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Background Mediation analysis aims at estimating to what extent the effect of an exposure on an outcome is explained by a set of mediators on the causal pathway between the exposure and the outcome. The total effect of the exposure on the outcome can be decomposed into an indirect effect, i.e. the effect explained by the mediators jointly, and a direct effect, i.e. the effect unexplained by the mediators. However finer decompositions are possible in presence of independent or sequential mediators. Methods We review four statistical methods to analyse multiple sequential mediators, the inverse odds ratio weighting approach, the inverse probability weighting approach, the imputation approach and the extended imputation approach. These approaches are compared and implemented using a case-study with the aim to investigate the mediating role of adverse reproductive outcomes and infant respiratory infections in the effect of maternal pregnancy mental health on infant wheezing in the Ninfea birth cohort. Results Using the inverse odds ratio weighting approach, the direct effect of maternal depression or anxiety in pregnancy is equal to a 59% (95% CI: 27%,94%) increased prevalence of infant wheezing and the mediated effect through adverse reproductive outcomes is equal to a 3% (95% CI: -6%,12%) increased prevalence of infant wheezing. When including infant lower respiratory infections in the mediation pathway, the direct effect decreases to 57% (95% CI: 25%,92%) and the indirect effect increases to 5% (95% CI: -5%,15%). The estimates of the effects obtained using the weighting and the imputation approaches are similar. The extended imputation approach suggests that the small joint indirect effect through adverse reproductive outcomes and lower respiratory infections is due entirely to the contribution of infant lower respiratory infections, and not to an increased prevalence of adverse reproductive outcomes. Conclusions The four methods revealed similar results of small mediating role of adverse reproductive outcomes and early respiratory tract infections in the effect of maternal pregnancy mental health on infant wheezing. The choice of the method depends on what is the effect of main interest, the type of the variables involved in the analysis (binary, categorical, count or continuous) and the confidence in specifying the models for the exposure, the mediators and the outcome.

Thermodynamics is a vast area of knowledge with a debatable role in explaining the evolution of ecosystems. In the case of soil ecosystems, this role is still unclear due to difficulties in determining the thermodynamic functions that are involved in the survival and evolution of soils as living systems. The existing knowledge is largely based on theoretical approaches and has never been applied to soils using thermodynamic functions that have been experimentally determined. In this study, we present a method for the complete experimental thermodynamic characterization of soil organic matter. This method quantifies all the thermodynamic functions for combustion and formation reactions which are involved in the thermodynamic principles governing the evolution of the universe. We applied them to track the progress of soil organic matter with soil depth in mature beech forests. Our results show that soil organic matter evolves to a higher degree of reduction as it is mineralized, yielding products with lower carbon but higher energy content than the original organic matter used as reference. These products have higher entropy than the original one, demonstrating how the soil ecosystem evolves with depth, in accordance with the second law of thermodynamics. The results were sensitive to soil organic matter transformation in forests under different management, indicating potential applicability in elucidating the energy strategies for evolution and survival of soil systems as well as in settling their evolutionary states.

Until recently, human embryonic stem cells (hESCs) were shown to exist in a state of primed pluripotency, while mouse embryonic stem cells (mESCs) display a naive or primed pluripotent state. Here we show the rapid conversion of in-house-derived primed hESCs on mouse embryonic feeder layer (MEF) to a naive state within 5–6 days in naive conversion media (NCM-MEF), 6–10 days in naive human stem cell media (NHSM-MEF) and 14–20 days using the reverse-toggle protocol (RT-MEF). We further observe enhanced unbiased lineage-specific differentiation potential of naive hESCs converted in NCM-MEF, however, all naive hESCs fail to differentiate towards functional cell types. RNA-seq analysis reveals a divergent role of PI3K/AKT/mTORC signalling, specifically of the mTORC2 subunit, in the different naive hESCs. Overall, we demonstrate a direct evaluation of several naive culture conditions performed in the same laboratory, thereby contributing to an unbiased, more in-depth understanding of different naive hESCs. Human embryonic stem cells (hESCs) in culture display a state of primed pluripotency, but recent protocols have been developed that enable hESCs to adopt a naive-like pluripotent state. Here the authors perform a side-by-side comparison of methods used to culture naive hESCs and confirm the role of PI3K/AKT/mTORC signalling in facilitating the induction of naive pluripotency.

Fosfomycin (FOM) is an antibiotic which has varying application indications across the globe. European, Japanese, South African and Brazilian usage practices are much broader, involving multiple formulations of FOM than the currently limited application of FOM in the United States, where uncomplicated urinary tract infection represents the only indication for FOM-tromethamine. Based on early difficulty in determining FOMs genuine in vitro activity, there was initial skepticism about its efficacy and application range. However, in the mid 1970s, correctly executed experiments coupled with an improved understanding of microbiological concepts opened the door for broader use of FOM. During the following 40 years FOM was evaluated in pre-clinical and clinical trials in a wide range of applications and in a multitude of settings. The gathering of pharmacokinetic and pharmacodynamic data was incorporated into large scale studies in which FOM efficacy was further explored and proven. Among European nations, intravenous FOM-disodium for patients presenting with soft tissue infections, sepsis or deep seated infectious processes has become well accepted over the last two decades. The recent emergence of bacterial strains, which impede and encumber pharmacotherapy, namely, MRSA, ESBL and MSSA, lends itself to the idea of reviving long-standing, sensibly used antimicrobial agents like FOM. This review provides a comprehensive conspectus on FOM's history, mode of action, tissue penetration characteristics, resistance, antibacterial activity, combination partners and clinical uses among other facets of interest.

Maternal mental disorders have been associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in children. Within the context of a mother-child cohort, we examined whether maternal anxiety, depression and sleep disorders are associated with pre-school ADHD symptoms. The study included 3634 singletons from the Italian NINFEA (Nascita e INFanzia: gli Effetti dell'Ambiente') cohort. Maternal doctor-diagnosed anxiety, depression and sleep disorders before and during pregnancy were assessed from the questionnaires completed during pregnancy and 6 months after delivery. Mothers rated child ADHD symptoms at 4 years of age, according to the Diagnostic and Statistical Manual of Mental Disorders. Hyperactive-impulsive (ADHD-H), inattentive (ADHD-I) and total ADHD scores were analysed in the models adjusted for child's gender, first-born status, maternal age, education, alcohol consumption and smoking during pregnancy. The total ADHD score at age 4 was associated with maternal lifetime anxiety (17.1% percentage difference in score compared with never; 95% CI 7.3-27.9%), sleep disorders (35.7%; 95% CI 10.7-66.5%) and depression (17.5%; 95% CI 3.2-33.8%). Similar positive associations were observed also for ADHD-H and ADHD-I traits, with slightly attenuated associations between maternal sleep disorders and child ADHD-I score, and maternal depression and both ADHD scores. All the estimates were enhanced when the disorders were active during pregnancy and attenuated for disorders active only during the pre-pregnancy period. Maternal anxiety, depression and sleep disorders are associated with a relative increase in the number of ADHD-H, ADHD-I and total ADHD symptoms in preschoolers.

Abstract STUDY QUESTION How did the field of stem cell research develop in the years following the derivation of the first human embryonic stem cell (hESC) line? SUMMARY ANSWER Supported by the increasing number of clinical trials to date, significant technological advances in the past two decades have brought us ever closer to clinical therapies derived from pluripotent cells. WHAT IS KNOWN ALREADY Since their discovery 20 years ago, the use of human pluripotent stem cells has progressed tremendously from bench to bedside. Here, we provide a concise review of the main keystones of this journey and focus on ongoing clinical trials, while indicating the most relevant future research directions. STUDY DESIGN, SIZE, DURATION This is a historical narrative, including relevant publications in the field of pluripotent stem cells (PSC) derivation and differentiation, recounted both through scholarly research of published evidence and interviews of six pioneers who participated in some of the most relevant discoveries in the field. PARTICIPANTS/MATERIALS, SETTING, METHODS The authors all contributed by researching the literature and agreed upon body of works. Portions of the interviews of the field pioneers have been integrated into the review and have also been included in full for advanced reader interest. MAIN RESULTS AND THE ROLE OF CHANCE The stem cell field is ever expanding. We find that in the 20 years since the derivation of the first hESC lines, several relevant developments have shaped the pluripotent cell field, from the discovery of different states of pluripotency, the derivation of induced PSC, the refinement of differentiation protocols with several clinical trials underway, as well as the recent development of organoids. The challenge for the years to come will be to validate and refine PSCs for clinical use, from the production of highly defined cell populations in clinical grade conditions to the possibility of creating replacement organoids for functional, if not anatomical, function restoration. LIMITATIONS, REASONS FOR CAUTION This is a non-systematic review of current literature. Some references may have escaped the experts’ analysis due to the exceedingly diverse nature of the field. As the field of regenerative medicine is rapidly advancing, some of the most recent developments may have not been captured entirely. WIDER IMPLICATIONS OF THE FINDINGS The multi-disciplinary nature and tremendous potential of the stem cell field has important implications for basic as well as translational research. Recounting these activities will serve to provide an in-depth overview of the field, fostering a further understanding of human stem cell and developmental biology. The comprehensive overview of clinical trials and expert opinions included in this narrative may serve as a valuable scientific resource, supporting future efforts in translational approaches. STUDY FUNDING/COMPETING INTEREST(S) ESHRE provided funding for the authors’ on-site meeting and discussion during the preparation of this manuscript. S.M.C.S.L. is funded by the European Research Council Consolidator (ERC-CoG-725722-OVOGROWTH). M.P. is supported by the Special Research Fund, Bijzonder Onderzoeksfonds (BOF01D08114). M.G. is supported by the Methusalem grant of Vrije Universiteit Brussel, in the name of Prof. Karen Sermon and by Innovation by Science and Technology in Flanders (IWT, Project Number: 150042). A.V. and B.A. are supported by the Plataforma de Proteomica, Genotipado y Líneas Celulares (PT1770019/0015) (PRB3), Instituto de Salud Carlos III. Research grant to B.H. by the Research Foundation—Flanders (FWO) (FWO.KAN.2016.0005.01 and FWO.Project G051516N). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable. ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

Study design:  Multi-center pilot study. Objectives: To investigate the use of an upper limb robotic rehabilitation device (Armeo Spring, Hocoma AG, Switzerland) in a subacute cervical spinal cord injury (SCI) population. Setting:  Two Canadian inpatient rehabilitation centers. Methods: Twelve subjects (motor level C4–C6, ASIA Impairment Scale A–D) completed the training, which consisted of 16.1±4.6 sessions over 5.2±1.4 weeks. Two types of outcomes were recorded: (1) feasibility of incorporating the device into an inpatient rehabilitation program (compliance with training schedule, reduction in therapist time required and subject questionnaires) and (2) efficacy of the robotic rehabilitation for improving functional outcomes (Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP), action research arm test, grip dynamometry and range of motion). Results: By the end of the training period, the robot-assisted training was shown to require active therapist involvement for 25±11% (mean±s.d.) of the total session time. In the group of all subjects and in a subgroup composed of motor-incomplete subjects, no statistically significant differences were found between intervention and control limbs for any of the outcome measures. In a subgroup of subjects with partial hand function at baseline, the GRASSP-Sensibility component showed a statistically significant increase (6.0±1.6 (mean±s.e.m.) point increase between baseline and discharge for the intervention limbs versus 1.9±0.9 points for the control limbs). Conclusion: The pilot results suggest that individuals with some preserved hand function after SCI may be better candidates for rehabilitation training using the Armeo Spring device.

Purpose Hearing loss, a complication of cancer treatment, may reduce health-related quality of life (HRQoL), especially in childhood cancer survivors of central nervous system (CNS) tumours who often have multiple late effects. We examined the effect of hearing loss on HRQoL in young survivors of CNS and other childhood cancers. Methods Within the Swiss Childhood Cancer Survivor Study, we sent questionnaires about hearing loss and HRQoL (KIDSCREEN-27) to parents of survivors aged 8–15 years. We stratified the effect of hearing loss on HRQoL by cancer diagnosis, using multivariable logistic regression and adjusting for sociodemographic and clinical factors. Results Hearing loss was associated with impaired physical well-being [unadjusted estimated differences − 4.6 (CI − 9.2, − 0.1); adjusted − 4.0 (CI − 7.6, − 0.3)] and peers and social support [unadjusted − 6.7 (CI − 13.0, − 0.3); adjusted − 5.0 (CI − 10.5, 0.9)] scores in survivors of CNS tumours ( n  = 123), but not in children diagnosed with other cancers (all p -values > 0.20, n  = 577). Conclusion Clinicians should be alert to signs of reduced physical well-being and impaired relationships with peers. Especially survivors of CNS tumours may benefit most from strict audiological monitoring and timely intervention to mitigate secondary consequences of hearing loss on HRQoL.

PurposeDespite the success of ICSI in treating severe male factor infertile patients, total fertilization failure (FF) still occurs in around 1–3% of ICSI cycles. To overcome FF, the use of calcium ionophores has been proposed to induce oocyte activation and restore fertilization rates. However, assisted oocyte activation (AOA) protocols and ionophores vary between laboratories, and the morphokinetic development underlying AOA remains understudied.MethodsA prospective single-center cohort study involving 81 in vitro matured metaphase-II oocytes from 66 oocyte donation cycles artificially activated by A23187 (GM508 CultActive, Gynemed) (n=42) or ionomycin (n=39). Parthenogenesis was induced, and morphokinetic parameters (tPNa, tPNf, t2-t8, tSB, and tB) were compared between the 2 study groups and a control group comprising 39 2PN-zygotes from standard ICSI cycles.ResultsIonomycin treatment resulted in higher activation rates compared to A23187 (38.5% vs 23.8%, p=0.15). Importantly, none of the A23187-activated parthenotes formed blastocysts. When evaluating the morphokinetic dynamics between the two ionophores, we found that tPNa and tPNf were significantly delayed in the group treated by A23187 (11.84 vs 5.31, p=0.002 and 50.15 vs 29.69, p=0.005, respectively). t2 was significantly delayed in A23187-activated parthenotes when compared to the double heterologous control embryo group. In contrast, the morphokinetic development of ionomycin-activated parthenotes was comparable to control embryos (p>0.05).ConclusionOur results suggest that A23187 leads to lower oocyte activation rates and profoundly affects morphokinetic timings and preimplantation development in parthenotes. Despite our limited sample size and low parthenote competence, standardization and further optimization of AOA protocols may allow wider use and improved outcomes for FF cycles.

Objective: To determine the clinical efficacy of functional electrical therapy in the rehabilitation of grasping function for quadriplegics. Study design: Randomized intervention- versus -control trial. Setting: Rehabilitation hospital for spinal cord injury in Toronto, Canada. Methods: A total of 21 people with new spinal cord injuries ranging from C3 to C7 were randomly assigned to two groups: Control ( N =9) and Intervention ( N =12). The intervention was functional electrical therapy, which consisted of repetitive grasping exercises using a neuroprosthesis that applied surface electrical stimulation to the arm to generate and/or assist grasping movements. It was applied by registered Occupational Therapists in a clinical setting. Main outcome measures were: Functional Independence Measure (FIM), Spinal Cord Independence Measure (SCIM), and the Rehabilitation Engineering Laboratory Hand Function Test. Consumer perceptions of functional electrical therapy were assessed via qualitative interviews. Results: Differences between the Control and Intervention groups could be observed although they are not significant due to an insufficient number of participants. Consumer perceptions were positive, including improved Activities of Daily Living and self-satisfaction. Conclusion: Functional electrical therapy has the potential to be an effective treatment modality to restore grasping function in quadriplegia. It can be implemented by occupational therapists in a clinical setting. Further research is required to establish suitable indications for participant selection. In addition, a larger number of participants is needed to demonstrate statistical significance of the Functional Electrical Therapy.