish best practice for developing and scaling up mHealth clinical decision-making tools, helping to improve maternal and perinatal healthcare in SSA.

Measurement, determinants and outcomes of maternal care satisfaction in Nigeria: a systematic review

IntroductionMaternal mortality rates are unacceptably high in Nigeria. Understanding women’s satisfaction with the maternity health system is fundamental, as perceived quality of care is a determinant of service utilisation and improved birth outcomes.ObjectivesThis systematic review aims to explore patients’ satisfaction with maternal healthcare in Nigeria, examining the measurement, determinants, and outcomes of satisfaction.DesignA systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines.Data sourcesSearches were conducted in Embase, Maternity and Infant Care, Global Health, Ovid, Africa Journals Online, Cochrane Central Register of Controlled Trials, MEDLINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus and Google Scholar, alongside citation searches of relevant studies.Eligibility criteriaOriginal studies assessing patient satisfaction with maternal health services in Nigeria were included. There were no restrictions on study design types. Studies were excluded if they did not clearly define how satisfaction was measured or did not focus on the maternal health service domains under review (ie, antenatal, delivery, and/or postnatal care).Data extraction and synthesisKey information relevant to this study was extracted into an Excel spreadsheet and narratively synthesised. The Quality Assessment for Diverse Studies tool was used to appraise the quality of the selected literature.ResultsMaternal care satisfaction (MCS) ratings are high in Nigeria, but this may either indicate genuine positive experiences or be influenced by measurement-related biases. Several factors determine women’s satisfaction with maternity services. Key factors influencing MCS in Nigeria are positive client-provider relationships, a favourable hospital environment with easy accessibility and affordable care costs. While our study demonstrated a correlation between MCS and socioeconomic and demographic factors, there is no complete consensus within the literature about this correlation. Furthermore, patient satisfaction was associated with women’s future health-seeking behaviour and willingness to recommend care to others.ConclusionUnderstanding the multifaceted nature of MCS determinants and outcomes can better equip us to provide the support and care that mothers need to thrive. The findings from this study can inform policy, improve health responsiveness and ensure that women are provided with satisfactory and patient-centred maternity care, hence leading to a decline in poor pregnancy outcomes in Nigeria. It also highlights the need for robust methodologies that accurately measure women’s experiences, which is essential for enhancing the quality of maternal health services.PROSPERO registration numberA protocol was developed for this study and published on PROSPERO, the International Prospective Register of Systematic Reviews (CRD42023414771).

PatchCTG: A Patch Cardiotocography Transformer for Antepartum Fetal Health Monitoring

Antepartum Cardiotocography (CTG) is a biomedical sensing technology widely used for fetal health monitoring. While the visual interpretation of CTG traces is highly subjective, with the inter-observer agreement as low as 29% and a false positive rate of approximately 60%, the Dawes–Redman system provides an automated approach to fetal well-being assessments. However, it is primarily designed to rule out adverse outcomes rather than detect them, resulting in a high specificity (90.7%) but low sensitivity (18.2%) in identifying fetal distress. This paper introduces PatchCTG, an AI-enabled biomedical time series transformer for CTG analysis. It employs patch-based tokenisation, instance normalisation, and channel-independent processing to capture essential local and global temporal dependencies within CTG signals. PatchCTG was evaluated on the Oxford Maternity (OXMAT) dataset, which comprises over 20,000 high-quality CTG traces from diverse clinical outcomes, after applying the inclusion and exclusion criteria. With extensive hyperparameter optimisation, PatchCTG achieved an AUC of 0.77, with a specificity of 88% and sensitivity of 57% at Youden’s index threshold, demonstrating its adaptability to various clinical needs. Its robust performance across varying temporal thresholds highlights its potential for both real-time and retrospective analysis in sensor-driven fetal monitoring. Testing across varying temporal thresholds showcased it robust predictive performance, particularly with finetuning on data closer to delivery, achieving a sensitivity of 52% and specificity of 88% for near-delivery cases. These findings suggest the potential of PatchCTG to enhance clinical decision-making in antepartum care by providing a sensor-based, AI-driven, objective tool for reliable fetal health assessment.

FIGO position statement on postpartum intrauterine devices (PPIUD)

AbstractPostpartum contraception is a critical intervention to address the unmet need for family planning, which affects over 218 million women globally, predominantly in low‐ and middle‐income countries (LMICs). Immediate postpartum family planning (PPFP) offers a unique opportunity to provide contraception during a crucial health‐seeking encounter, particularly given the rise in institutional births worldwide. Short inter‐pregnancy intervals are associated with increased maternal and neonatal morbidity and mortality, making timely postpartum contraception essential. The postpartum intrauterine device (PPIUD), a long‐acting reversible contraceptive (LARC), is a highly cost‐effective, non‐hormonal method with a low failure rate. It can be safely inserted immediately after vaginal or cesarean delivery, offering women a reliable and accessible option. However, successful implementation of PPIUD services requires overcoming barriers such as fragmented health services, provider bias, sociocultural misconceptions, and supply chain challenges. FIGO advocates for integrating PPFP, including PPIUD, into routine maternity care and emphasizes task sharing, community engagement, and comprehensive counseling as critical strategies. By incorporating postpartum contraception into standard maternal care, particularly in LMICs, health systems can improve maternal and child health outcomes, advance Sustainable Development Goals (SDGs), and empower women to make informed reproductive choices.

Review: The potential role of placental extracellular vesicles in blood-brain barrier disruption and neuroinflammation in preeclampsia

Preeclampsia is a complex pregnancy disorder characterized by hypertension and multisystem organ damage, notably affecting the liver, kidneys, and brain. Eclampsia, a severe form of preeclampsia, is marked by the sudden onset of generalized tonic-clonic seizures. Brain complications, including eclampsia, are responsible for 60–70 % of preeclampsia-related maternal deaths, particularly in low-income regions. Despite the significant impact of brain complications in preeclampsia, their underlying pathophysiology remains unclear. Evidence suggests that brain edema in preeclampsia and eclampsia results from disruption of the blood-brain barrier (BBB). Although direct analysis of the BBB is challenging, in vitro studies indicate that plasma from women with preeclampsia can compromise the BBB, with the specific circulating factors involved still unidentified. Among the potential culprits, recent findings highlight placental-derived small extracellular vesicles (PDsEVs) as key players in BBB disruption observed in preeclampsia. This review examines the role of PDsEVs in the pathophysiology of brain edema associated with preeclampsia, emphasizing areas for future research, including neuroinflammation and neuron dysfunction. Additionally, we discuss the protective role of magnesium sulfate in these processes.

Towards Multi-resolution Spatiotemporal Graph Learning for Medical Time Series Classification

Spectrum of congenital anomalies detected through anatomy ultrasound at a referral hospital in Ghana

Protocol for the Cultural Translation and Adaptation of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project Endometriosis Participant Questionnaire (EPHect)

Endometriosis affects 10% of women worldwide and is one of the most common causes of chronic pelvic pain and infertility. However, causal mechanisms of this disease remain unknown due to its heterogeneous presentation. In order to successfully study its phenotypic variation, large sample sizes are needed. Pooling of data across sites is not always feasible given the large variation in the complexity and quality of the data collected. The World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) have developed an endometriosis participant questionnaire (EPQ) to harmonize non-surgical clinical participant characteristic data relevant to endometriosis research, allowing for large-scale collaborations in English-speaking populations. Although the WERF EPHect EPQs have been translated into different languages, no study has examined the cross-cultural translation and adaptation for content and face validity. In order to investigate this, we followed the standard guidelines for cross-cultural adaptation and translation of the minimum version of the EPQ (EPQ-M) using 40 patients who underwent laparoscopic surgery in Turkey and 40 women in Northern Cyprus, aged between 18 and 55. We assessed the consistency by using cognitive testing and found the EPHect EPQ-M to be comprehensive, informative, and feasible in these two Turkish-speaking populations. The translated and adapted questionnaire was found to be epidemiologically robust, taking around 30–60 min to complete; furthermore, participants reported a similar understanding of the questions, showing that common perspectives were explored. Results from the cognitive testing process led to minor additions to some items such as further descriptive and/or visuals in order to clarify medical terminology. This paper illustrates the first successful cross-cultural translation and adaptation of the EPHect EPQ-M and should act as a tool to allow for further studies that wish to use this questionnaire in different languages. Standardized tools like this should be adopted by researchers worldwide to facilitate collaboration and aid in the design and conduction of global studies to ultimately help those affected by endometriosis and its associated symptoms.

Impact of Endometriosis in Women of Arab Ancestry on: Health-Related Quality of Life, Work Productivity, and Diagnostic Delay.

Introduction: Endometriosis has a negative effect on health-related quality of life (HRQoL), wellbeing and daily functioning. Endometriosis is an under-researched condition within non-western populations. Cultural representations are needed to understand the relative roles of societal norms, traditional factors, and religious sensitivities on the impact of endometriosis on HRQoL in various populations. In particular, there is a lack of emphasis placed in understanding the association of HRQoL on endometriosis in Arab women. Method: In this prospective case-control study, 2,610 Arab ancestry women in the United Arab Emirates were recruited to investigate the impact of endometriosis on HRQoL, diagnostic delay, psychological co-morbidities, work productivity, and physical activity. Participants completed the following standardized, validated questionnaires: Short Form-36 version 2 questionnaire, the World Endometriosis Research Foundation EPHect minimum clinical questionnaire version, and Work Productivity and Activity Impairment questionnaire. Translations to the Arabic language, validated using the forward-backward translation method, of the questionnaires were utilized. Results: HRQoL scores were significantly impaired in women with endometriosis, as demonstrated in the Physical Composite Scores and Mental Composite Scores in the symptomatic control group (p = 0.001; p = 0.003, respectively) and the asymptomatic control group (p < 0.001; p < 0.001, respectively). Susceptibility and severity of multiple pain syndromes and infertility in women with endometriosis was the main indicator of lower HRQoL. Anxiety (p = 0.007) and depression (p = 0.005) were significantly associated with endometriosis, in comparison to symptomatic controls. The average diagnostic delay was 11.61 years, however single women experience 15.81 years of diagnosis delay, with approximately 18% (n = 15) of the single women experiencing more than a 20-year delay in diagnosis. The intensity of physical activity was not associated with endometriosis, when compared to symptomatic (p = 0.405) or asymptomatic controls (p = 0.144). Conclusion: For the first time, we provide evidence from a combined hospital, clinic, and population-based study that Arab women with endometriosis experience significant impacts on HRQoL, substantial diagnostic delay after the onset of symptoms, significant association to psychological disorders (anxiety and depression), and a negative impact on work productivity. Future research must focus on understanding the personal and culturally centered beliefs of Arab women to ensure a positive HRQoL trajectory by improving diagnosis and management strategies.

Predictors and trends of Caesarean section and breastfeeding in the Eastern Mediterranean region: Data from the cross-sectional Cyprus Women’s Health Research (COHERE) Initiative

Introduction Caesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population. Methods Using self-reported data from the representative Cyprus Women’s Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration. Results C-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14–2.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06–1.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length. Conclusion Prevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.

The phenotypic and genetic association between endometriosis and immunological diseases

Abstract STUDY QUESTION Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk? SUMMARY ANSWER Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis. WHAT IS KNOWN ALREADY The epidemiological evidence for an increased risk of immunological diseases among women with endometriosis is limited in scope and has varied in robustness due to the opportunity for biases. The presence of a biological basis for increased comorbidity across immunological conditions has not been investigated. Here we investigate the phenotypic and genetic association between endometriosis and 31 immune conditions in the UK Biobank. STUDY DESIGN, SIZE, DURATION Phenotypic analyses between endometriosis and immune conditions (17 classical autoimmune, 10 autoinflammatory, and 4 mixed-pattern diseases) were conducted using two approaches (8223 endometriosis, 64 620 immunological disease cases): (i) retrospective cohort study design to incorporate temporality between diagnoses and (ii) cross-sectional analysis for simple association. Genome-wide association studies (GWAS) and meta-analyses for those immune conditions that showed phenotypic association with endometriosis (1493–77 052 cases) were conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS Comprehensive phenotypic association analyses were conducted in females in the UK Biobank. GWAS for immunological conditions were conducted in females-only and sex-combined study populations in UK Biobank and meta-analysed with existing largest available GWAS results. Genetic correlation and Mendelian randomization (MR) analyses were conducted to investigate potential causal relationships. Those immune conditions with significant genetic correlation with endometriosis were included in multi-trait analysis of GWAS to boost discovery of novel and shared genetic variants. These shared variants were functionally annotated to identify affected genes utilizing expression quantitative trait loci (eQTL) data from GTEx and eQTLGen databases. Biological pathway enrichment analysis was conducted to identify shared underlying biological pathways. MAIN RESULTS AND THE ROLE OF CHANCE In both retrospective cohort and cross-sectional analyses, endometriosis patients were at significantly increased (30–80%) risk of classical autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis), and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic correlation (rg) = 0.28, P = 3.25 × 10−15), rheumatoid arthritis (rg = 0.27, P = 1.5 × 10−5) and multiple sclerosis (rg = 0.09, P = 4.00 × 10−3) were significantly genetically correlated with endometriosis. MR analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR = 1.16, 95% CI = 1.02–1.33). eQTL analyses highlighted genes affected by shared risk variants, enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis (BMPR2/2q33.1, BSN/3p21.31, MLLT10/10p12.31) and one with rheumatoid arthritis (XKR6/8p23.1). LIMITATIONS, REASONS FOR CAUTION We conducted the first female-specific GWAS analyses for immune conditions. Given the novelty of these analyses, the sample sizes from which results were derived were limited compared to sex-combined GWAS meta-analyses, which limited the power to use female-specific summary statistics to uncover the shared genetic basis with endometriosis in follow-up analyses. Secondly, the 39 genome-wide significant endometriosis-associated variants used as instrumental variables in the MR analysis explained approximately 5% of disease variation, which may account for the nominal or non-significant MR results. WIDER IMPLICATIONS OF THE FINDINGS Endometriosis patients have a moderately increased risk for osteoarthritis, rheumatoid arthritis, and to a lesser extent, multiple sclerosis, due to underlying shared biological mechanisms. Clinical implications primarily involve the need for increased awareness and vigilance. The shared genetic basis opens up opportunities for developing new treatments or repurposing therapies across these conditions. STUDY FUNDING/COMPETING INTEREST(S) We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from the Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by the National Natural Science Foundation of China (grant 32170663). N.R., S.A.M., and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). K.T.Z. and C.M.B. reported grants in 3 years prior, outside the submitted work, from Bayer AG, AbbVie Inc., Volition Rx, MDNA Life Sciences, PrecisionLife Ltd., and Roche Diagnostics Inc. S.A.M. reports grants in the 3 years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio, outside this submitted work. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A

Pre-oviposition development of the brown anole (Anolis sagrei).

BACKGROUND: The brown anole, Anolis sagrei, has emerged as a representative squamate species for developmental studies during the past decades. Novel functional tools have been established to manipulate embryogenesis through genome editing or the introduction of small molecule inhibitors, and their effective use requires a thorough understanding of early anole embryogenesis. To enable precise and reproducible staging of anole embryos, we need knowledge of the progression of anole embryogenesis and morphogenesis. While post-oviposition development has been described, the pre-oviposition period remains to be explored. RESULTS: We provide the first staging series of pre-oviposition development for the brown anole. Analyzing the follicles and embryos through brightfield imaging, SEM, STEM, histology, and DAPI staining, we define 26 distinct developmental stages. Furthermore, we followed heart development, neural crest cell migration, and central nervous system development using immunofluorescence analyses and provide new comparative insights into the morphogenesis of each of these organ systems. CONCLUSIONS: Our dataset reveals that peri-gastrulation morphogenesis up to the initiation of neurulation diverges significantly from chick, the common representative model of reptile embryogenesis. With this study, we establish the brown anole as a squamate model organism for cross-clade evolutionary studies of early embryogenesis.

A core outcome set for future male infertility research: development of an international consensus

A core outcome set for future male infertility research: development of an international consensus

Abstract STUDY QUESTION Can a core outcome set be developed through a global consensus to standardize outcome selection, collection, comparison, and reporting in future male infertility trials? SUMMARY ANSWER A minimum dataset, known as a ‘core outcome set’, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential interventions for male infertility. WHAT IS KNOWN ALREADY Numerous factors, including a failure to consider the perspectives of men with lived experiences of infertility or their partners when developing and conducting RCTs can limit their clinical utility. Selection of outcomes, variations in outcome definitions, and the selective reporting of outcomes based on statistical analysis make the results of infertility research challenging to interpret, compare, and implement. For male infertility, this is further compounded by there being potentially three participants, the male, their female partner, and any offspring born, all with outcomes to be reported. This has led to significant heterogeneity in trial design and reporting. While a core outcome set for general infertility trials has been developed, there is no such outcome set for male infertility trials. STUDY DESIGN, SIZE, DURATION A two-round Delphi survey (334 participants from 39 countries) and consensus development workshops (44 participants from 21 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS Healthcare professionals, researchers, and men and women with infertility were brought together in a transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE The core outcome set for male infertility trials has been developed by the inclusion of specific male-factor outcomes in addition to the general infertility core outcome set. These outcomes include assessment of semen using the World Health Organization recommendations for semen analysis; viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancies); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Although not a requirement as part of the core outcome set, other outcomes were identified as potentially useful in certain study settings. LIMITATIONS, REASONS FOR CAUTION We used consensus development methods in this work, which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes, which are inconsistently reported at present. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set for male infertility trials. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by The Urology Foundation, Small Project Fund awarded to Michael P Rimmer at the University of Edinburgh, UK. RTM was supported by a United Kingdom Research and Innovation (UKRI) Future Leaders Fellowship (MR/Y011783/1). C.L.R.B. is the co-editor in chief of Human Reproduction and recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. R.P.B. receives royalties from Flow diagnósticos. M.L.E. is an advisor to the companies Hannah, Illumicell, Next, Legacy, Doveras, Vseat and received a consultancy fee for this. B.W.M. is a paid consultant for Norgine and Organon and has received research funding from Ferring and Merck, he also receives consultancy and travel support from Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. has been an associate editor with Human Reproduction Open. K.Mc.E. received funding to attend Fertility 2025 by the British Fertility Society and is the Chair of the British Fertility Society. He is a member of the HFEA’s Scientific and Clinical Advances Advisory Committee and a Committee Member of the NICE Fertility Problems Guideline Group. M.H.V.L. receives consultation fees for the WHO Manual Spanish translation, and travel expenses for the ESHRE MRHI meeting in Budapest. She is a member of the editorial board for Fertility & Sterility, F&S Science, Human Reproduction, and Frontiers in Endocrinology. She is also a panel member of the World Health Organization (WHO) Human Reproduction Programme (HRP) Research Project Review Panel. R.S.M. is a member of the NICE Guideline Committee on Fertility and former chair of the British Fertility Society. A. Perheentupa receives an honoraria for lecturing from Merck for the Tackling Infertility manifest, Gedeon Richter & Ferring. A. Perheentupa declares lecture honoraria from Merck, Gideon Richter, and Ferring; and payment from Merck for the Tackling Infertility manifesto. A. Pacey receives consultancy fees for Carrot Fertility and Cryos International as well as lecturing for IBSA Institut Biochimique SA and Mealis Group—all fees paid to The University of Manchester. He is also a Trustee of Progress Educational. Trust (Charity Number 1139856) and Chairman of UKNEQAS Reproductive Sciences Advisory Committee. F.T. is the recipient of a Bayer research grant, as well as DFG Clinical Research Unit ‘Male Germ Cells’ (CRU326, project number 329621271) and BMBF Junior Scientist Research Centre ‘ReproTrack.MS’ (grant 01GR2303), he has received travel support from IBSA and Organon. M.v.W. is the Editor-in-Chief of Human Reproduction Update. R.W. is a former Deputy Editor of Human Reproduction and is currently a Deputy Editor of Human Reproduction Update. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586.

Metabolic symbiosis between oxygenated and hypoxic tumour cells: An agent-based modelling study.

Deregulated metabolism is one of the hallmarks of cancer. It is well-known that tumour cells tend to metabolize glucose via glycolysis even when oxygen is available and mitochondrial respiration is functional. However, the lower energy efficiency of aerobic glycolysis with respect to mitochondrial respiration makes this behaviour, namely the Warburg effect, counter-intuitive, although it has now been recognized as source of anabolic precursors. On the other hand, there is evidence that oxygenated tumour cells could be fuelled by exogenous lactate produced from glycolysis. We employed a multi-scale approach that integrates multi-agent modelling, diffusion-reaction, stoichiometric equations, and Boolean networks to study metabolic cooperation between hypoxic and oxygenated cells exposed to varying oxygen, nutrient, and inhibitor concentrations. The results show that the cooperation reduces the depletion of environmental glucose, resulting in an overall advantage of using aerobic glycolysis. In addition, the oxygen level was found to be decreased by symbiosis, promoting a further shift towards anaerobic glycolysis. However, the oxygenated and hypoxic populations may gradually reach quasi-equilibrium. A sensitivity analysis using Latin hypercube sampling and partial rank correlation shows that the symbiotic dynamics depends on properties of the specific cell such as the minimum glucose level needed for glycolysis. Our results suggest that strategies that block glucose transporters may be more effective to reduce tumour growth than those blocking lactate intake transporters.

Long COVID: mechanisms, risk factors and recovery

AbstractLong COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS‐CoV‐2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post‐viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post‐viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID‐related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro‐clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Development of a novel microfluidic perfusion 3D cell culture system for improved neuronal cell differentiation.

Three-dimensional (3D) cell cultures have recently gained popularity in the biomedical sciences because of their similarity to the in vivo environment. SH-SY5Y cells, which are neuronal cells and are commonly used to investigate neurodegenerative diseases, have particularly been reported to be differentiated as neuron-like cells expressing neuron-specific markers of mature neurons in static 3D culture environments when compared to static 2D environments, and those in perfusion environments have not yet been investigated. Microfluidic technology has provided perfusion environment which has more similarity to in vivo through mimicking vascular transportation of nutrients, but air bubbles entering into microchannels drastically increase instability of the flow. Furthermore, static incubation commonly used is incompatible with perfusion setup due to its air conditions, which is a critical huddle to the biologists. In the present study, we developed a novel microfluidic perfusion 3D cell culture system that overcomes the disturbance from air bubbles and intuitionally sets the incubation with the perfusion 3D culture. The system is capable of generating concentration gradients between 5 and 95% and air bubble traps were included to increase stability during incubation by collecting air bubbles. To evaluate the perfusion 3D culture, SH-SY5Y differentiation was examined in static 2D, static 3D, and perfusion 3D cultures. Our system supported significantly increased clustering of SH-SY5Y compared to static 2D and 3D methods, as well as increasing neurite growth rate. This novel system therefore supports differentiation of SH-SY5Y and can be used to more accurately model the in vivo environment during cell culture experiments.

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

Correction: Kujawski et al. Autonomic and Cognitive Function Response to Normobaric Hyperoxia Exposure in Healthy Subjects. Preliminary Study. Medicina 2020, 56, 172.

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