The importance of access to healthcare for all is internationally recognised as a global goal, high on the global agenda. Yet inequalities in health exist within and between countries which are exacerbated by inequalities in access to healthcare. In order to address these inequalities, we need to better understand what drives them. While there exists a wealth of research on access to healthcare in different countries and contexts, and for different patient groups, to date no attempt has been made to bring this evidence together through a global lens. This study aims to address that gap by bringing together evidence of what factors affect patients’ access to healthcare and exploring how those factors vary in different countries and contexts around the world. An overview of reviews will be conducted using a comprehensive search strategy to search four databases: Medline, Embase, Global Health and Cochrane Systematic Reviews. Additional searches will be conducted on the Gates Foundation, the World Health Organisation (WHO) and World Bank websites. Titles and abstracts will be screened against the eligibility criteria and full-text articles will be obtained for all records that meet the inclusion criteria or where there is uncertainty around eligibility. A data extraction table will be developed during the review process and will be piloted and refined before full data extraction commences. Methodological quality/risk of bias will be assessed for each included study using the AMSTAR 2 tool. The quality assessment will be used to inform the narrative synthesis, but a low-quality score will not necessarily lead to study exclusion. Factors affecting patients’ ability to access healthcare will be identified and analysed according to different country and context characteristics to shed light on the importance of different factors in different settings. Results will be interpreted accounting for the usual challenges associated with conducting such reviews. The results may guide future research in this area and contribute to priority setting for development initiatives aimed at ensuring equitable access to healthcare for all. PROSPERO CRD42019144775

It was well-known that Berberine, a major bioactive compound extracted from natural plants Coptis chinensis, has anti-diabetic effects for decades in china. Other types of pharmacological activities, such as anti-inflammatory, antimicrobial, hypolipidemic, and anti-cancer effects, have also been examined. At cellular level, these pharmacological activities were mostly an inhibitory effect. However, the cytoprotective effect of berberine was also observed in various types of cells, such as neurons, endothelial cells, fibroblasts, and β-cells. The paradoxical result may be closely associated with characteristics and distribution of berberine within cells, and they can be explained mechanically by mitohormesis, one particular form of hormesis. Here, we reviewed the mitohormetic response and assessed the berberine-induced effects and the possible signaling pathway involved. These findings may contribute to better clinical applications of berberine and indicate that some mitochondria-targeted conventional drugs should be considered carefully in clinical application.

We have previously shown that HCC patients and healthy subjects are equally responsive to a RNAdjuvant®, a novel TLR-7/8/RIG-I agonist based on noncoding RNA developed by CureVac, by an ex vivo evaluation. However, the immunological effect of adjuvants on immune cells from cancer patients undergoing chemotherapy remains to be demonstrated. Different adjuvants currently used in cancer vaccine clinical trials were evaluated in the present study on immune cells from cancer patients before and after chemotherapy in an ex vivo setting. PBMCs were obtained from 4 healthy volunteers and 23 patients affected by either colon (OMA) or lung cancer (OT). The effect of CpG, Poly I:C, Imiquimod and RNA-based adjuvant (RNAdjuvant®) was assessed using a multiparametric approach to analyze network dynamics of early immune responses. Evaluation of CD80, CD86 and HLA-DR expression as well as the downstream effect on CD4+ T cell phenotyping was performed by flow cytometry; cytokine and chemokine production was evaluated by Bio-Plex ProTM. Treatment with RNAdjuvant® induced the strongest response in cancer patients in terms of activation of innate and adoptive immunity. Indeed, CD80, CD86 and HLA-DR expression was found upregulated in circulating dendritic cells, which promoted a CD4+ T cell differentiation towards an effector phenotype. RNAdjuvant® was the only one to induce most of the cytokines/chemokines tested with a pronounced Th1 cytokine pattern. According to the different parameters evaluated in the study, no clear cut difference in immune response to adjuvants was observed between healthy subjects and cancer patients. Moreover, in the latter group, the chemotherapy treatment did not consistently correlate to a significant altered response in the different parameters. The present study is the first analysis of immunological effects induced by adjuvants in cancer patients who undergo chemotherapy, who are enrolled in the currently ongoing cancer vaccine clinical trials. The results show that the RNAdjuvant® is a potent and Th1 driving adjuvant, compared to those tested in the present study. Most importantly, it is demonstrated that chemotherapy does not significantly impair the immune system, implying that cancer patients are likely to respond to a cancer vaccine even after a chemotherapy treatment.

Recently, involvement of IL-19, IL-20 and IL-24 has been reported in inflammatory diseases associated with tissue remodeling. However, their impact on the pathomechanism of coeliac disease (CD) is still completely unknown. Expression of IL19, IL20 and IL24 was measured by real-time RT-PCR, protein amount of IL-24, α smooth muscle actin (α-SMA) and fibronectin (FN) was determined by Western-blot analysis in the duodenal biopsies of therapy naive children with CD and controls. Localization of IL-24 and IL-20RB was investigated by immunofluorescent staining in the duodenal mucosa. Effect of recombinant IL-1β, TNF-α, TGF-β and IL-17 treatment on the expression of IL19, IL20, IL24 and their receptors was investigated by real-time RT-PCR in small intestinal epithelial cells (FHs74Int), in primary duodenal myofibroblasts (pdMFs) and in peripheral blood mononuclear cells (PBMCs). Effect of IL-24 on H2O2 treated FHs74Int cells and on pdMFs was measured by MTT, LDH, Annexin V assays, real-time RT-PCR and by fluorescent microscopy. We found increased level of IL-24 (3.3×, p < 0.05), α-SMA (2.4×, p < 0.05) and FN (2.3×, p < 0.05) in the duodenal mucosa and increased expression of IL19 (3.6×, p < 0.05) and IL24 (5.2×, p < 0.05) in the PBMCs of children with CD compared to that of controls. IL-1β was a strong inducer of IL24 expression of FHs74Int cells (9.9×, p < 0.05), pdMFs (552.9×, p < 0.05) or PBMCs (17.2×, p < 0.05), as well. IL-24 treatment reduced the number of apoptotic cells (0.5×, p < 0.05) and decreased the expression of inflammatory factors, including IL1A, IL6 and TNF of H2O2-treated FHs74Int cells. IL-24 decreased the proliferation (0.6×, p < 0.05) of PDGF-B treated pdMFs. Moreover, IL-24 treatment altered the morphology of pdMFs by influencing the size of the angles between stress fibers and the longitudinal axis of the cells (2.0×, p < 0.05) and the expression of cytoskeletal components, including ACTA2, ACTB, VIM, SNAI1 and SNAI2. Our results suggest that IL-24 plays a significant role in the maintenance of duodenal mucosal integrity in CD.

Anxiety disorders are the most prevalent class of lifetime disorders in China, and generalized anxiety disorder (GAD) is one of the most common but frequently overlooked anxiety disorders. Conventional pharmacological treatments for GAD have varying degrees of side effects, dependency, and/or withdrawal syndromes. Traditional Chinese medicine (TCM) is considered a valuable therapeutic option for anxiety disorders and a potentially effective technique to reduce the side effects associated with antipsychotic drugs. This trial aimed to evaluate the clinical efficacy and safety of Antianxiety Granule, a granular Chinese medicine compound, for treatment of GAD. The current work is a multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial with a 6-week treatment schedule. The study consists of three periods: a 1–7-day screening period, a 6-week primary treatment period, and a 1-week follow-up period. Follow-up assessments will be conducted 1 week after the last visit with a face-to-face interview or by telephone. The clinical efficacy of Antianxiety Granule for the treatment of GAD will be evaluated by examining the change in the Hamilton anxiety scale (HAMA) score, state-trait anxiety inventory (STAI) score, and TCM symptom scale in patients with GAD who receive daily TCM treatment. Moreover, an intention-to-treat (ITT) analysis will also be used in this randomized controlled trial (RCT). Our study is a multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the safety and efficacy of Antianxiety Granule for the treatment of GAD. The results of this trial will provide valuable clinical evidence for the treatment of GAD. Chinese Clinical Trial Registry, ChiCTR1800016039. Registered on 8 May 2018.

Voluntary medical male circumcision (VMMC) is a key component of combination HIV-prevention programmes. Several high-HIV-prevalence countries in sub-Saharan Africa, including Zimbabwe, are looking to scale up VMMC activities. There is limited evidence on how a combination of social learning from peer education by a role model with different behavioural incentives influences demand for VMMC in such settings. This matched-cluster randomised controlled trial with 1740 participants will compare two behavioural incentives against a control with no intervention. In the intervention clusters, participants will participate in an education session delivered by a circumcised young male (“role model”) on the risks of HIV infection and the benefits from medical male circumcision. All participants will receive contributions towards transport costs to access medical male circumcision at participating clinics. Via blocked randomisation, in the intervention clusters participants will be randomly assigned to receive one of two types of incentives – fixed cash payment or lottery payment – both conditional on undergoing surgical VMMC. In two sites, a community-led intervention will also be implemented to address social obstacles and to increase support from peers, families and social structures. Baseline measures of endpoints will be gathered in surveys. Follow-up assessment at 6 months will include self-reported uptake of VMMC triangulated with clinic data. This is the first trial to pilot-test social learning to improve risk perception and self-efficacy and to address the fear of pain associated with VMMC and possible present-biased preferences with front-loaded compensations as well as fixed or lottery-based cash payments. This study will generate important knowledge to inform HIV-prevention policies about the effectiveness of behavioural interventions and incentives, which could be easily scaled-up. This trial has been registered on ClinicalTrials.gov (identifier: NCT03565588). Registered on 21 June 2018.

Point OutWords is a caregiver-delivered, iPad-assisted intervention for non-verbal or minimally verbal children with autism. It aims to develop prerequisite skills for communication such as manual and oral motor skills, sequencing, and symbolic representation. This feasibility trial aims to determine the viability of evaluating the clinical efficacy of Point OutWords. We aim to recruit 46 non-verbal or minimally verbal children with autism and their families, approximately 23 per arm. Children in the intervention group will use Point OutWords for half an hour, five times a week, for 8 weeks. Children in the control group will have equal caregiver-led contact time with the iPad using a selection of control apps (e.g. sensory apps, drawing apps). Communication, motor, and daily living skills are assessed at baseline and post-intervention. Parents will keep diaries during the intervention period and will take part in focus groups when the intervention is completed. Point OutWords was developed in collaboration with children with autism and their caregivers, to provide an intervention for a subgroup of autism that has been historically underserved. As autism is a heterogeneous condition, it is unlikely that one style of intervention will address all aspects of its symptomatology; the motor skills approach of Point OutWords can complement other therapies that address core autistic symptoms of social cognition and communication more directly. The current feasibility trial can inform the selection of outcome measures and design for future full-scale randomised controlled trials of Point OutWords and of other early interventions in autism. ISRCTN, ISRCTN12808402. Prospectively registered on 12 March 2019.

A cluster-Randomised Controlled Trial evaluation of the impact of the Community Health Clubs (CHCs) in the Community Based Environmental Health Promotion Programme in Rwanda in 2015 appeared to find little uptake of 7 hygiene indicators 1 year after the end of the intervention, and low impact on prevention of diarrhoea and stunting. Monitoring data was revisited through detailed community records with all the expected inputs, outputs and external determinants analysed for fidelity to the research protocol. Five household inventory observations were taken over a 40-month period including 2 years after the end of the cRCT in a random selection of the 50 intervention CHCs and data compared to that of the trial. Focus Group Discussion with all Environmental Health Officers of the Ministry of Health provided context to understand the long-term community dynamics of hygiene behaviour change. It was found that the intervention had been jeopardised by external determinants with only 54% fidelity to protocol. By the end of the designated intervention period in June 2014, the treatment had reached only 58% of households with 41% average attendance at training sessions by the 4056 registered members and 51% mean completion rate of 20+ sessions. Therefore only 10% of 50 CHCs provided the full so-called ‘Classic’ training as per-protocol. However, sustainability of the CHCs was high, with all 50 being active 2 years after the end of the cRCT and over 80% uptake of recommended practices of the same 7 key indicators as the trial was achieved by 2017. The cRCT conclusion that the case study of Rusizi District does not encourage the use of the CHC model for scaling up, raises concerns over the possible misrepresentation of the potential of the holistic CHC model to achieve health impact in a more realistic time frame. It also questions the appropriateness of apparently rigorous quantitative research, such as the cluster-Randomised Controlled Trial as conducted in Rusizi District, to adequately assess community dynamics in complex interventions.

Social engagement forms the basis of social relationships by providing a sense of belonging, social identity, and fulfillment. Previous research demonstrates that social engagement was associated with positive health behaviors among older adults. However, the results have been different across health-related behaviors, and mostly based on data from high-income countries. For example, studies from the US and UK showed that social engagement was protective against smoking, while others found social engagement encouraged more smoking in many Asian cultures. In this study, we aim to examine the association between social engagement and a range of health-related behaviors and subjective well-being among older adults in six low- to middle-income countries. Data from the WHO Study on Global Ageing and Adult Health (SAGE Wave 1) were used. A total of 33,338 individuals aged 50 and older in China, Russia, India, Ghana, South Africa, and Mexico were included. Social engagement, tobacco use, alcohol consumption, fruit and vegetable intake, physical activity, sedentary behavior, sleep duration, depression symptoms, self-rated health status, and quality of life were assessed using established self-reported measures. Multiple logistic regression models were used to examine the relationship between social engagement and nine outcome variables, adjusting for socio-demographic characteristics. Lower levels of social engagement were positively related to physical inactivity, prolonged sitting time, unhealthy sleep duration, perceived depression, poor self-rated health, and low quality of life. However, the associations between social engagement and tobacco use, excessive drinking, and insufficient fruit and vegetable intake were mixed across countries. This international study found high social engagement as a potential health-promoting factor in some low- to middle-income countries. Although the impacts of social engagement on tobacco and alcohol use and diet were complicated and culture-specific, interventions at both individual and community levels should encourage healthy lifestyles through positive social engagement.

Routine immunization programs face many challenges in settings such as Papua New Guinea with dispersed rural populations, rugged geography and limited resources for transport and health. Low routine coverage contributes to disease outbreaks such as measles and the polio that re-appeared in 2018. We report on an in-depth local assessment that aimed to document immunization service provision so as to review a new national strategy, and consider how routine immunization could be better strengthened. In East New Britain Province, over 2016 and 17, we carried out a cross-sectional assessment of 12 rural health facilities, staff and clients. The study was timed to follow implementation of a new national strategy for strengthening routine immunization. We used interview, structured observation, and records review, informed by theory-based evaluation, a World Health Organization quality checklist, and other health services research tools. We documented strengths and weaknesses across six categories of program performance relevant to national immunization strategy and global standards. We found an immunization service with an operational level of staff, equipment and procedures in place; but one that could reach only half to two thirds of its target population. Stronger routine services require improvement in: understanding of population catchments, tracking the unvaccinated, reach and efficiency of outreach visits, staff knowledge of vaccination at birth and beyond the first year of life, handling of multi-dose vials, and engagement of community members. Many local suggestions to enhance national plans, included more reliable on-demand services, integration of other family health services and increased involvement of men. The national strategy addresses most local gaps, but implementation and resourcing requires greater commitment. Long-term strengthening requires a major increase in centrally-allocated resources, however there are immediate locally feasible steps within current resources that could boost coverage and quality of routine immunization especially through better population-based local planning, and stronger community engagement. Our results also suggest areas where vaccination campaigns in PNG can contribute to routine immunization services.

It was highlighted that the original article [1] contained a spelling mistake in the name of Hamid R. Baradaran. This was incorrectly captured as Bradaran. The original article has been updated.

In recent years, much effort has been made in determining the clinical outcomes of infertility treatment. In 2013, consensus was reached that the preferred primary outcome of all infertility treatment trials is the live birth rate or cumulative live birth rate [1]. Smith et al. [2] compared a segmented versus non-segmented in vitro fertilization (IVF) cycle with the primary outcome of cumulative live birth, an important outcome to comprehensively assess the effectiveness of an IVF cycle [3]. However, the cumulative live birth rate requires a long period of follow-up until all embryos have been transferred. Furthermore, in addition to the fact that studies employ different lengths for follow-up, there are varying methods to calculate the numerator and denominator of the cumulative live birth rate [3]. As Smith et al. highlighted, frozen embryo transfer has become an integral component of IVF following the refinement of the technique for embryo cryopreservation and is being increasingly used in the clinic. Nevertheless, whether frozen embryo transfer is better than fresh embryo transfer has recently become a major topic of investigation, with several studies of varying primary outcomes being conducted. Study findings Elective freezing of all embryos and the performance of a frozen embryo transfer, also known as a freeze-only strategy, has been demonstrated by randomized trials to result in a higher rate of live births in women with polycystic ovary syndrome [4] and in ovulatory women who undergo single blastocyst transfer [5] compared with a fresh embryo transfer. Nevertheless, most of the available evidence regarding the cumulative live birth rate after a freeze-only strategy compared with a fresh embryo transfer strategy is from observational studies [6, 7], including the current study by Smith et al. [2]. This study [2] represents the power of ‘big data’ to illuminate many aspects of fresh versus frozen embryo transfer, and the authors should be lauded for their thorough and exhaustive analysis of the Human Fertilisation and Embryology Authority database. The authors found that a segmented IVF cycle was associated with a 20% lower rate of cumulative live birth, compared to a non-segmented cycle, after adjusting for confounders. The decrease in the cumulative live birth rate after frozen embryo transfer was attributed to a partial reduction in the number of embryos after freezing and thawing as well as the lack of optimal regimens for endometrial preparation. Thus, their findings question the rationale of a freeze-only strategy. However, during the study period, most clinics used a slow freezing method to cryopreserve the embryos at the cleavage stage, suboptimal compared to the currently widely used method of vitrification of embryos at the blastocyst stage. Additionally, no rationale to freeze all embryos was recorded in the study, likely due to medical reasons such as high risk of ovarian hyperstimulation syndrome (OHSS), prematurely elevated progesterone, a thin endometrium, or other medical comorbidities. Thus, the scenarios assessed by Smith et al. [2] are different from the current elective freeze-only strategy, through which patients can opt for a freeze-only approach without necessarily meeting the abovementioned comorbidities. It cannot be ruled out the difference in prognosis of the study population may contribute to the difference in the rate of cumulative live birth. Additionally, results from different studies are inconsistent, with some reporting that a freeze-only strategy resulted in a similar rate of cumulative live birth compared with a fresh embryo transfer strategy [4, 5, 8]. Furthermore, as clinicians, we must frame the full view of the risk-to-benefit ratio of a treatment. If we informed a patient that segmented IVF could significantly reduce the major causes of perinatal morbidity and mortality, that is, severe prematurity (by 24%) and small-for-gestational-age (by 36%), she may accept a 20% reduction in the cumulative live birth rate since her ultimate goal is a healthy baby. More importantly, we must consider all maternal complications of the therapies to fully estimate the risk-to-benefit ratio. Smith et al. [2] found that a freeze-only strategy was associated with a higher risk of macrosomia and large-for-gestational-age as well as a lower risk of low birth weight and small-for-gestational-age babies. However, whether such an increase in birthweight is negative or positive for the long-term health of the offspring remains unknown. Additionally, a freeze-only approach has been associated with a lower risk of OHSS, but a higher risk of pre-eclampsia [4, 5]. A weakness of the study of Smith et al. [2] was that OHSS and pre-eclampsia data were not collected and thus not analyzed. We cannot make a recommendation without knowing the risks to the mother. Thus, when the authors concluded that application of a freeze all embryos strategy “should be restricted to those with a clinical indication” [2], we concur it is still premature to apply a freeze-only strategy to an unselected population, but disagree with using level 2 evidence, or what the Oxford Center for Evidence-Based Medicine Levels of Evidence scale would grade as 2b evidence (equivalent to a low quality randomize controlled trial by that scale), for that conclusion. Based on level 2 evidence we would still recommend a combined hormone replacement therapy to all postmenopausal women to prevent cardiovascular disease [9]; such recommendations were ultimately refuted by level 1b evidence (i.e., a high quality randomized controlled trial) with the publication of the primary outcome of the Women’s Health Initiative [10]. In the future, as the authors also supported in their discussion, further studies, especially hypothesis-driven, high-quality randomized controlled trials, are needed to confirm the effectiveness of an elective freeze-only strategy, replicated by other similar trials, ultimately followed by their synthesis into meta-analyses forming level 1a evidence. However, since this requires years of follow-up until all embryos are used, it is difficult to design randomized trials with the cumulative live birth rate as the primary outcome unless a reasonable time period for follow-up is accepted and followed (we chose 1 year for our studies). The benefits and risks of a freeze-only strategy remain inconsistent and relatively unknown. Further level 1 studies are needed before we apply this technique to the general population. Not applicable. 1. Legro RS, Wu X, Barnhart KT, Farquhar C, Fauser BC, Mol B. Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement. Hum Reprod. 2014;29:2075–82. Article Google Scholar 2. Smith ADAC, Tilling K, Lawlor DA, Nelson SM. Live birth rates and perinatal outcomes when all embryos are frozen compared with conventional fresh- and frozen-embryo transfer: a cohort study of 337,148 in vitro fertilisation cycles. BMC Med. 2019;17:202. https://doi.org/10.1186/s12916-019-1429-z. Article PubMed PubMed Central Google Scholar 3. Maheshwari A, McLernon D, Bhattacharya S. Cumulative live birth rate: time for a consensus? Hum Reprod. 2015;30:2703–7. PubMed Google Scholar 4. Chen ZJ, Shi Y, Sun Y, et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375:523–33. Article Google Scholar 5. Wei D, Liu JY, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393:1310–8. Article Google Scholar 6. Polyzos NP, Drakopoulos P, Parra J, et al. Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including approximately 15,000 women. Fertil Steril. 2018;110:661–70. Article Google Scholar 7. Zaca C, Bazzocchi A, Pennetta F, Bonu MA, Coticchio G, Borini A. Cumulative live birth rate in freeze-all cycles is comparable to that of a conventional embryo transfer policy at the cleavage stage but superior at the blastocyst stage. Fertil Steril. 2018;110:703–9. Article Google Scholar 8. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019;25:2–14. Article Google Scholar 9. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991;325:756–62. CAS Article Google Scholar 10. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–33. CAS Article Google Scholar Download references None. Funding None. Affiliations Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250001, China Daimin Wei  & Zi-Jiang Chen Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA, 17033, USA Richard S. LegroAuthors Search for Daimin Wei in: PubMed • Google Scholar Search for Richard S. Legro in: PubMed • Google Scholar Search for Zi-Jiang Chen in: PubMed • Google Scholar Contributions ZJC was approached and invited for the Commentary. DW wrote the first draft. RSL substantially revised the manuscript. All authors read and approved the final manuscript. Corresponding author Correspondence to Zi-Jiang Chen. Ethics approval and consent to participate Not applicable. Consent for publication All the authors consent to publication. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Please see related article: https://doi.org/10.1186/s12916-019-1429-z Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Wei, D., Legro, R.S. & Chen, Z. The cumulative live birth rate after a freeze-only strategy versus a conventional fresh embryo transfer strategy: a call for more level 1 evidence. BMC Med 18, 12 (2020). https://doi.org/10.1186/s12916-019-1479-2 Download citation Received: 22 November 2019 Accepted: 09 December 2019 Published: 23 January 2020 DOI: https://doi.org/10.1186/s12916-019-1479-2 Keywords Freeze-only strategy Cumulative live birth In vitro fertilization

Abstract Primary hydatid cysts typically occur in the lungs or the liver, but can be found elsewhere without involving these organs. Primary bone cysts are rare and frequently missed. No standard treatment exists, especially for inoperable patients. A 53-year-old female patient with pain and swelling in the left gluteal region for a month was first admitted 3 years ago, with an initial diagnosis of DVT. Incidentally, magnetic resonance imaging showed cystic involvement of the pelvis, and an iliac bone biopsy suggested a diagnosis of hydatidosis. The cyst was inoperable, and praziquantel and albendazole chemotherapy was initiated. The patient was followed after 3 years, having a palpable 12 × 9 cm mass and showing minor radiographic changes. We report an unusual and inoperable case of primary bone hydatid cyst, with involvement of pelvic bones and surrounding soft tissue. This case suggests that cystic mass, especially where disease is endemic, should raise suspicion of echinococcosis. The chemotherapy regimen appears to have limited the growth of the cysts.

In January 1971, a young biologist braved strong currents to dive on a massive spawning aggregation (gathering of reproductive adults) of Nassau grouper (family Epinephelidae) at Cat Cay in The Bahamas. The paper he published was the first-ever eye-witness account in the scientific literature describing a spectacular gathering of 30,000 to 100,000 large adult Nassau grouper (Epinephelus striatus) preparing to spawn (1). Historically, this grouper was among the most important fishery species in the tropical western Atlantic, with earlier accounts also documenting abundance during its reproductive season (2⇓⇓⇓–6). In 2003, barely 30 y after Lavett-Smith’s (1) account, the species was listed as threatened on the International Union for Conservation of Nature (IUCN) Red List. By 2016 it was included on the United States Endangered Species List and in 2017 was added to Annex III of the Specially Protected Areas and Wildlife (SPAW) protocol. All listings were unusual for a commercial reef fish and highlighted the growing crisis for this iconic species brought about by uncontrolled fishing on its spawning aggregations and a many-hundredfold decline in production from historic levels.

Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.

The surface protein Pfs47 allows Plasmodium falciparum parasites to survive and be transmitted by making them “undetectable” to the mosquito immune system. P. falciparum parasites express Pfs47 haplotypes compatible with their sympatric vectors, while those with incompatible haplotypes are eliminated by the mosquito. We proposed that Pfs47 serves as a “key” that mediates immune evasion by interacting with a mosquito receptor “the lock,” which differs in evolutionarily divergent anopheline mosquitoes. Recombinant Pfs47 (rPfs47) was used to identify the mosquito Pfs47 receptor protein (P47Rec) using far-Western analysis. rPfs47 bound to a single 31-kDa band and the identity of this protein was determined by mass spectrometry. The mosquito P47Rec has two natterin-like domains and binds to Pfs47 with high affinity (17 to 32 nM). P47Rec is a highly conserved protein with submicrovillar localization in midgut cells. It has structural homology to a cytoskeleton-interacting protein and accumulates at the site of ookinete invasion. Silencing P47Rec expression reduced P. falciparum infection, indicating that the interaction of Pfs47 with the receptor is critical for parasite survival. The binding specificity of P47Rec from distant anophelines (Anopheles gambiae, Anopheles dirus, and Anopheles albimanus) with Pfs47-Africa (GB4) and Pfs47-South America (7G8) haplotypes was evaluated, and it is in agreement with the previously documented compatibility between P. falciparum parasites expressing different Pfs47 haplotypes and these three anopheline species. Our findings give further support to the role of Pfs47 in the adaptation of P. falciparum to different vectors.

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early afterdepolarizations (EADs) are triggered in failing heart cells. To examine EAD initiation, high-sensitivity intracellular Ca2+ measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca2+ release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca2+ release events (“late” Ca2+ sparks) during phase 2–3 of the action potential. These late Ca2+ sparks prolong the Ca2+ transient that activates contraction and can trigger propagating microscopic Ca2+ ripples, larger macroscopic Ca2+ waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca2+ sparks and their (subsequent) spatiotemporal summation into Ca2+ ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca2+ sparks provide a mechanism for EAD initiation. Computer simulations confirmed that this forms the basis of a strong oscillatory positive feedback system that can act in parallel with other purely voltage-dependent ionic mechanisms for EAD initiation. In failing heart cells, restoration of the action potential to a nonfailing phase 1 configuration improved the synchrony of excitation–contraction coupling, increased Ca2+ transient amplitude, and suppressed late Ca2+ sparks. Therapeutic control of late Ca2+ spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death.

Transition fronts, moving through solids and fluids in the form of propagating domain or phase boundaries, have recently been mimicked at the structural level in bistable architectures. What has been limited to simple one-dimensional (1D) examples is here cast into a blueprint for higher dimensions, demonstrated through 2D experiments and described by a continuum mechanical model that draws inspiration from phase transition theory in crystalline solids. Unlike materials, the presented structural analogs admit precise control of the transition wave’s direction, shape, and velocity through spatially tailoring the underlying periodic network architecture (locally varying the shape or stiffness of the fundamental building blocks, and exploiting interactions of transition fronts with lattice defects such as point defects and free surfaces). The outcome is a predictable and programmable strongly nonlinear metamaterial motion with potential for, for example, propulsion in soft robotics, morphing surfaces, reconfigurable devices, mechanical logic, and controlled energy absorption.

Water, often termed as the “lubricant of life,” is expected to play an active role in navigating protein dissociation–association reactions. In order to unearth the molecular details, we first compute the free-energy surface (FES) of insulin dimer dissociation employing metadynamics simulation, and then carry out analyses of insulin dimerization and dissociation using atomistic molecular-dynamics simulation in explicit water. We select two sets of initial configurations from 1) the dissociated state and 2) the transition state, and follow time evolution using several long trajectories (∼1–2 μs). During the process we not only monitor configuration of protein monomers, but also the properties of water. Although the equilibrium structural properties of water between the two monomers approach bulklike characteristics at a separation distance of ∼5 nm, the dynamics differ considerably. The complex association process is observed to be accompanied by several structural and dynamical changes of the system, such as large-scale correlated water density fluctuations, coupled conformational fluctuation of protein monomers, a dewettinglike transition with the change of intermonomeric distance RMM from ∼4 to ∼2 nm, orientation of monomers and hydrophobic hydration in the monomers. A quasistable, solvent-shared, protein monomer pair (SSPMP) forms at around 2 nm during association process which is a local free-energy minimum having ∼50–60% of native contacts. Simulations starting with arrangements sampled from the transition state (TS) of the dimer dissociation reveal that the final outcome depends on relative orientation of the backbone in the “hotspot” region.

Human gut microbiota development has been associated with healthy growth but understanding the determinants of community assembly and composition is a formidable challenge. We cultured bacteria from serially collected fecal samples from a healthy infant; 34 sequenced strains containing 103,102 genes were divided into two consortia representing earlier and later stages in community assembly during the first six postnatal months. The two consortia were introduced alone (singly), or sequentially in different order, or simultaneously into young germ-free mice fed human infant formula. The pattern of fitness of bacterial strains observed across the different colonization conditions indicated that later-phase strains substantially outcompete earlier-phase strains, although four early-phase members persist. Persistence was not determined by order of introduction, suggesting that priority effects are not prominent in this model. To characterize succession in the context of the metabolic potential of consortium members, we performed in silico reconstructions of metabolic pathways involved in carbohydrate utilization and amino acid and B-vitamin biosynthesis, then quantified the fitness (abundance) of strains in serially collected fecal samples and their transcriptional responses to different histories of colonization. Applying feature-reduction methods disclosed a set of metabolic pathways whose presence and/or expression correlates with strain fitness and that enable early-stage colonizers to survive during introduction of later colonizers. The approach described can be used to test the magnitude of the contribution of identified metabolic pathways to fitness in different community contexts, study various ecological processes thought to govern community assembly, and facilitate development of microbiota-directed therapeutics.

In PNAS, Fayet et al. (1) report on two cases of tool use in a seabird. In two distant populations they recorded Arctic puffins (Fratercula arctica) using sticks to scratch themselves (Fig. 1). The documentation of tool use in this species expands the ever-growing list of tool-using birds through rare observations under natural conditions. Although it is neither the first observation of tool use in wild seabirds, nor the first of stick-tool use outside of a foraging context in wild birds, these findings contribute to the debate on the evolutionary and cognitive origins of tool use.

Transparency in science is a laudable goal. By describing with sufficient clarity, detail, and completeness the methods they use, and by making available the raw data that underlie their analyses, scientists can help ensure the reproducibility of their results and thus increase the trustworthiness of their findings and conclusions. At the same time, transparency is not in an of itself a definitive standard for the usefulness of science in policy making. A proposed rule at the Environmental Protection Agency (EPA), “Strengthening Transparency in Regulatory Science,”1 goes too far in barring from pivotal consideration in regulations any scientific study that does not have all data and analytic models made publicly available, unless special dispensations are granted. In particular, epidemiological and clinical studies that are designed to protect the confidentiality of personal health information may be highly germane to establishing environmental standards yet ethically barred from making all data publicly available. Other studies may rely on proprietary information, and their main findings may have been replicated in independent, proprietary studies, yet under the proposed rule, such studies similarly could not be relied on as a basis for regulation. The proposed rule provoked hundreds of thousands of comments and also was the subject of a recent congressional hearing.2 While sometimes falling short in its use of science,3 the EPA has traditionally strived to base regulations on the best available scientific evidence. For example, in 1997 the EPA adopted new air pollution regulations based mainly on 2 large epidemiological studies. The Harvard Six Cities study had begun in the 1970s to monitor the health of more than 8000 adults and children in 6 cities over 15 years while simultaneously tracking levels of air pollution, mainly related to burning of fossil fuels to generate electricity. Published in December 1993, the study found a strong gradient of mortality associated with increasing levels of airborne small particulates (diameter <2.5 μm).4 A second, independent study by the American Cancer Society followed 500 000 people in 154 cities for 8 years and reached similar conclusions in 1995.5

The process of securing a residency position following medical school has become increasingly arduous and complicated. The mean number of applications per applicant for US and Canadian medical school graduates has increased across all specialties in the last decade, with several specialties seeing a doubling in number of applications. For instance, from 2011 to 2019, applications per applicant increased from 15.2 to 34.8 for family medicine, from 30.5 to 61.3 for obstetrics and gynecology, and from 21.6 to 51.9 for psychiatry.1 Similarly, the number of applications received by each program also has increased across all specialties, some by more than 200%. For example, from 2011 to 2019, the mean number of applications received by family medicine programs increased from 76 to 251 and received by psychiatry programs increased from 115 to 446.1 A cycle involving increased numbers of applications and increased reliance on standardized testing has resulted in behavioral changes in both applicants and residency programs. Currently, senior medical students spend large amounts of time and money during the last year of medical school applying to an increasing number of programs and meeting the demands of the residency application process. Yet, in 2019, even though the ratio of first-year positions available per active US senior medical student was 1.7 (32 194 positions offered to 18 925 US applicants), the highest on record, the percentage of all US senior medical students who matched to their first-choice programs was 47.1%, the lowest on record (down from 52.6% in 2011). Furthermore, 5.8% of students did not match, an increase from 5.2% in 2011, and more than 20% of students matched to a program they ranked fourth or lower on their list.2 Meanwhile, to process the high volume of applications received, programs are likely relying more on quantitative metrics, such as United States Medical Licensing Examination (USMLE) Step 1 scores, for screening. Results of the 2018 National Resident Matching Program’s Program Director Survey showed that 94% of residency programs cited the USMLE Step 1 score/COMLEX Level 1 score as an important factor in selecting applicants to interview, an increase from 73% in 2012.3 Moreover, some programs report using minimum USMLE Step 1 scores when screening applications in an effort to reduce the number of applications to be reviewed. For example, 83% (89 of 107) of the 151 orthopedic surgery programs that responded to a survey reported use of a USMLE Step 1 minimum score when screening applications, and 53% of programs reported requiring a score greater than 230.4 Whether this is true for all applicants, or some, is unknown.

Human coronaviruses (HCoVs) have long been considered inconsequential pathogens, causing the “common cold” in otherwise healthy people. However, in the 21st century, 2 highly pathogenic HCoVs—severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)—emerged from animal reservoirs to cause global epidemics with alarming morbidity and mortality. In December 2019, yet another pathogenic HCoV, 2019 novel coronavirus (2019-nCoV), was recognized in Wuhan, China, and has caused serious illness and death. The ultimate scope and effect of this outbreak is unclear at present as the situation is rapidly evolving. Coronaviruses are large, enveloped, positive-strand RNA viruses that can be divided into 4 genera: alpha, beta, delta, and gamma, of which alpha and beta CoVs are known to infect humans.1 Four HCoVs (HCoV 229E, NL63, OC43, and HKU1) are endemic globally and account for 10% to 30% of upper respiratory tract infections in adults. Coronaviruses are ecologically diverse with the greatest variety seen in bats, suggesting that they are the reservoirs for many of these viruses.2 Peridomestic mammals may serve as intermediate hosts, facilitating recombination and mutation events with expansion of genetic diversity. The surface spike (S) glycoprotein is critical for binding of host cell receptors and is believed to represent a key determinant of host range restriction.1 Until recently, HCoVs received relatively little attention due to their mild phenotypes in humans. This changed in 2002, when cases of severe atypical pneumonia were described in Guangdong Province, China, causing worldwide concern as disease spread via international travel to more than 2 dozen countries.2 The new disease became known as severe acute respiratory syndrome (SARS), and a beta-HCoV, named SARS-CoV, was identified as the causative agent. Because early cases shared a history of human-animal contact at live game markets, zoonotic transmission of the virus was strongly suspected.3 Palm civets and raccoon dogs were initially thought to be the animal reservoir(s); however, as more viral sequence data became available, consensus emerged that bats were the natural hosts.

Using an unbiased genetic screen, To et al. map genes that enhance or suppress growth defects in response to different mitochondrial inhibitors to model mitochondrial disease. The findings have novel implications for the interconnectivity of bioenergetic pathways, and suggest a provocative strategy to treat primary mitochondrial disorders.

Imported across the plasma membrane by SLC1A5, glutamine has emerged as a metabolic fuel that is catabolized by mitochondrial glutaminase to support tumor growth. The missing link between cytoplasmic and mitochondrial glutamine metabolism is now provided by Yoo et al., identifying the mitochondrial glutamine importer as a variant of SLC1A5.

Cardiac ATP production primarily depends on oxidative phosphorylation in mitochondria and is dynamically regulated by Ca2+ levels in the mitochondrial matrix as well as by cytosolic ADP. We discuss mitochondrial Ca2+ signaling and its dysfunction which has recently been linked to cardiac pathologies including arrhythmia and heart failure. Similar dysfunction in other excitable and long-lived cells including neurons is associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Central to this new understanding is crucial Ca2+ regulation of both mitochondrial quality control and ATP production. Mitochondria-associated membrane (MAM) signaling from the sarcoplasmic reticulum (SR) and the endoplasmic reticulum (ER) to mitochondria is discussed. We propose future research directions that emphasize a need to define quantitatively the physiological roles of MAMs, as well as mitochondrial quality control and ATP production.

In the hierarchy of evidence, randomised trials are near the top, trumped only by meta-analysis of such trials, with blinding of patients and clinicians firmly established as being key to their validity. But new research published in The BMJ this week casts doubt on the benefits of blinding. Helene Moustgaard and colleagues have meta-analysed 142 Cochrane meta-analyses, incorporating 1153 randomised trials. They conclude that there’s no evidence that a lack of blinding leads to exaggerated estimates of treatment effects (doi:10.1136/bmj.l6802). This apparent lack of benefit should be seen in the …

Mitochondrial diseases are a heterogeneous group of inherited or acquired devastating disorders that affect the energy metabolism of the body. Many strategies have been investigated, but currently there is no FDA-approved drug that can alleviate disease symptoms or slow disease progression. This review analyzes to what extent growing knowledge over the past two decades about the etiology and pathogenesis of mitochondrial diseases is reflected in the design and development of new experimental drugs for the therapy of these disorders. All currently registered clinical trials involving new experimental drug entities are reviewed to evaluate how far away we are from the first FDA-approved drug therapy for mitochondrial disease.

Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major contributors of chemical energy and building blocks. It is therefore pivotal for cellular function to coordinate the metabolic roles of mitochondria and lysosomes. However, these organelles do more than metabolism, given their function as fundamental signaling platforms in the cell that regulate many key processes such as autophagy, proliferation, and cell death. Mechanisms of crosstalk between mitochondria and lysosomes are discussed, both under physiological conditions and in diseases that affect these organelles.

Health professionals and medical organisations must act now How do we restore hope for humanity? Many of us feel despair at a disintegrating political consensus to save our planet from fire, flood, disease, and conflict. We feel trapped in our high carbon lives and disempowered by commercial influence of companies whose products damage the planet and people’s wellbeing. Evidence for the effects of the politico-commercial complex is clear and alarming.1 On our current trajectory we will miss carbon emission targets and sustainable development goals, both agreed by international consensus.2 Populist politicians rubbish science confirming the harmful effects of climate change. Big business obfuscates, distorts, and denies evidence for the adverse effects of its products. When future historians, if such a future exists, look back on our stewardship of Planet Earth, what will be their judgment? That we allowed politics and profits to harm our home planet and ourselves? Health professionals and medical organisations should not accept the world as it is. This is not a matter of playing party politics or anticorporate posturing. Taking action is a duty to the people we serve and to future generations. And we can act: by divesting from health harming industries. Divestment offers health professionals and medical organisations, for the duty is both individual and collective, an opportunity to influence politicians and industry towards behaviours that are better for the planet and people’s health (box 1). Box 1 ### What do we mean by divestment for health? Divestment is the opposite of investment. It is the reduction or, as in this case, the complete removal of stocks, bonds, or investment funds that are unethical because of the harm to health.RETURN TO TEXT The case for divestment from the tobacco industry is established. Tobacco products are harmful, and the industry’s history of manipulating science on the effects of tobacco …

Mitochondrial dysfunction is involved in the pathology of two major blinding retinal diseases, diabetic retinopathy (DR) and age-related macular degeneration (AMD). These diseases accumulate mitochondrial defects in distinct retinal subcellular structures, the vascular/neural network in DR and the retinal pigment epithelium (RPE) in AMD. These mitochondrial defects cause a metabolic crisis that drives disease. With no treatments to stop these diseases, coupled with an increasing population suffering from AMD and DR, there is an urgent need to develop new therapeutics targeting the mitochondria to prevent or reverse disease-specific pathology.

The challenges facing new WHO leadership in Europe The imminent change of leadership at the top of the World Health Organization’s European region gives member states an important opportunity to extend policy making on health and wellbeing for all. Hans Kluge takes over as European regional director from Zsuzsanna Jakab in early February, having been elected last September by a large majority of member states. This makes it an opportune time to take stock and consider what has been achieved and what more needs to be done under new leadership. Health has improved across the WHO European region, but not everywhere and not equally. For example, life expectancy varies between 70 and 83.1 years across countries.1 The region faces many challenges, including a high burden of non-communicable diseases; the increasing prevalence of mental health problems; health effects of climate change; inequitable access to, and affordability of, care and medicines; increasing migration; shortages of healthcare workers; and poor progress in realising the opportunities in digital health. Dealing with these challenges requires …

The identification of senolytics, compounds that eliminate senescent cells, is presently a key priority given their therapeutic promise in cancer and aging-associated diseases. Two recent papers by Triana-Martínez et al. and Guerrero et al. report the senolytic activity of cardiac glycosides (CGs) and their efficacy in these pathophysiological contexts.

A previously well and active 25 year old woman with no underlying structural heart disease presented with recurrent episodes of new onset syncope over a period of six hours. Her pulse was irregularly irregular at a rate of 230 beats/min. She was hypotensive with a blood pressure of 80/60 mm Hg. Twelve lead surface electrocardiogram (ECG) taken on admission is shown in fig 1. She was immediately electrically cardioverted to sinus rhythm with 150 J. She reported no history of recreational drug use or family history of sudden cardiac death. Surface electrocardiogram during …

The nerve surgeon Susan Mackinnon discovered that an old but precise textbook she relied on was created by a Viennese anatomist who had dissected Hitler’s victims to produce his detailed illustrations. Should we still be using the illustrations, she asks I first met the Atlas of Topographical and Applied Human Anatomy1 in 1982, when I was 32, during my hand fellowship at the Curtis National Hand Center in Baltimore and later at the University of Toronto. The atlas became my dissection partner during the many long hours spent in the anatomy laboratory at Johns Hopkins Hospital. For several years, I knew the Pernkopf atlas (named after its author, Eduard Pernkopf, chair of anatomy and president of the University of Vienna) only as a unique and valued piece of science and art. However, in the late 1980s, I came across essays by Gerald Weissman, an Austrian born US physician-scientist at New York University, and David Williams, a medical illustrator of Purdue University, Indiana, exposing the origin of my dissection partner,23 calling it the “atlas of the Shoah,” derived during the Holocaust. Once I, a gentile, came to know the truth of its origin, my attitude changed. I secured the atlas in my operative room locker, with printed copies of Weissman’s and Williams’s essays slipped into the atlas as a marker to anyone who might use it and a warning to “enter with caution.” However, having already spent many years with the atlas, still the most detailed anatomy book I’ve ever seen, I continued to feel the need to refer to it occasionally for the sake of improving my patients’ surgical outcomes. Several times a month, while operating, I would struggle with the anatomical nuances of nerve pathways. The atlas showed me the way—an exact and safe surgical approach to the …

The title of Klaber and Bailey’s editorial, Kindness: an underrated currency, conceals a greater wisdom embedded in the text—namely, the promotion in medical practice of “relationships, connections, challenge, and trust” and “gentle honesty in discussions.” …

I agree with Klaber and Bailey that we should all try to be more kind to each other.1 How one achieves that in …

Scurvy once occurred in seafarers and long distance travellers. Currently, the most vulnerable group seems to be children with autism or developmental delay who will eat only highly selective diets. Ten children seen at a rheumatology clinic in North America had been referred because of pain and difficulty in walking and weight bearing (J Pediatr doi:10.1016/j.jpeds.2019.10.059). Before the correct diagnosis was made, conditions such as juvenile arthritis, osteomyelitis, and vasculitis were considered and investigated. All responded quickly to vitamin C supplements. In rich countries, obesity is commonest among poorer people, while overweight …

This is a picture of phytophotodermatitis (fig 1). The patient was a 50 year old man with three days of erythematous blistering across …

Around 20% of patients with acute aortic dissection die before reaching any hospital and 50% die before reaching a specialist centre, according to an investigation by the Healthcare Safety Investigation Branch.1 The report on delayed recognition of acute aortic dissection analysed hospital activity and other national datasets, and found that it may occur in around 4.5 per 100 000 of the population per year, equal to around 2500 cases per year in England. It showed that a delay in diagnosis occurs in around 16-40% of cases and is more likely if patients walk in to the hospital or if doctors initially suspect that there is a cardiac cause for chest pain. The report said hospitals in England …

People living in England’s most deprived areas of England seem to receive the worst quality of healthcare across various types of service, concludes new research from health experts.1 Examples of inequality included spending longer in hospital accident and emergency departments and having worse experiences when making GP appointments. The research from QualityWatch, a joint programme of the health think tanks the Nuffield Trust and the Health Foundation, involved looking at 23 measures of healthcare quality to see how these were affected by deprivation. The measures included avoidable mortality rate, smoking prevalence, emergency admissions for various types of care, obesity prevalence in children, infant mortality rate, experience of making a GP appointment and …

The European Union’s highest court has decisively upheld the European Medicines Agency’s right to publish clinical trial data from drug companies’ applications to market their products in the EU. In two keenly awaited judgments, the European Court of Justice has comprehensively rejected appeals by two companies against rulings in 2018 by the General Court of the European Union upholding the European Medicines Agency’s open data policy.12 In 2010 the agency adopted a policy of making available all documents underlying a successful drug licence application from January 2014, setting aside its previous presumption of confidentiality. But the move was resisted by pharmaceutical companies, which mounted legal challenges, arguing that their commercial confidentiality was at risk. Now the European Court …

The emergency department doctor and Tooting MP tells Elisabeth Mahase about her priorities as a politician “I’m a doctor first. I didn’t become an MP to stop being a doctor. Working shifts in the emergency department also helps me form coherent evidence based arguments. I see the effects of austerity every time I do a shift, and I can talk about that with real legitimacy. An emergency waiting room is like a microcosm of society. When I’m working, I can see the impact of cuts not …

The Care Quality Commission (CQC) is to carry out dozens of reinspections of care and nursing homes after an internal audit revealed that inspection reports contained “duplicate material.” The regulator found evidence of duplication in 108 reports. Some 68 care homes will now be reinspected. The remaining 40 reports will …

The digital provider Babylon Health is in talks with a “significant number” of hospital trusts in England as it seeks to expand its service in the NHS, the company has told The BMJ. Babylon’s managing director for NHS services, Paul Bate, said that the company wanted to spearhead a “fundamental transformation” in the way people accessed healthcare. His comments came as Babylon announced a major 10 year partnership with Royal Wolverhampton NHS Trust, a large acute and community provider that also runs 10 general practices, to deliver joined-up digital care to the city’s population. The service, which is expected to go live later this year, will allow patients …

Only 41% of clinical trials reported their results to the US clinical trials registry within a year of completion as required by law, a study found. Researchers from Oxford University, UK, who identified 2497 clinical trials that had breached the rules, called for better enforcement from the US Food and Drug Administration. The FDA Amendments Act 2007 requires trial sponsors to report results directly to ClinicalTrials.gov within one year of completion, whether results are positive or negative. Medical leaders in the UK warned that doctors and patients were being placed at risk after an NHS hospital encouraged doctors to discharge patients early because of a lack of beds. In an internal email to senior clinicians the Royal Cornwall Hospitals Trust had said that it was considering discharging patients “earlier than some clinicians would like” because of “significant pressure” on services. Chaand Nagpaul, BMA council chair, said that the BMA was writing to the trust and the General Medical Council to express “serious concerns.” (Full story doi:10.1136/bmj.m164) Cancer-causing HPV 16 and 18 infections are now extremely uncommon in young sexually active women in England after the introduction of human papillomavirus (HPV) vaccination in 2008, said Public Health England. The infections were found in under 2% of women aged 16-18 in 2014-18, down from 15% in 2008. HPV …

Yeshi Dhonden, the foremost Tibetan doctor in the world, has died from respiratory failure at his residence in Dharamsala, northern India, surrounded by his family. He was born in Namrao village, in Tibet, into a farming family. He entered monastic life when he was 6 years old and took novice vows as a Buddhist monk two years later. When he was 11, he joined the Chakpori Institute of Tibetan Medicine, where he studied for nine years and displayed impressive skills during the study of the four tantra. One of his teachers was his uncle, the famous Tibetan doctor and teacher Khenrab Norbu. At 20, Dhonden was recognised as the best in his class. He passed his exams with distinction and was made an honorary doctor of the 14th Dalai Lama. From 1951 onwards, he practised medicine in Tibet in his native region, where he became renowned for his skill as a physician after he managed an influenza epidemic. He became the foremost expert in Sowa-Rigpa, the Tibetan herbal medicinal system that combines the ancient healing systems of India and China, practised for thousands of years in Tibet. In 1959 he chose to accompany the Dalai Lama into exile in India, when he fled the Chinese invasion of Tibet. In 1961, when the Dalai Lama re-established the Men-Tsee-Khang, the Tibetan Medical and Astro-Science Institute, …

Consider Duchenne muscular dystrophy in boys with delayed motor milestones, positive Gowers’ sign, abnormal gait, muscle pains, calf hypertrophy, unexplained elevated liver enzymes, learning difficulties, behavioural problems, or speech and language delay Test for creatine kinase levels if you suspect any neuromuscular condition. Refer children with raised creatine kinase promptly to a neuromuscular specialist Early diagnosis means early access to treatment, improved outcomes, and better informed family planning Early genetic diagnosis is important, as it can enable entry into appropriate clinical trials Where patients have breathlessness, palpitations and arrhythmias, morning headaches, and repeated chest infections or weight loss, suspect deterioration and refer for prompt specialist review Duchenne muscular dystrophy (DMD) is a progressive and disabling neuromuscular condition that is often diagnosed late.1 In the UK the mean age of diagnosis has remained fairly static over the past 30 years, currently around 4.3 years of age.2 On average it takes 1.6 years from first parental concern to diagnosis of DMD,2 by which time muscle function has already declined (box 1, case study). Delayed diagnosis of DMD can be devastating for patients and their families. Outcomes for people with DMD can be improved with optimum care at the earliest opportunity, and patients are now living into their fourth decades.34 Early diagnosis also enables parents to make informed decisions about family planning and can provide access to innovative treatments and clinical trials. International guidelines for diagnosis and management of DMD have been established by the DMD Care Considerations Working Group.567 Patient A presented with speech delay at age 2 and poor fine and gross motor skills at 2.5 years. He had been referred to several different teams for these symptoms, including physiotherapy for his poor motor skills and behavioural psychology. He initially walked at …

The UK’s infant vaccination programme against group B meningococcal disease has resulted in a significant reduction in cases of the disease in young children, according to research from Public Health England published in the New England Journal of Medicine.1 However, an Australian study published in the same journal found that while the meningitis B vaccine also works in teenagers it does not provide herd protection against the meningococcal bacteria so will only protect those who are adequately immunised.2 In September 2015 the UK became the first country to offer the 4CMenB vaccine (Bexsero) to babies at 8 and 16 weeks of age, followed by a booster at 12 months. The results show that from September 2015 through to August 2018 there …