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To perform the first systematic review of all available GAS publications across all procedures to assess outcomes reported in the literature and the methods used for outcome assessment.Assessment of GAS results is complex and multidimensional, involving not only complication rates but also anatomic (eg, vaginal depth), functional (eg, urinary), and psychosocial outcomes. A fully comprehensive aggregation of all prior research would offer an essential cornerstone for continued progress.A systematic review was performed after PRISMA guidelines to identify all outcomes measures in GAS cohorts, including patient-centered outcomes, complications, and functional outcomes. Data were aggregated to assess pooled rates of complications, satisfaction, and other outcomes.Overall, 15,186 references were identified, 4162 papers advanced to abstract review, and 1826 underwent full-text review. After review, there were 406 GAS cohort publications, including 171 vaginoplasty, 82 phalloplasty, 16 metoidioplasty, 23 oophorectomy/vaginectomy, and 21 with multiple procedures.Although 68.7% of genitoplasty papers addressed patient-centered outcomes, only 1.0% used metrics validated in the transgender population. Forty-three different outcome instruments were used. No instrument was used in more than 15% of published series and 38 were used in only 1 or 2 publications.Our review found high patient satisfaction for genital procedures but little concordance between study methods, with almost 90% of patient-focused outcome metrics appearing only once or twice. Standardization of outcome instruments and measurement methods through patient-inclusive, multidisciplinary consensus efforts is the essential next step for quality improvement. As GAS continues to mature, building on current foundations with the goal of improving both surgical and patient-reported outcomes is essential.

Stress-activated p38 kinases control a plethora of functions and their dysregulation has been linked to development of steatosis, obesity, immune disorders and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here we demonstrate that lack of MKK6 reduces the life span in mice. Longitudinal study of cardiac function in Mkk6-/- mice showed that young mice have cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mTOR signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in Mkk6-/- mice is reverted by knocking out either p38γ or p38δ, or by inhibiting mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.eLife’s Review ProcesseLife works to improve the process of peer review so that it more effectively conveys the assessment of expert reviewers to authors, readers and other interested parties. In the future we envision a system in which research is first published as a preprint and the outputs of peer review are the primary way research is assessed, rather than journal title.Our editorial process produces two outputs: i) an assessment by peers designed to be posted alongside a preprint for the benefit of the readers; ii) detailed feedback on the manuscript for the authors, including requests for revisions and suggestions for improvement.Therefore we want to change how we construct and write peer reviews to make them useful to both authors and readers in a way that better reflects the work you put into reading and thinking about a paper.eLife reviews now have three parts: An evaluation summary (in two or three sentences) that captures the major conclusions of the review in a concise manner, accessible to a wide audience.A public review that details the strengths and weaknesses of the manuscript before you, and discusses whether the authors’ claims and conclusions are justified by their data.A set of private recommendations for the authors that outline how you think the science and its presentation could be strengthened.All three sections will be used as the basis for an eLife publishing decision, which will, as always, be made after a consultation among the reviewers and editor. Each of the public reviews will be published (anonymously) alongside the preprint, together with a response from the authors if they choose. In the case of papers we reject after review, the authors can choose to delay posting until their paper has been published elsewhere.If this is your first time going through this new process, we ask that you take some time to read our Reviewer Guide, which discusses how we see each section will be used, what it should contain, and what we hope it accomplishes. And we remind you that, with the shift of reviews from private correspondence to public discourse, it is more important than ever that reviews are written in a clear and constructive manner appropriate for a public audience and mindful of the impact language choices might have on the authors.

Background How contextual factors may influence GP decisions in real life practice is poorly understood. The authors have undertaken a scoping review of antibiotic prescribing in primary care, with a focus on the interaction between context and GP decision-making, and what it means for the decisions made. Method The authors searched Medline, Embase and Cinahl databases for English language articles published between 1946 and 2019, focusing on general practitioner prescribing of antibiotics. Articles discussing decision-making, reasoning, judgement, or uncertainty in relation to antibiotic prescribing were assessed. As no universal definition of context has been agreed, any papers discussing terms synonymous with context were reviewed. Terms encountered included contextual factors, non-medical factors, and non-clinical factors. Results Three hundred seventy-seven full text articles were assessed for eligibility, resulting in the inclusion of 47. This article documented the experiences of general practitioners from over 18 countries, collected in 47 papers, over the course of 3 decades. Contextual factors fell under 7 themes that emerged in the process of analysis. These were space and place, time, stress and emotion, patient characteristics, therapeutic relationship, negotiating decisions and practice style, managing uncertainty, and clinical experience. Contextual presence was in every part of the consultation process, was vital to management, and often resulted in prescribing. Conclusion Context is essential in real life decision-making, and yet it does not feature in current representations of clinical decision-making. With an incomplete picture of how doctors make decisions in real life practice, we risk missing important opportunities to improve decision-making, such as antibiotic prescribing.

A systematic review of studies providing evidence of the linkage between human factors (HF) in the design and management of operations to production quality performance was conducted. 71 peer reviewed research papers were found to provide evidence of the HF-Quality relationship. These studies identified 178 design factors relating to quality. These included 1) Product Design (54), 2) Production Process Design (75), and 3) Workstation Design aspects (49). In addition 26 Individual quality risk factors were identified. Of the studies identified, about half studied the effects on the human finding associations with the operator workload and fatigue indicators and quality performance. These intermediary variables may provide insight into the mechanism by which HF flaws in the design of production lead to quality deficits in running manufacturing. These results provide useful information for operations managers and production system design teams to secure higher quality performance in their systems by applying human factors.

Co-authors received external funding linked to the project, but these are non-UK based and not at DMU. The financial support from the National Natural Science Foundation of China (No.72174163, No. 71974026, No. 71804140 and No. 71672138) is gratefully acknowledged. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Where venture capitalists have traditionally focused on early-stage innovative firms, increasingly venture capitalists are investing in late-stage firms, especially in Asia. The performance consequences of this novel phenomenon of late-stage venture capital remain unexplored. This paper provides novel insight into this phenomenon by examining the impact of late-stage venture capital on two key dimensions of firm performance in the venture capital literature: innovation and financial performance. We link VC investment events to financial indicators of Chinese listed firms to account for the timing of VC entry and identify the firm performance impacts. Utilizing a matching and difference-in-differences procedure to account for selection biases, our results show that late-stage venture capital improves investee firms’ financial performance but reduces their innovation performance. Our findings advance understanding about the emergence of late-stage venture capital and its performance consequences, especially in emerging economies. Our work has implications for entrepreneurs and policymakers.

We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information.

Highlights • Dietary pattern is poorer among children of employed mothers. • Children of employed mothers are more physically active. • Children of employed mothers experience greater prevalence of sedentary activity., Since approximately 40% of the global workforce are women, a comprehensive understanding of association of maternal employment with child dietary patterns, physical activity and sedentary behaviour needs more focus. This systematic review aims to identify the association between maternal employment and dietary patterns (DP), physical activity (PA) and sedentary behaviour (SB) of children and adolescents (6 to 18 years). Searches were performed using electronic databases and manual searches. Peer reviewed journal articles, conference papers, theses at masters/doctoral levels in English were included. A total 42 studies met selection criteria, which indicated associations between maternal employment and at least one of the domains of interest: DP, PA and/or SB. Using individual samples of analysis, it was found that, 9 samples of DP, 11 samples of PA and 12 samples of SB were positively correlated with maternal employment, whereas 25 samples of DP, 5 samples of PA and 5 samples of SB showed an opposite association. Results suggest that PA and SB were positively related with maternal employment, whereas DP had an inverse relationship. Findings from this review provide evidence that children of employed mothers had poorer DP and greater prevalence of SB, however, their children are more physically active. Future interventions need to create a positive environment at the workplace and for families to support employed mothers and improve children’s dietary patterns and decrease sedentary behaviours. Future studies should prioritise the domains of DP, PA and SB that have been studied inadequately and have inconsistent results.

Reports of "positive" results in early phase trials as presented at ASH presumably herald therapeutic advances, or at a minimum, a larger, potentially confirmatory, randomized trial. However, the predictive value of an ASH abstract reporting positive results in AML for subsequent clinical utility seems low (Estey 2006, ASH). Furthermore, not all results presented at ASH are published in peer-reviewed journals, and selectively publishing positive results leads to publication bias. Moreover, truly negative studies may be scientifically more rigorous and accurate than positive studies given the unequivocal findings. The extent of publication bias is unknown as is the frequency with which positive or negative abstracts lead to subsequent investigation in phase III and the reasons why positive phase II studies might not progress to phase III. We downloaded all 2013 - 2015 ASH abstracts (N = 17,251) and evaluated all abstracts reporting phase II clinical trials (N = 371) of novel drugs and therapeutic regimens presented at ASH in these years, covering investigational treatments of MM, CLL, AML, DLBCL, MDS, NHL, ALL, CML, MCL, SLL, other lymphomas and POEMS. We first scored abstracts "positive", "negative" or "inconclusive". Criteria for a positive abstract were words/phrases such as "encouraging", "promising", "could represent a novel therapeutic option" and "warrants investigation in a randomized trial". Negative abstracts included terms such as "does not support further research" and "demonstrates no clinical activity". The remainder were scored as inconclusive. Using this approach, we scored 296/371 (80%) abstracts as positive, 37/371 (10%) as negative, and 38/371 (10%) as inconclusive. 292/371 abstracts (79%) were published in peer-reviewed journals. The abstract conclusion (positive, negative or inconclusive) was not associated with publication in a peer-reviewed journal. Most frequently, studies were published in Blood (34/292 [11.6%]) and British Journal of Haematology (39/292 [13.4%]) . In Blood, 91% (31/34) of the studies were positive. British Journal of Haematology published significantly more negative studies than Blood (26%, Fisher Exact p = 0.02). Abstracts reporting studies with larger sample sizes tended to be published more often (p = 0.066). Differences exist between the abstract conclusion and later peer-reviewed publications. Of positive ASH abstracts, 6% changed to a negative conclusion in the peer-reviewed publication. Similarly, 6.5% of the initial negative abstract later reversed to a positive conclusion. 53% of positive abstracts did not lead to phase III studies, as registered on clinicaltrials.gov. Subsequently, regimens described in positive peer-reviewed publications did not proceed to phase III research in 48%. To explore why, we sent questionnaires to the first and/or last authors of positive studies not prompting phase III trials. 52% responded. Failure of positive phase II trials to proceed to phase III was due to the decision by the pharmaceutical company to halt clinical investigation (44%), lack of any intent to study the drug in phase III in the first place (40%), insufficient funding (35%), insufficient efficacy (despite the "positive" abstract; 33%) and safety concerns (4%) (Figure). Additional reasons for not proceeding to phase III were the availability of newer regimens, the rarity of the disease, or when regulatory approval had already been obtained after phase II. In conclusion, "positive" and "negative" ASH abstracts are published as full papers equally often, although the positive ones may be published more often in journals with higher "impact factors". More than half of the regimens presented in positive ASH abstracts remain unevaluated in randomized phase III trials. A separate problem is the likely tendency to disproportionately submit (and/or accept) positive, rather than negative, studies to ASH in the first place. We believe our findings raise issues in clinical research that may not be in the best interest of patients. This demands more consideration than it currently receives. Figure 1 Figure 1. Disclosures Ossenkoppele: Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Rowe: Biosight Inc.: Consultancy.

Objective Midwifery philosophy and practice is grounded in providing woman-centred care. The available evidence was reviewed to better understand how to provide Woman-centred midwifery care in complex pregnancy situations. Complexity in this context is defined as psychosocial or biomedical risk factors that place the mother and/or her baby at increased risk for adverse outcomes. Design A comprehensive integrative review was undertaken to identify peer reviewed research in English over the last 5 years. The quality of the studies was assessed using the Critical Appraisal Skills Programme Tool. Setting/Participants Published studies which discussed enablers and barriers to woman-centred care for pregnant women with complex needs. 13 papers met the inclusion criteria for this review. Findings This review identifies that Organisational and Professional power differentials create barriers to woman-centred care and provoke professional boundary tensions. For a woman with a complex pregnancy, this places her at risk for ‘falling through the gaps’ between maternity services, models of care and health providers. Key conclusions Women, birth and midwifery care are still largely constrained within a biomedical model of maternity care. Whilst barriers to woman-centred care have been identified, for women with complexity in pregnancy there appear to be few solutions when care requires multi-specialist input and crossing the boundaries and silos of healthcare.