Measurements to understand oxygen transfer in vivo in the human are limited, with no general agreement on the most appropriate methods. An invasive method for measuring partial pressure of oxygen in the intervillous space through needle electrode insertion at the time of Caesarean sections has been reported. This allows for direct measurements in vivo whilst maintaining near normal placental conditions; however, there are practical and ethical implications in using this method for determination of placental oxygenation. Furthermore, oxygen levels are likely to be highly heterogeneous within the placenta. Emerging non‐invasive techniques, such as MRI, and ex vivo research are capable of enhancing and improving current imaging methodology for placental villous structure and increase the precision of oxygen measurement within placental compartments. These techniques, in combination with mathematical modelling, have stimulated novel cross‐disciplinary approaches that could advance our understanding of placental oxygenation and its metabolism in normal and pathological pregnancies, improving clinical treatment options and ultimately outcomes for the patient.The placenta is crucial for life. It is an ephemeral but complex organ acting as the barrier interface between maternal and fetal circulations, providing exchange of gases, nutrients, hormones, waste products and immunoglobulins. Many gaps exist in our understanding of the detailed placental structure and function, particularly in relation to oxygen handling and transfer in healthy and pathological states  Despite this, there remain many unanswered questions in our detailed understanding of placental structure, function and transfer efficacy in both normal and diseased states PO2) differs between normal pregnancies and those complicated by placental diseases. A full understanding of spatio‐temporal oxygenation and associated placental villous architecture in healthy and diseased states, aiding mathematical model development on transplacental oxygen transfer, will ultimately be useful to obstetricians trying to understand and treat placental disease. In this review, we will present current views on human placenta structure and function with respect to oxygen transfer. This will include discussions on the strengths and weaknesses of the current methods used to measure placental oxygenation both in vivo and ex vivo. It will also summarise reported oxygen levels within the placenta–fetal unit, with an emphasis on dysregulated materno‐fetal oxygen transfer in pregnancy pathologies.It is an ephemeral but complex organ acting as the interface between mother and fetus, providing a hub for exchange. One of the key functions of the placenta is to mediate transfer of oxygen to the fetus. However, there is poor consensus on the oxygenation of placental compartments, most notably oxygen gradients within the intervillous space (IVS) of the maternal circulation, and how the partial pressure of this gas  where the fetus fails to reach its genetic growth potential. Over half of neonatal deaths worldwide are associated with low birth weight UNICEF, . Surviviet al. et al. PO2 in the maternal circulation, diminishing placental oxygen transfer , will provide further answers. This may then permit an interrogation of transplacental transfer efficacy of oxygen, providing translational tools for obstetricians in their diagnosis and management of FGR associated with oxygen transfer deficiency.A comprehensive study including mathematical modelling of complex placental architecture, coupled with in vivo measurement of placental oxygen has proved difficult and has only been recorded in a handful of studies. Schaaps et al. published the most recent cross‐sectional study , can effectively measure changes in placental oxygen saturation following a maternal oxygen challenge. Deoxyhaemoglobin acts as an endogenous contrast agent, due to the differing magnetic properties of both oxyhaemoglobin and deoxyhaemoglobin. Changes in oxygen saturation, and therefore deoxyhaemoglobin levels, alter the local magnetic field susceptibility, thus affecting transverse relaxation times and BOLD signal. The first human placental BOLD MRI study  MRI Fig. A, can ePO2 have been determined using a complementary technique, oxygen‐enhanced (OE) MRI. In OE MRI, changes in longitudinal relaxation rates (R1) occur due to an increase in the paramagnetic dissolved oxygen content in the tissue with maternal hyperoxia. An increase in R1 following maternal hyperoxia, reflecting an increase in PO2, was first demonstrated in the placenta in 2013   may be of benefit through the measurement of placental perfusion and oxygen status, its use in the placenta is still limited by a lack of data and there are no accepted MRI‐based definitions of normal/abnormal placental tissue flow rates . Perfusion has advantages over cell culture, tissue slices and explant studies due to the maintenance of villous architecture and relative IVS volume density  to reduce the overall resistance encountered during the experiment. Placental blood flow on the fetal side is calculated to be approximately 0.35 mL min g−1in vivo at term, based on the placenta receiving 40% of fetal left ventricular output, being 480 mL min−1 at term. This compares to an ex vivo fetal‐side flow of 0.17 mL min−1 based on a perfused tissue mass of 35 g being perfused at 6 mL min−1 . Unlike in vivo oxygen sampling, extensive IVS oxygen sampling under steady‐state experimental conditions is possible by means of an oxygen‐sensitive needle optode inserted through the decidual plate at set X–Y–Z planes controlled with a micromanipulator . With further experimentation the placental metabolic component of IVS oxygen consumption can be elucidated. IVS oxygen gradient data can be acquired and interrogated for metabolism and transfer, and it may be possible to discover how variable perfusate flow rates and fetoplacental vasoactive endocrine agents affect fetal‐side oxygen acquisition, gaining an understanding of how the associated underlying villous architecture enhances or constrains oxygen transfer across the placental barrier.To simplify our understanding of placental oxygen transfer, a new adapted version of this model is being trialled by our laboratory. This involves scaling down the established maternal‐side multi‐cannula dual perfusion model, so that the IVS irrigation volume is limited, employing just one maternal cannula delivering normoxic perfusate and measuring oxygen gradients within the IVS Fig. B. Unliktor Fig. B. With A), and allow the surface of the villi and the fetal vascular system to be differentially labelled . However, these higher‐resolution approaches are only able to image smaller regions of tissue. Micro‐computed tomography (MicroCT) allows the visualisation of larger regions of placental villi placenta but at different scales . Imaging of the fetoplacental vascular system can be enhanced by perfusing contrast agents into the fetal circulation to image the arterial and venous circulation . Mathematical models have also been created to explain properties of the placenta that it would not be possible to understand using in vivo measurements alone . However, there is the open challenge of effective extraction of structural information from imaging data as well as of identifying key parameter values necessary for mathematical modelling. Once validated, theoretical models could provide a bridge between in vivo and ex vivo or in vitro approaches to characterise placental structure and oxygenation in normal and pathological pregnancies (Lecarpentier et al. The increased availability of 3‐D imaging approaches, including confocal microscopy and microCT, have made possible the recent increase in efforts to build multiscale computational models that go hand‐in‐hand with refined experimental models (Pearce in vivo human placentas, which are compounded by slow advances of ex vivo, in vitro and in silico work.The physiology of placental oxygen transfer is crucial for optimal fetal development and survival. Gross placental structure is well characterised and newer techniques, such as MRI, microCT and advanced microscopy scanning techniques, are affording greater detail. However, the function of the placenta remains poorly understood. Key measurements of oxygen and carbon dioxide levels in a normal human placenta remain elusive due to logistical and ethical complications with experimenting on in vivo.This lack of fundamental understanding has led to slow progress in terms of treating pathological states such as in cases of fetal growth restriction. It is our theory that impaired placental oxygen transfer and metabolism (Schneider, None declared.All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.Funding was provided by the Medical Research Council, MR/N011538/1.


HIV is a unique sexually transmitted infection (STI) that is greatly affected by other concomitant “classical” bacterial and viral STIs that cause genital ulcers and/or mucosal inflammation. STIs also serve as a marker for risky sexual behaviours. STIs increase infectiousness of people living with HIV by increasing the viral concentration in the genital tract, and by increasing the potential for HIV acquisition in people at risk for HIV. In addition, some STIs can increase blood HIV concentration and promote progression of disease. This review is designed to investigate the complex relationship between HIV and classical STIs.STIs with appropriate antibiotics reduces HIV in blood, semen and female genital secretions. However, community‐based trials could not reliably reduce the spread of HIV by mass treatment of STIs. Introduction of antiretroviral agents for the treatment and prevention of HIV has led to renewed interest in the complex relationship between STIs and HIV. Antiretroviral treatment (ART) reduces the infectiousness of HIV and virtually eliminates the transmission of HIV in spite of concomitant or acquired STIs. However, while ART interrupts HIV transmission, it does not stop intermittent shedding of HIV in genital secretions. Such shedding of HIV is increased by STIs, although the viral copies are not likely replication competent or infectious. Pre‐exposure prophylaxis (PrEP) of HIV with the combination of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) prevents HIV acquisition in spite of concomitant STIs.Treatment of STIs remain pandemic, and the availability of ART may have led to an increase in STIs, as fear of HIV has diminished. Classical STIs present a huge worldwide health burden that cannot be separated from HIV, and they deserve far more attention than they currently receive. In part, this can be explained by transmission from HIV‐positive people who do not know their status over many years of asymptomatic infection. HIV transmission reported in stable discordant couples before availability of antiretroviral treatment (ART) was as high as 8.2 to 12.0 per 100 person‐years 22.1The connection between classical STIs  and HIV surfaced early in the epidemic 2.2et al. studied HIV in semen of men with concomitant gonorrhoea et al. reported increased HIV in female genital secretions with bacterial vaginosis, with significantly increased risk of HIV transmission to sexual partners Cohen Indeed, higher concentrations of HIV in blood 2.3Over the course of untreated infection, a diverse quasispecies emerges within an individual Regional  differences in viral diversity can be observed when virus that has been sequestered in an anatomic region undergoes replication independently from virus circulating in the blood. Over time, this independent replication can result in the formation of genetically distinct, compartmentalized viral populations. This phenomenon has been extensively studied in the central nervous system For example, early on Ping and colleagues We have recently reexamined the relationship between HIV and STIs using single genome amplification followed by Sanger sequencing et al. noted genotypically and phenotypically different HIV‐1 envelopes from viruses recovered from the female genital tract as compared with the blood Studies examining HIV‐1 diversity in the female genital tract during early infection have observed multiple variants not detected in the blood plasma However, as PCR techniques and sequencing methods that limit recombination and resampling were developed, a different picture of compartmentalization in the female genital tract has emerged 2.4Transmission of classical STIs is generally more efficient than HIV, and therefore may set the stage for increased risk of HIV acquisition The foreskin is a critical point of acquisition of HIV by men. It has been argued that low‐grade inflammation in this tissue, perhaps critical to decrease commensal bacterial colonization and to resist STIs, increases the risk of HIV acquisition et al. reported that in men who have sex with men (MSM) with a history of syphilis and two rectal gonorrhoea or chlamydia infections in the past two years, there was an eightfold risk of HIV acquisition Rectal mucosa is a vulnerable tissue and unprotected anal intercourse has the greatest risk for HIV acquisition 2.5The role of STIs in the spread of HIV led to a series of randomized clinical trials designed to reduce the incidence of HIV infection in communities et al. An alternative approach has been to focus on HSV‐2 treatment to prevent individual HIV acquisition 2.6et al. reported that in a continuation of the Partner study, 779 MSM couples reported 76,088 episodes of condomless anal intercourse with no linked HIV transmission events Several studies have shown that ART prevents secondary HIV transmission independent of STI coinfections 2.7However, while HIV treatment reliably prevents HIV transmission, it does not prevent shedding of the virus in the genital secretions of men 2.8There are a large series of reports of detection of HIV virus in the female genital tract with a wide variety of STIs 2.9et al. studied the relationship between blood and seminal plasma, and shedding of HIV in semen in spite of ART et al. reviewed the association between seminal cells and HIV transmission, and the possibility that ART may not eliminate cells that remain infectious Kalichman et al. studied the blood and seminal fluid of 24 men receiving ART who acquired urethritis Only a few studies of the effects of STIs on semen shedding in men receiving ART have been reported. Sadiq To further investigate the issue, we have enrolled HIV‐infected men with acute urethritis into an ongoing prospective observational cohort 10 copies/mL respectively) 10 copies/mL in the blood and semen respectively); semen viral loads showed higher variability over time.In men with acute urethritis who were not on ART at enrolment but initiated treatment within one week, HIV copy number in both blood and semen were comparable  from the cell, or release of latent virus, or viral replication. However, failure of HIV‐positive people to infect their sexual partners 2.10. As noted above, genital ulcers significantly increase the amount of viral RNA shed in both the male et al. reported increased HIV in blood in people with primary and secondary syphilis et al. et al. et al. A related question is the effects of STIs on blood viral burden10 increase in HIV‐1 viral load suggesting that when an individual is suppressed on ART, STIs have little effect on blood viral load Antiretroviral therapy is highly effective at suppressing HIV‐1 replication in the blood, including in people with STIs. In a meta‐analysis of 14 studies looking at the effects of STI infection on HIV‐1 blood viral load, Champredon and colleagues concluded that co‐infection with an STI correlates with a 0.11 log2.11A series of clinical trials demonstrated that TDF/FTC can prevent HIV acquisition in MSM et al. noted a modest increase  in STI risk associated with TDF/FTC PrEP, especially in more recent studies TDF/FTC prophylaxis was approved by the US CDC in 2012 and guidelines are available et al. Most recently, Traeger A second critical question is the efficacy of TDF/FTC PrEP when an STI is acquired. This question was addressed in an observational report from Kaiser Permanente California 2.12PrEP effectiveness in either partner in serodifferent heterosexual couples et al. The VOICE trial 2.13et al. identified a dose and dosage schedule for cabotegravir as PrEP Most recently the results of a clinical trial that directly compared TDF/FTC with tenofovir alfenamide TAF and FTC demonstrated the equivalency of the latter combination, although very few incident infections were detected 2.14Mathematical modelling has been used to understand the spread of HIV and compare prevention strategies et al. Jenness 2.15et al. et al. As already noted, HIV PrEP trials have found high incidence of classical STIs 3The early history of the HIV pandemic was marked by realization that HIV infection led to a new, fatal sexually transmitted disease with risk to both sexually active men and women, and that several classical STIs amplified both infectiousness and acquisition of HIV Where do we go from here? We have no choice but to rethink STI research goals and intervention funding, and the relationship between STIs and HIV; and new questions have arisen. We do not understand the biology of shedding of HIV in the genital tract that persists despite clearance in the blood with ART. This problem is highly relevant to thinking about the cure of HIV. Several strategies are now being pursued to permit remission (no drugs required) or sterilising cure of HIV. Among the most popular is the “kick and kill” strategy with reactivation of latent HIV virus and concomitant elimination of HIV infected cells Finally, there is the complex and evolving relationship between PrEP, STIs and HIV acquisition. Currently, the only agent approved in the US as pre‐exposure prophylaxis (PrEP) is the fixed dose combination of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC). The use of TDF/FTC has been accompanied by recognition of high incidence of STIs in PrEP users STIs are a harbinger of HIV acquisition, depending on the prevalence of HIV in the community, the number of people on treatment, and the degree of difficulty in detection and treatment of STIs and HIV. STIs serve as a critical surrogate for the need for PrEP MSC is on the Advisory Board for Merck and Gilead. ODC and JSC have no potential conflicts.MSC provided conception and design, as well as analysis and interpretation of data; drafted manuscript, provided critical revisions and gave final approval of submission. ODC participated in drafting the article and critically revising for intellectual content. JSC participated in drafting the article and critically revising for intellectual content.


With over 3 million US prostate cancer survivors, ensuring high‐quality, coordinated cancer survivorship care is important. However, implementation of recommended team‐based cancer care has lagged, and determinants of quality care across primary and specialty care remain unclear. Guided by the theoretical domains framework (TDF), we explored multidisciplinary determinants of quality survivorship care in an integrated delivery system.We conducted semistructured interviews with primary (4) and specialty (7) care providers across 6 Veterans Health Administration clinic sites. Using template analysis, we coded interview transcripts into the TDF, mapping statements to specific constructs within each domain. We assessed whether each construct was perceived a barrier or facilitator, examining results for both primary care providers (PCPs) and prostate cancer specialists.Knowledge and Environmental context and resources. Both groups noted knowledge (about survivorship care) and procedural knowledge (about how to deliver survivorship care) as positive determinants or facilitators, whereas resources/material resources (to deliver survivorship care) was noted as a negative determinant or barrier to care. Additional domains more commonly referenced by cancer specialists included Social/professional role and identity and Goals, while PCPs reported the domain Beliefs about capabilities as relevant.Cancer specialists and PCPs identified 2 primary TDF domains impacting their prostate cancer survivorship care: We used the TDF to identify several behavioral domains acting as determinants of high‐quality, team‐based prostate cancer survivorship care. These results can inform prostate cancer survivorship care plan content, and may guide tailored, multidisciplinary implementation strategies to improve survivorship care across the primary and specialty care interface. Not only are the number of cancer survivors rapidly growing, many older with several medical comorbidities, there is also an increasing oncologist shortage leading to an inability to meet the demands of the cancer survivor population.Over a decade ago, the National Academies of Sciences released “From Cancer Patient to Cancer Survivor” calling for research on the determinants of high‐quality survivorship care across the primary and specialty care interface.For these reasons, we explored prostate cancer survivorship care among PCPs and cancer specialists within an integrated healthcare delivery system. We used an innovative implementation research framework to characterize multidisciplinary determinants associated with quality care. Our approach to provider interviews informs survivorship care content and tailored interventions to support cancer specialists and PCPs to deliver quality prostate cancer survivorship care.22.1We recruited providers from three different Veterans Health Administration (VHA) clinical sites within the Midwest region. We purposefully sampled participants from primary care, urology, medical oncology, and radiation oncology clinics to maximize variation in the sample and achieve a sample representative of the types of providers involved in prostate cancer survivorship care. We first contacted service chiefs to obtain permission to contact their providers. Once permission was obtained, an e‐mail was sent to providers that explained the study and gave them the option to opt‐out of participating. Providers were excluded if they had not provided care to at least 3 men with prostate cancer within the past year. This study was approved by the VA Ann Arbor Healthcare System Institutional Review Board.2.2Beliefs about capabilities domain of TDF  can be intervened upon by providing written or visual information to clarify provider roles and responsibilities. This may, in turn, improve the patient's professional confidence in their PCP to provide cancer care.We developed our interview guide based on the theoretical domains framework (TDF) to understand determinants of provider behavior regarding prostate cancer survivorship care, and to inform future implementation strategies aimed at improving care across the primary and specialty care interface.We designed our interview guide to assess several aspects of survivorship care including: (1) provider recognition of prostate cancer survivorship care  and the benefits of survivorship interventions ; 2) the interface between PCPs and cancer specialists  and survivorship care practice patterns; (3) behavioral control barriers to delivering survivorship care ; and (4) intention to perform prostate cancer survivorship care (see Appendix  the inteEleven semi‐structured interviews were conducted by 2 members of the study team (JH and TS) and included 4 PCPs, 4 urologists, and 3 oncologists . No new major themes arose by the end of 11 interviews, implying that saturation had been reached. Based on the location and availability of the provider, we conducted 5 in‐person and 6 telephone interviews. All participants gave verbal consent prior to beginning the interview. Each interview began with a description of an index patient who was 1‐year postrobotic prostatectomy that the interviewee was told to keep in mind while responding to the interview questions. Interview questions probed the content areas highlighted above. Interviews were audio‐recorded, transcribed verbatim, and entered into NVivo software  for analysis.2.3We conducted data analysis in 2 steps. First, we mapped all content from each interview to a relevant TDF domain . Then, our research team , including a prostate cancer specialist (TS) and primary care physician (AR) both with extensive survivorship care clinical and research expertise, mapped all TDF domain content to TDF constructs  lack of communication from cancer specialists regarding the standardized follow‐up care a patient needs ; (2) lack of access to specialists ; (3) lack of time during clinic visits to properly address all of the patient's concerns, especially in the context of other chronic conditions ; and 4) lack of support services for providers  and patients .Defined as “any circumstance of a person's situation or environment that discourages or encourages the development of skills and abilities, independence, social competence, and adaptive behavior,” environmental context and availability of resources were often noted by providers as barriers to delivering quality prostate cancer survivorship care Figure . Specifiorganizational culture/climate. Often, this was described as having:… good relationships with urology, medical oncology … it makes a big difference in really getting these patients where they need to be in a timely fashion and getting the answers that they need because when they sit in your office and they're asking you questions that you can't necessarily deal with, it's very comforting that I can tell a patient, you know “I don't know that answer but I can go find out …”In contrast, what providers reported as a facilitator to providing survivorship care involved the person × environment interaction was also noted as a facilitator to be able to deliver survivorship care. In other words, colocation of PCPs with cancer specialists was endorsed as facilitating communication between providers. As one PCP noted, “I think it's definitely helpful to be onsite, you can actually ask questions … It's not always that we know what we're doing, so it's kind of nice to curbside and ask …”In addition, the 3.3Beliefs about capabilities in their delivery of prostate cancer survivorship care  in handling many aspects of follow‐up care for their patients and feeling comfortable doing so. One PCP noted, “… I think we try to manage them … most of the time probably. Primary Care does the majority of managing of the symptoms … and then for the ones that are really refractory we end up sending them back to urology, but I do feel kind of responsible for a pretty broad range.” Cancer specialists, on the other hand, reported Social/professional role and identity more frequently as relevant to their care . The majority of cancer specialists discussed feeling responsible for the patient's cancer control  and assessing quality of life . Cancer specialists varied in their views on sharing care with PCPs. One cancer specialist determined their continued involvement in their patient's care based on how involved the PCP was. But several others reported being involved in all aspects of their patient's survivorship care and even assuming primary care roles.Compared to cancer specialists, PCPs made more references to 4Knowledge (as a facilitator) and Environmental context and resources (as a barrier) as relevant to their survivorship care delivery. As the population of cancer survivors grows, understanding factors that influence provider abilities to deliver high‐quality survivorship care is critical. Increasingly, team‐based care models have been proposed to meet the diverse health needs of cancer survivors, however, how PCPs and cancer specialists deliver coordinated care have remained unclear. Our study helps clarify issues facing primary and specialty care and suggests directions forward to support them in their care for men surviving prostate cancer.This study used the TDF to identify determinants of team‐based prostate cancer survivorship care within an integrated delivery system. Both PCPs and cancer specialists endorsed Knowledge was the most frequent domain referenced by providers in this study, with both PCPs and cancer specialists endorsing having knowledge about prostate cancer survivorship care and perceiving it as a facilitator to delivering care. Prior studies have highlighted that PCPs often report lacking knowledge about survivorship care but also that cancer specialists lack confidence in PCPs’ abilities to do so.We found that Environment domain among cancer specialists. Additionally, in an example of an intervention implemented to improve survivorship care, resources specifically included dedicated staff members to complete survivorship care plans, an oncology nurse practitioner to review treatment summaries and recommendations, and a social worker to address late‐ and long‐term psychosocial effects.Quality survivorship care delivery requires both time and resources, and this was a barrier frequently reported as negatively impacting clinical practice. As increasing calls to improve cancer survivorship care delivery have been made over the past decade, policy changes at various levels  to facilitate implementation of efficient and effective survivorship care programs are needed.One key challenge to team‐based survivorship care models is a lack of clarity among providers regarding responsibility for survivor follow‐up care. Results from our study highlight the discrepancy between cancer specialists and PCPs on their respective roles. While some cancer specialists perceived their roles as extending to addressing primary care needs, PCPs reported feeling comfortable and having confidence in managing their patient's prostate cancer follow‐up care. This suggests that improving care coordination between cancer specialists and PCPs requires clear delineation of responsibilities for what each provider will handle, and this ideally needs to be communicated to patients. For example, strategies, such as web‐based patient tools that describe team‐based models of survivorship care and specific roles for cancer specialists and PCPs, can be helpful in accomplishing this.This study has some limitations. First, because we were able to achieve thematic saturation with 11 providers, it is likely that we identified the two key domains necessary for quality survivorship care. In fact, our findings are consistent with others regarding resources as a determinant of survivorship care plan use.PCPs and cancer specialists identified several constructs within the TDF domains as relevant to their prostate cancer survivorship care delivery. While knowledge about survivorship care was perceived as a facilitator, limited resources to be able to deliver survivorship care was reported as a barrier. Our results provide critical insight into factors that providers perceive as being important in their clinical practices. These behavioral theory‐based results may inform future efforts in the design and implementation of prostate cancer survivorship care plan content, and guide tailored, multidisciplinary implementation strategies to improve prostate cancer survivorship care across the specialty and primary care interface.Dr. Wittmann is funded by the Movember Foundation and Dr. Skolarus’ R37 CA222885 from the National Cancer Institute.


To investigate detailed trends in malignant brain tumour incidence over a recent time period. UK Office of National Statistics (ONS) data covering 81,135 ICD10 C71 brain tumours diagnosed in England (1995–2015) were used to calculate incidence rates (ASR) per 100k person–years, age–standardised to the European Standard Population (ESP–2013). We report a sustained and highly statistically significant ASR rise in glioblastoma multiforme (GBM) across all ages. The ASR for GBM more than doubled from 2.4 to 5.0, with annual case numbers rising from 983 to 2531. Overall, this rise is mostly hidden in the overall data by a reduced incidence of lower-grade tumours. The rise is of importance for clinical resources and brain tumour aetiology. The rise cannot be fully accounted for by promotion of lower–grade tumours, random chance or improvement in diagnostic techniques as it affects specific areas of the brain and only one type of brain tumour. Despite the large variation in case numbers by age, the percentage rise is similar across the age groups, which suggests widespread environmental or lifestyle factors may be responsible. This article reports incidence data trends and does not provide additional evidence for the role of any particular risk factor. The causes of brain tumours in adults remain largely unknown . In 2011The International Classification of Diseases for Oncology (ICD–O) is a dual classification, with coding systems for both topography and morphology . The relThere are 102 different ICD–O–3.1 morphology codes used in the data set, though many have few cases. The morphology code describes the cell type and its biological activity / tumour behaviour.WHO last updated their classifications in 2016, but their changes have minimal impact on our analysis of the data , 5. MaliWe used anonymised individual–level national cancer registration case data from the UK Office of National Statistics (ONS) for all 81,135 ICD10–C71 category primary malignant brain tumours diagnosed in England for the years from 1995 to 2015, plus 8,008 ICD10–D43 supratentorial malignant tumours without histology/morphology data from 1998–2015. The initial data is supplied by the National Cancer Registration Service (NCRS). The ONS then apply further validation checks and the UK Department of Health use the ONS data to inform policy making. The ONS state their cancer data are generally within 2% of the correct values . Until aGlioblastoma Multiforme (GBM), the most common and most malignant primary tumour of the brain, is associated with one of the worst five–year survival rates among all human cancers, with an average survival from diagnosis of only about 1 year. This ensures that few cases will be unrecorded in the ONS database and we show that their number of GBM tumours is similar to NHS hospital inpatient numbers. The data include the year of diagnosis, age at diagnosis, sex of patient, primary site and morphology code. National population estimates of age and gender by calendar year were also obtained from ONS data  and age–Some published incidence analyses have used different criteria as to which glioma and astrocytoma should be considered malignant. WHO considers Grades I to IV as biologically malignant even if they have not been graded histologically malignant. We have taken the WHO/IARC morphology behaviour codes /3, /6 and /9 as being histologically malignant which means that Grade I and II tumours are classed as low–grade malignancies.th July 2017.We are not aware of any specific bias in the ONS data. There is a slight data–lag in cancer registry data, which are regularly checked and updated if necessary, but are generally stable after 3 to 5 years. Our ONS data extract is dated 4Brodbelt et al. (2015)  reportedWe had a large number of categories and sub–categories in the data. It was necessary to combine some of these to increase the resolving power. We ran analyses separately for each site (C71.0 to C71.9), for each main type of tumour, and for tumour grade (I to IV). It was immediately obvious that the most significant change was in the incidence of GBM in frontal and temporal lobes. The obvious potential confounders would be the C71.8 (overlapping) and C71.9 (unspecified) categories due to better imaging techniques and we discuss this later.Incidence rates rise dramatically with age and standardisation is necessary as population age profiles are changing with time. We calculated age–standardised incidence rates (ASR) per 100k person–years to the current recommended European Standard Population (ESP–2013), as it best represents the reality of the case burden on society (ln(rate) de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary glioblastomas). Secondary glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis.”In a major 2013 review article, Hiroko Ohgaki and Paul Kleihues  wrote “GOverall primary malignant brain tumour ASRs are only rising slowly and are often considered fairly static. Overall adult survival for all malignant brain tumours after diagnosis during 2006–2010 was about 35% for one year and 15% for five years, falling to about 3% for aggressive grades–III and IV tumours. ONS data show age-standardised death rates from malignant brain tumours (C71) have increased by 7% between 2001 and 2015, showing that improvements in treatment alone are inadequate and that there is a need to find ways of preventing brain cancer .Comparing new case numbers in 2015 with 1995 shows an extra 1548 aggressive GBM tumour cases annually.  de novo and promoted tumours. We estimated the maximum possible number of promoted tumours using the change in the grades II and III diffuse and anaplastic astrocytomas. The results are shown in Figures Ohgaki and Kleihues  reportedWe found a large decrease of ASR over time for Grade–II diffuse astrocytoma, a slight rise in ASR for WHO Grade–III anaplastic astrocytoma . There was little change in rates of anaplastic oligodendroglioma , anaplastic ependymoma  Grade–II oligodendroglioma , embryonal, or ependymal tumours.Using sufficiently high–quality data, we present a clearer picture of the changing pattern in incidence of brain tumour types than any previously published. We report a sustained and highly statistically significant ASR rise in GBM across all ages and throughout the 21 years (1995–2015), which is of importance both for clinical resources and brain tumour aetiology.Dobes et al. (2011)  reportedZada et al. (2012)  using USThere were no material classification changes over the analysis period that might explain our findings , though  de novo GBMs [ de novo glioblastoma and accounts for about 90% of cases. The remaining 10% are IDH–mutant cases, which usually arise in younger patients and mostly correspond to secondary or promoted lower–grade diffuse glioma [ de novo GBMs dominate in the over-54 age group. It is important that this pattern is monitored using modern genetic techniques.Most GBM cases seem to originate without any known genetic predisposition. GBMs from promoted lower–grade gliomas usually have different molecular genetic markers fromovo GBMs . The 201ovo GBMs , 4 highle glioma , 21. Fige glioma  that proGBM tumours are almost always fatal and are not likely to have been undiagnosed in the time-frame of our data. It is possible that some elderly cases were not fully classified, but then they should have been recorded as ICD10–D43. However, as D43 rates have remained very constant over this time period see , this isWe cite examples of some possible causal factors that have been discussed in the literature that could contribute changes in GBM incidence. In an important 2014 “state of science” review of glioma epidemiology, Ostrom et al.  list andIonising radiation, especially from X-rays used in CT scans, has the most supportive evidence as a causal factor. Due to the easy availability of CT imaging and relative lack and higher cost of MRI imaging in UK NHS hospitals, CT scans are often used, especially for initial investigations. Their use over the period 1995-2013 is shown in the Supplementary File . Given tPreston et al. (2007)  concludeThe European Study of Cohorts for Air Pollution Effects by Andersen et al. (2017)  found suThere is increasing evidence literature that many cancers including glioma have a metabolic driver due to mitochondrial dysfunction resulting in downstream genetic changes in the nucleus –28.The International Agency for Research on Cancer (IARC) judged both power–frequency ELF (2002)  and radiWe show a linear, large and highly statistically significant increase in primary GBM tumours over 21 years from 1995–2015, especially in frontal and temporal lobes of the brain. This has aetiological and resource implications.Although most of the cases are in the group over 54 years of age, the age–standardised AAPC rise is strongly statistically significant in all our three main analysis age groups.The rise in age–standardised incidence cannot be fully accounted for by improved diagnosis, as it affects specific areas of the brain and just one type of brain tumour that is generally fatal. We suggest that widespread environmental or lifestyle factors may be responsible, although these results do not provide additional evidence for the role of any particular risk factor.Our results highlight an urgent need for funding more research into the initiation and promotion of GBM tumours. This should include the use of CT imaging for diagnosis and also modern lifestyle factors that may affect tumour metabolism.


The laser was also used to resect epiglottitis, false focal cords, and aryepiglottic fold completely due to supraglottic swelling with a thick oedematous epiglottis. A 1.5‐ms pulse‐duration CO2 laser attached to a microscope is an effective technique of treating laryngeal sarcoidosis and preventing its hazardous complication. Beneficial effects of this method are not only an immediate improvement of the symptoms, but also this method decreases the need for long‐term medical therapy with its side effects or avoid tracheostomy due to upper airway obstruction.To improve diagnosis and treatment of laryngeal sarcoidosis, we present a rare case of upper airway obstruction of unclear aetiology, with life‐threatening complication.The patient was a 19‐year boy who presented with progressive severe dyspnoea for eight months. After extensive diagnostic evaluations with no conclusive diagnosis, biopsy showed non‐caseating granulomatous inflammation consistent with laryngeal sarcoidosis that was treated with a CO To improve diagnosis and treatment of laryngeal sarcoidosis, we present a rare case of upper airway obstruction of unclear aetiology, with life‐threatening complication in a 19‐year‐old boy. Sarcoidosis is a chronic systemic granulomatosis disease that affects usually lungs, eyes, or skin. Upper respiratory tract involvement is less common as laryngeal sarcoidosis accounts for less than 5% of all patients 2 laser attached to a microscope was used . The laser was also used to resect epiglottitis, false focal cords and aryepiglottic fold completely due to supraglottic swelling with a thick oedematous epiglottis. Patient was discharged on oral medical therapy after surgery with cefixime and omeprazole and was followed up to 4 weeks. After his final treatment there was resolution of the symptoms and the laryngeal oedema had diminished (Fig. A 19‐year‐old with no past medical history, presented with eight months of progressively worsening snoring and dyspnoea. At initial evaluation, spirometry showed upper airway obstructive pattern Fig. . Finallyhed Fig. . He is cSarcoidosis is a multisystem disease with unknown aetiology. Laryngeal sarcoidosis is a less common that usually was appeared in third decades of patients' life Timely diagnosis and treatment of laryngeal sarcoidosis due to obstruction of upper airway that is its hazardous complication is an important issue.Appropriate written informed consent was obtained for publication of this case report and accompanying images.


HIV pandemic; however, the pace of incidence decline has slowed or stalled in many East and Southern African countries, especially among young women. This stall is worrying because many countries have burgeoning youth populations. There is an important window of opportunity to halt the epidemic as well as the potential for millions more infections if primary prevention efforts are not strengthened.Significant progress has been made in the African HIV incidence among young women has remained high. In this paper, we characterize the intervention context and examine how it can be strategically utilized to maximize HIV prevention interventions among young women. We begin by examining how contextual dynamics drive HIV risk. We illustrate how epidemiological contexts, gendered normative and economic contexts, and environmental contexts work synergistically to make young women especially vulnerable to HIV infection. We then examine how these contexts can undermine HIV prevention interventions. Finally, we discuss the importance of fully mapping out the intervention context to enhance the effectiveness of HIV prevention interventions.Many hyper‐endemic settings have been exposed to numerous interventions; however, HIV incidence among young women and help to limit the reach of the HIV pandemic into new generations of Africans.Understanding an intervention context, and how its features work together to amplify young women's risk in hyper‐endemic settings can contribute to sustained momentum in reducing  STI prevalence is 13%, and young women under age 25 are at significantly higher risk Hyper‐endemics are often characterized by interacting epidemiological factors that work together to make even a single sexual encounter risky for young women In sum, in hyper‐endemic settings like these, young women's sexual lives unfold in epidemiological contexts with high community viral loads of HIV and amplifying STIs. Furthermore, high prevalence means they are likely to encounter a partner with HIV, and their most likely sexual partners – men in their 20s and 30s – generally have low rates of circumcision, report relatively low rates of condom use, and among those living with HIV, have relatively low viral suppression. This combination of interacting epidemiological factors places young women at significant risk for HIV acquisition 2.1.2When layered on to a dangerous epidemiological context, the gendered normative context works to further amplify young women's HIV risk. Social norms regulate sexual behaviour by setting “group level expectations for appropriate behavior that result in negative sanctions for people who violate them.” [Hyper‐endemic HIV risk environments share similar gendered normative contexts characterized by high levels of women's autonomy in entering and exiting relationships, but unequal gender power norms within them that are exacerbated when they are transactional It is important to note that gender and relationship norms also amplify men's HIV risk. Masculinity norms in many historically polygamous cultures are supportive of concurrency, and may also lead to men's lower uptake of HIV testing and treatment Overall, the gendered normative context encourages young women to pursue the riskiest partners in their community – men in their 20s and 30s who are able to provide, but who are also more likely to afford and have cultural support in seeking multiple partners, and who are less likely to be reached by epidemiological programming.2.1.3Many hyper‐endemic settings also have similar economic configurations characterized by widespread inequality and poor employment opportunities Finally, it is important to note that the environmental context is often an underlying driver of gendered economic contexts. For example, unsustainable agricultural livelihoods may contribute to male out‐migration; widows displaced from land may turn to sex work; new resource extraction may attract many more men to an area; and an imbalanced lake eco‐system may exacerbate fishermen's migratory patterns leading to extended sexual networks and increased vulnerability for women While many features of these social contexts are not unique to hyper‐endemic settings, they are distinguished by how they synergistically work together to significantly amplify young women's HIV vulnerability.2.2There is now a widespread consensus that strategic combinations of multi‐level HIV prevention approaches are the way forward, and many hyper endemic settings have been exposed to numerous interventions over the past few decades 2.2.1Epidemiological contexts are often the Achilles heel of HIV prevention interventions. Major pre‐exposure prophylaxis (PrEP) trials among young women in high incidence settings have had limited success 2.2.2Many HIV prevention interventions do not adequately work to meaningfully alter the gendered normative context that will ultimately determine prevention uptake and its long‐term sustainability 2.2.3Many promising micro‐finance or cash transfer interventions have been conducted with limited impact on HIV incidence with few exceptions 2.3As Figure An important first step is to map out the pre‐existing intervention context in a given setting, and then locate the new intervention – and its intended mechanisms to reduce HIV incidence – within it. This will enable intervention designers to clearly see potential barriers and/or catalysts to their proposed intervention. Fully mapping the intervention context also enables designers to assess how much weight is being placed on the new intervention to achieve incidence control, and whether a longer duration or multi‐level approach might increase the chances of success Mapping the intervention context also enables a strategic utilization of pre‐existing features of social and programmatic contexts to increase the chances of intervention success. For example, intervening at multiple levels may be beyond the funding scope of an intervention; however, as noted earlier, numerous interventions are often ongoing in hyper‐endemic settings 3Each year, millions of adolescent African girls begin their sexual debut in hyper‐endemic settings where one‐fifth to one‐third will be HIV positive by the time they are in their late 20s and early 30s. This commentary has examined how contextual drivers might contribute to stalling epidemics, and how they might be deployed to maximize HIV prevention. Understanding how contexts synergistically work together in hyper‐endemic settings, and fully mapping and strategically utilizing the intervention context could enable sustained momentum in reducing HIV incidence among young women, and limiting the reach of the HIV pandemic into new generations of Africans.The authors report no competing interests.S.M. wrote the first draft of the manuscript. J.W. contributed to writing the manuscript. Both authors approved the final draft.


Cancer epidemic led to worldwide to search for a new “game changer” concept to govern cancer research and cancer treatment. Western medicine-based cancer research has been extending the impasse without resolution in sigh for improving survival of patients with solid malignant tumors in the last four decades due to heterogeneity in cancer tissues. Such a deadlock charts a course to learn lessons from the developing countries, directly or indirectly to complement the exhausted Western medicine. We propose a new concept of “Cancer niche as a garbage disposal machine” with implications of traditional Chinese medicine-mediated restoration of normal balance between body and disease to bring the fight against cancer under control. Published based on data in the most recent (2006 – 2015), “the rate of new cancer diagnoses decreased by about 2% per year in men and stayed about the same in women. The cancer death rate (from year 2007 to year 2016) declined by 1.4% per year in women and 1.8% per year in men”  guided Chinese herbal medicine [CHM] therapy was associated with reduced mortality among patients with pancreatic cancer. Specifically, “CHM users had a lower hazard ratio of mortality risk . Those who received CHM therapy for more than 90 days had significantly lower hazard ratios of mortality risk than non-CHM users , The survival probability was higher for patients in the CHM group.” . The mecThe concept cancer niche as a garbage disposal machine implies TCM-mediated balance of body-disease for treatment of cancer. We need to make peace with cancer by sharing the resources of the body and environment. AI-based research will develop a mathematical framework to explain how the cancer garbage disposal represents an organ of dynamic cell debris, in an aging body, with predicted changes through a lifetime. Experiments will verify the framework model to guide healthcare.


Plants display a remarkable capacity for somatic cell totipotency, as demonstrated by single plant cells that can develop into embryos and complete plants. How does a single somatic cell become a whole plant? This represents the forefront of the most compelling puzzles since Haberlandt's prediction of totipotency (1902) and is one of the top 25 big questions that face scientific inquiry today Vogel, . Elucidaet al., As a notable illustration of totipotency, somatic embryogenesis (SE) is quite interesting and provides an ideal system for investigation of the whole process of single cell differentiation as well as the expression of totipotency  that was markedly activated in proembryogenic masses (PEMs; Zeng Using these systems, cellular organization and activity during transdifferentiation were analysed in living cells; these elements are crucial for proper cell functioning. Our results demonstrated that the somatic‐to‐embryogenic transition was divided into two different steps: the embryogenic pathway induction phase, followed by the phase of acquisition of embryogenic competence. Two new notable cellular events determining somatic‐to‐embryogenic transition during totipotency were identified in this study.In the first induction phase, somatic dedifferentiated cells Figure g are divInduction of embryogenic totipotency requires cell fate change through initiating division and establishing a new polarity in somatic cells. The typical cell polarization and the high amyloplast accumulation in our study were interpreted as the first observable steps towards the acquisition of a competent state. Concomitant with the somatic‐to‐embryogenic transition, the increase in the endogenous content of starch appeared to be related to an increasing demand for energy, which is an essential point in the conversion of embryogenic fate acquisition. Our results suggested that cellular polarities were driven by SELTP‐assembled amyloplasts in a single embryogenic cell precursor, which primed embryogenic pathway initiation.In the second phase, our results revealed that as proembryogenic cells progressed, SELTP‐assembled amyloplasts crumbled away Figure m and degEmbryogenic fate was determined following the two cellular events of polarization and sharp energy release. The cells continued to proliferate and progress, forming perfect embryogenesis and embryoids in solid media culture Figure p, q. HowSELTP gene for competent cells expressing totipotency and show that SELTP and the corresponding amylase could serve as markers for early detection of the embryonic cell progenitor, enabling an early diagnosis of embryogenic potential.In this study, successive amyloplast polarization, accumulation and breakdown in single cells were interpreted as the early reflection of somatic‐to‐embryogenic transition and acquisition of cell totipotency during SE. Cellular amyloplast polarity establishment was suggested as the primary driver for inducing plant somatic cell totipotency. Then, the charge and subsequent discharge rhythm of the SELTP‐associated battery triggered cell totipotency fate and the acquisition of embryogenic competence. These results suggested the importance of SELTP for assembling amyloplasts in somatic dedifferentiated cells. These SELTP‐associated organelles serve as powerful batteries that drive embryonic activation. The increased amyloplasts associated with SELTP were likely to be limiting factors during SE. Our findings highlight the significance of the At the single‐cell level, our findings demonstrate and highlight the importance of SELTP‐assembled amyloplasts for single cell polarization and cell totipotency determination during transdifferentiation for the acquisition of embryogenic competence. This provides new information that helps to identify embryogenic cells and direct future strategies for SE induction, holding great promise for its advancement in recalcitrant plant species.The authors declare no conflict of interest.


Understanding classical and nonclassical mechanisms of crystal nucleation and growth at the atomic scale is of great interest to scientists in many disciplines. However, fulfilling direct atomic‐scale observation still poses a significant challenge. Here, by taking a thin amorphous bismuth (Bi) metal nanosheet as a model system, direct atomic resolution of the crystal nucleation and growth initiated from an amorphous state of Bi metal under electron beam inside an aberration‐corrected transmission electron microscope is provided. It is shown that the crystal nucleation and growth in the phase transformation of Bi metal from amorphous to crystalline structure takes place via the particle‐mediated nonclassical mechanism instead of the classical atom‐mediated mechanism. The dimension of the smaller particles in two contacted nanoparticles and their mutual orientation relationship are critical to governing several coalescence pathways: total rearrangement pathway, grain boundary migration‐dominated pathway, and surface migration‐dominated pathway. Sequential strain analyses imply that migration of the grain boundary is driven by the strain difference in two Bi nanocrystals and the coalescence of nanocrystals is a defect reduction process. The findings may provide useful information to clarify the nanocrystal growth mechanisms of other materials on the atomic scale. We demonstrate that particle coalescence is crucial to the growth of initial stable crystal nucleus and subsequently single crystals. We offer definitive evidence to the cluster coalescence‐driven crystallization and identify the critical diameter of the formed stabilized crystal in the amorphous to crystalline phase transformation of Bi metal. Interestingly, the coalescence mode of nanoparticles can be controlled by the dimension of the smaller particle in the two contacted nanoparticles and their mutual orientation relationship. Further sequential geometrical phase analyses (GPAs) reveal a stress‐driven grain boundary migration.2Amorphous Bi nanosheets were synthesized using a simple ultrasonic route.Figure−2 s−1) . Figures S4 and S5 (Supporting Information) show that the Bi nanocrystal under electron irradiation possesses a hexagonal structure (JCPDS Card No. 44‐1246). From Figure dc ≈10 nm, the nanoparticle eventually develops into a nanocrystal with a stable crystal structure. Subsequent to the formation of many such small unstable nanoparticles, the nucleation and growth mediated by nanoparticle coalescence take place rapidly . Based on the FFT analyses , the rotation angle between the two nanocrystals alters from 11° before contact to 0° after contact. It is worth noting that the main atomic rearrangement takes place in the smaller nanocrystal. Figure 1¯2¯1¯] and [22¯1¯] before coming into contact , as also confirmed by FFT analyses . After coming into contact , the slow atomic migration and rearrangement rates are observed in the big nanocrystals, resulting in the formation of relatively stable grain boundary after contact of the two particles.To gain insight into the influence of particle size and orientation on the coalescence mechanisms in the amorphous to crystalline phase transformation, we investigate the coalescence of nanocrystals with different sizes and orientations, as shown in dc), leading to the formation of a small high‐angle grain boundary with a rotation angle of 20° , as also confirmed by the corresponding FFT analyses . The dynamic process confirms that the coalescence pathway is dominated by the grain boundary migration in the two nanocrystals with a small high‐angle grain boundary. Figure Figure In contrast to the grain boundary migration‐dominated coalescence pathway for the two nanocrystals with a small high‐angle grain boundary, the two nanocrystals with a large high‐angle grain boundary show a surface migration‐dominated coalescence pathway, as shown in Figure s), number (n) of nanocrystal, and number (m) of drop‐like amorphous precursor as a function of crystallization time , as shown in Figuren) and drop‐like amorphous precursors (m) show a nonlinear correlation with time, which is attributed to the coalescence‐driven rapid crystallization at the initial stage and also to the nanocrystal coalescence‐induced slow growth of bigger nanocrystals  as a function of width of smaller particles (d) and coalescence time  for the pairs of particles in Figure l and Δt, indicating that all coalescence processes are completed based on atomic rearrangement and migration. Comparing the three brown, orange, and blue curves, we can see that as the size of the smaller nanoparticles in the pair of particles is smaller than dc, their coalescence is finished in a short time after contact with each other. It implies that a similar coalescence pathway of small particle rotation and rearrangement is involved in these processes and the orientation relationship has a limited influence on the pathway. In contrast, when the size of the nanocrystal is larger than dc , the grain boundary migration‐dominated  pathway, and surface migration‐dominated (ds > dc and a large tilt angle after contact) pathway for the coalescence process.2¯1¯3] direction and the corresponding sequential strain tensor analyses in Figurexxε, xyε, and xyε are the expansion, shear components, and contraction of strain. From the initial HRTEM image (Figure To further shed light on the migration of dislocation in the coalescence process, we show an atomic‐scale sequential HRTEM image of dislocation arrays at a grain boundary with a rotation angle of ≈16° viewed along [To further understand the origin of strain evolution during the coalescence process, we investigate the change of rotation angle between the two nanocrystals with time employing the sequential FFT analyses (Figure 3The ability to perform in situ atomic‐resolution observation of dynamic process of crystallization and growth represents a significant step forward in understanding crystal nucleation and growth mechanisms at the atomic scale. We show that Bi crystal nucleation and growth in the transformation process from amorphous to crystalline phase take place via the nonclassical mechanism mediated by particle coalescence and that the coalescence pathway of two nanoparticles is governed by the dimension of the smaller particle and their orientation relationship. When the size of the smaller one in the two nanoparticles is less than the critical size, coalescence takes a thorough rearrangement and the rotation mechanism as well as the orientation has a negligible effect on the pathway. The coalescence of two crystals takes place via a grain boundary migration‐dominated pathway if the formed grain boundary is a small high‐angle grain boundary, while via a surface migration‐dominated pathway if a large high‐angle grain boundary is formed. Further sequential strain analyses imply that migration of a grain boundary is driven by strain difference in the two nanocrystals. These findings reveal the atomic‐scale dynamic information on the nonclassical particle‐mediated crystal nucleation and growth mechanism, which helps to advance our general understanding of dynamic process of phase transformation and nucleation.4Sample Preparation and Characterization: The ultrasonic method was used to fabricate amorphous Bi nanosheets.In Situ TEM Observation and Chemical Analysis: The obtained samples were dispersed in ethanol under ultrasonication for 30 min, and several drops of this dispersion were placed onto a holey carbon grid, which were subsequently dried for in situ TEM experiments. TEM imaging was conducted using a Titan Themis TEM equipped with both probe and image Cs correctors and a Super‐X EDS detector operated at 200 keV, which offered an unprecedented opportunity to probe structures with sub‐Ångström resolution. Series images were acquired using the Tecnai Imaging and Analysis software. The electron dose was tuned by manipulating spot size.The authors declare no conflict of interest.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.


Global migration policy discussions are increasingly driven by moral panics – public anxiety about issues thought to threaten the moral standards of society. This includes the development of two Global Compacts – agreed principles to guide an international response – for (1) “Refugees” and (2) “Safe, Regular and Orderly Migration.” While the need to address migration and health is increasingly recognized at the global level, concerns are raised about if this will be reflected in the final Compacts. The Compacts focus on securitization, an approach that aims to restrict the movement of people, presenting potentially negative health consequences for people who move. Globally, concern is raised that migration‐aware public health programming initiatives could be co‐opted through a global health security agenda to further restrict movement across borders. This is particularly worrying in the Southern African Development Community (SADC) – a regional economic community associated with high levels of migration and the largest population of people living with HIV globally; this case is used to explore concerns about the health implications of the Global Compacts.Current HIV responses in SADC do not adequately engage with the movement of healthcare users within and between countries. This negatively affects existing HIV interventions and has implications for the development of universal HIV testing and treatment (UTT) programmes. Drawing on literature and policy review, and ongoing participant observation in policy processes, I outline how Global Compact processes may undermine HIV prevention efforts in SADC.The global health imperative of developing migration‐aware and mobility‐competent health responses must not be undermined by moral panics; the resultant international policy processes run the risk of jeopardizing effective action at the local level. Globally, migration is increasingly recognized as a central public health concern, providing strategic opportunities to strengthen public health responses for all. Without mainstreaming migration, however, health responses will struggle. This is particularly concerning in SADC where HIV programmes – including UTT initiatives – will struggle, and key health targets will not be met. Globally, contextually appropriate migration‐aware responses to health are needed, including and a specific focus on HIV programming in SADC. In spite of recent calls at the global level to improve responses to migration and health, and the development of a global research agenda to support this In this commentary, I explore the implications of the current global migration policy terrain for the Southern African Development Community (SADC), a regional economic community made up of 15 member states that is associated with high levels of both internal (within country) and cross‐border (between country) migration and a high communicable disease burden, including the largest population of people living with HIV globally 22.1As evidenced by the current Global Compact processes, we find ourselves in a world increasingly concerned with securitizing national borders and restricting the movement of people between nation states. Much of this focus on security is driven by moral panics – public anxiety about issues thought to threaten the moral standards of society – associated with migration, including human trafficking and the independent movement of women The “draft zeros” of the two Global Compacts were released in early 2018 2.2In spite of the SADC region being associated with a long history of diverse population movements, current public health responses to HIV still fail to adequately engage with migration and the movement of healthcare users – both within and between countries Globally – and in SADC – key population groups currently targeted for HIV prevention initiatives are often highly mobile, including sex workers and men who have sex with men However, a key challenge exists – evidence suggests that SADC remains poorly equipped to initiate and manage the political discussions within and between member states that are required to develop appropriate regional responses to migration, mobility, and HIV 2.3Within the SADC region, South Africa is the recipient of the largest number of cross‐border migrants (most of whom come from other SADC states), has a long history of internal migration, and a continued high prevalence and incidence of HIV Civil society and international organizations have attempted to step in to provide migration‐aware responses in spaces where the state is absent, including through HIV interventions supported by the International Organization for Migration (IOM)  3There is an urgent need to develop migration‐aware Concerns about how the Global Compact processes may undermine efforts to improve responses to health and migration globally should not be taken lightly. Vigilance is required to ensure that migration‐aware public health programming is not co‐opted to support securitization agendas that place the health and wellbeing of people on the move at risk. Globally, contextually appropriate migration‐aware responses to health are required; migration is a central public health imperative that provides a strategic opportunity to strengthen public health responses for all – including universal healthcare coverage The author has no conflicts of interest to declare.


Mental illness is a leading cause of disability in South East Asia among those 15 to 49 years of age, with over 7.6 million disability‐adjusted life‐years lost in 2016 alone lowest levels of mental health assessments across this global consortium Barrier #1: Multiple stigmas. With 5.2 million PLHIV, the region has the second largest epidemic in the world which is primarily concentrated among key populations, including men who have sex with men, people who inject drugs, sex workers and transgender individuals Barrier #2: Lack of integration between HIV and mental healthcare. Despite the prevalence of mental illness among PLHIV, mental health screening is not commonly integrated into HIV clinic procedures, which is problematic because the bulk of care to PLHIV in the region is delivered by HIV providers primarily focused on ART management. Public health systems have separately functioning HIV and mental health departments or ministries, and national policies and practices have rarely supported cross‐disciplinary collaboration or clinical management.Barrier #3: Limited data to drive policy change. There is a relatively small evidence base around mental illness among PLHIV in the Asia‐Pacific that is primarily focused on depression as an outcome. There are fewer studies that evaluate the utility of interventions to improve mental healthcare delivery in the context of HIV care.However, integration of mental health and HIV care is uncommon in the region. In a survey of global IeDEA  clinical sites, only 43% of those in the Asia‐Pacific reported screening for depression, 39% for substance use disorders, 11% for post‐traumatic stress disorder and 29% for any other mental disorder – overall, representing the A key intervention to overcome the substantial human resource limitations for mental healthcare for PLHIV in the region is to train non‐mental health specialists to deliver basic psychotherapeutic interventions with expert supervision. An example of this is the WHO's Mental Health Gap Action Programme (mhGAP), which has developed tools to accelerate task‐shifting in low‐ and middle‐income country settings (LMICs) In addition, research should be conducted within real‐world care settings to determine optimal strategies to diagnose and treat those in need as well as quantify the impact on adherence, retention and mortality for mental healthcare interventions. Identification and evaluation of optimal implementation strategies to scale and sustain integrated HIV and mental healthcare could provide the data needed to justify proactive policies and the allocation of limited health resources. Implementation science offers a platform particularly well‐suited to conduct research around the intersection of HIV and mental health, and can address complex questions related to the adoption, adaptation, integration, scale‐up and sustainability of evidence‐based practices, as well as monitoring and evaluating of outcomes at the patient, provider and system levels. Evidence‐based tools and treatments developed in high‐income countries must be “translated” across cultures, which requires more than linguistic adaptation in order to balance fidelity  and fit (for a novel context) to achieve the desired outcomes of the interventions Central to these potential solutions for bridging the gaps between HIV and mental health is public health leadership and the political will behind it to prioritize mental healthcare within HIV programmes. As external HIV funding declines to Asia‐Pacific LMICs While countries in the Asia‐Pacific continue to make progress with HIV testing and treatment scale‐up, we need a clear way forward to address mental health challenges among PLHIV. Access to potent antiretroviral medicines and laboratory monitoring alone will not solve these problems, which pose very real threats to adherence, retention and quality of life. Delivering sustainable and cost‐effective mental health services and addressing human resource, data and policy gaps are essential to address the intersection between HIV and mental illness, and will help maintain the public health gains made in controlling regional HIV epidemics.AHS has received travel and research support to her institution from ViiV Healthcare.AHS and MLW developed the idea for and drafted the Viewpoint. All authors participated in research think tanks where ideas presented in the Viewpoint were discussed, and revised and approved the text.


Much theoretical evidence has demonstrated that a trade‐off between competitive and dispersal ability plays an important role in facilitating species coexistence. However, experimental evidence from natural communities is still rare. Here, we tested the competition–dispersal trade‐off hypothesis in an alpine grassland in the Tianshan Mountains, Xinjiang, China, by quantifying competitive and dispersal ability using a combination of 4 plant traits . Our results show that the competition–dispersal trade‐off exists in the alpine grassland community and that this pattern was primarily demonstrated by forbs. The results suggest that most forb species are constrained to be either good competitors or good dispersers but not both, while there was no significant trade‐off between competitive and dispersal ability for most graminoids. This might occur because graminoids undergo clonal reproduction, which allows them to find more benign microenvironments, forage for nutrients across a large area and store resources in clonal structures, and they are thus not strictly limited by the particular resources at our study site. To the best of our knowledge, this is the first time the CD trade‐off has been tested for plants across the whole life cycle in a natural multispecies plant community, and more comprehensive studies are still needed to explore the underlying mechanisms and the linkage between the CD trade‐off and community composition. For a long time, the hypothesis that there is a trade‐off between competitive and dispersal abilities in a given species has been considered to be an important mechanism underlying species coexistence  trade‐off has been demonstrated in many theoretical studies , located in Hejing County in the Bayingolin Mongol Autonomous Prefecture of Xinjiang Uygur Autonomous Region (referred to as Xinjiang), China. This grassland is in the southern Tianshan Mountains basin, with a mean altitude of 2,500 m, and covers a total area of approximately 23,000 km2.2From August to October in 2017, 15 sites were regularly sampled along a 98‐km‐length transect  were weighed for each species to measure the seed mass (g/100 seeds).2.3.2−4 g in the laboratory.For each species, nine undamaged ramets  were randomly collected. The ramet height (cm) was measured from the base to the highest point of the plant. The aboveground parts (stem and leaves) of the measured ramets were then clipped, oven dried at 75°C, and weighed with an accuracy of 102.3.3In the method used by Tamme et al. , the lif2.3.4The dispersal modes of the studied species were divided into four groups in accordance with the morphological features of the seeds: wind dispersal without special mechanisms , wind dispersal with special mechanisms , animal dispersal , and ballistic dispersal  undergo clonal reproduction in 29 forb species  also undergo clonal reproduction in their life history. In contrast, only one species (4Our results showed that the CD trade‐off existed for species in the alpine grassland community but that there was a difference between the functional groups of graminoids and forbs. A significant trade‐off between competitive ability and dispersal ability was found for the forbs but not for the graminoids. This result might have occurred because of different resource capture and allocation strategies between the forb species and graminoid species.Many previous studies have documented the trade‐offs between competitive and dispersal ability due to resource constraints during the life history of organisms (Leishman, Leymus secalinus, Festuca gigantea, and Festuca ovina.In contrast to forbs, the relationship between competitive and dispersal ability in graminoid species was not significant at our study site, suggesting that the CD trade‐off might not exist in those species. A probable explanation is that graminoid species may not be restrictedly constrained by resources, largely because, unlike forbs, which are strongly restricted to sexual reproduction, 94.44% the graminoid species undergo both sexual and clonal reproduction at our study site. The ability to undergo clonal reproduction allows graminoid species to find more benign microenvironments, forage for nutrients across a large area, transport acquired resources among different clone parts and store resources in clonal structures (Evans & Cain, In this study, we revealed that the CD trade‐off depends on plant traits that are closely related to competitive or dispersal ability. Indeed, previous studies have suggested that relationships among species’ traits related to species’ competitive and dispersal ability play an important role in determining the absence or presence of a CD trade‐off (Pastore et al., 5In a natural alpine grassland community, we quantified the competitive and dispersal abilities of different species based on 4 plant functional traits. We found that the CD trade‐off existed in forb species but not in graminoid species, perhaps because graminoid species undergo clonal reproduction and are thus not strictly limited by resource availability. In the future, more comprehensive studies are needed to detect the effects of limiting environmental factors on the patterns of CD trade‐offs and link them to community assembly and species coexistence.None declared.Xiaolong Zhou and Qingdong Shi conceived and designed the experiments. Xiaolong Zhou and Chengzhi Li performed the experiments. Xiaolong Zhou and Honglin Li analyzed the data and wrote the manuscript. Click here for additional data file. Click here for additional data file.


Exercise also induced changes in the insulin and lipid signaling pathways in obese dams that were different from those observed in control and sedentary‐obese dams. The changes induced by obesity and exercise were tissue‐specific and related to alterations in tissue lipid, protein and glycogen content and plasma insulin, leptin and triglyceride concentrations. We conclude that the beneficial effects of exercise on metabolic outcomes in obese mothers may be related to specific molecular signatures in metabolically active maternal tissues during pregnancy. These findings highlight potential metabolic targets for therapeutic intervention and the importance of lifestyle in reducing the burden of the current obesity epidemic on healthcare systems.Obesity during gestation adversely affects maternal and infant health both during pregnancy and for long afterwards. However, recent work suggests that a period of maternal exercise during pregnancy can improve metabolic health of the obese mother and her offspring. This study aimed to identify the physiological and molecular impact of exercise on the obese mother during pregnancy that may lead to improved metabolic outcomes. To achieve this, a 20‐min treadmill exercise intervention was performed 5 days a week in diet‐induced obese female mice from 1 week before and up to day 17 of pregnancy. Biometric, biochemical and molecular analyses of maternal tissues and/or plasma were performed on day 19 of pregnancy. We found exercise prevented some of the adverse changes in insulin signaling and lipid metabolic pathways seen in the liver, skeletal muscle and white adipose tissue of sedentary‐obese pregnant dams (p110 Worldwide, the prevalence of obesity is increasing rapidly  that were purchased from Charles River, UK were group housed under dark: light 12:12 conditions and were randomly assigned to be fed for 6 weeks before their first pregnancy and thereafter one of two diets ad libitum; either a standard RM1 diet  or a semi‐synthetic energy‐rich highly palatable obesogenic diet  supplemented with sweetened condensed milk  , which was supplemented with the vitamin and mineral mix AIN93G. Both diets were purchased from Special Dietary Services . Dams were allowed to litter their first pregnancy and their pups were culled at weaning. The first pregnancy ensured fertility and nurturing in the experimental mice. Six control dams and fourteen obese dams were then mated with control males fed the standard RM1 chow to generate a second pregnancy. The dams were maintained on their respective diets throughout their second pregnancy (copulatory plug defined as day 1 of pregnancy). It is known that this diet is associated with hyperinsulinemia and glucose intolerance in the dam and this model of preexisting obesity leads to small for gestational age pups  Act 1986 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Board. The dietary method of inducing obesity and the exercise intervention have been described previously , white adipose tissue , kidneys, heart, placentas, and fetuses were weighed  and immediately snap frozen on dry ice for biochemical analysis and quantification of protein abundance. Blood was collected for plasma analyses. All tissues and plasma samples were collected from our dams under fed conditions to avoid introducing stress as a confounder.On day 19 of pregnancy, dams were killed by COLeptin and insulin were measured by enzyme‐linked immunosorbent assay, ELISA . Samples were assayed in duplicate and intra and inter‐assay coefficients of variation of less than 10.0% was considered acceptable for both assays. Serum triglycerides, nonesterified fatty acids, and total cholesterol concentrations were measured by the Medical Research Council Metabolic Diseases Unit Mouse Biochemistry Laboratory .µg of protein per sample and measured the receptors that can respond to insulin , mitogen‐activated protein kinase (MAPK), which regulates cell proliferation and phosphoinositide‐3 kinases  and protein kinase B (AKT) that transduce the metabolic actions of insulin. We assessed the abundance of a glucose storage enzyme , proteins that control protein translation downstream of the mechanistic target of rapamycin, mTORC1  and lipid metabolic proteins . The ponceau‐stained membranes confirmed equal protein loading and transfer.Glycogen, fat, and protein content were quantified using standard biochemical assays  correlation. All statistical analyses were performed on GraphPad Prism 4.0 and findings P < 0.05 were considered significant.To compare all three groups of mice, data were analysed by one‐way analysis of variance (ANOVA), followed by pairwise Bonferroni post hoc analyses (significant differences were denoted by different superscripts). Relationships between variables were assessed by Pearson , total Akt, and total GSK3 relative to the control group  were decreased in sedentary and exercised obese dams, which may have minimised further lipid deposition in those tissues.In line with the observed increased overall adiposity in both obese sedentary and exercised mice  in the maternal liver, compared to lean controls. Genetic loss of AKT is known to prevent hepatic accumulation of lipids in response to high dietary fat consumption . Moreover, a few components of the insulin signaling pathway were restored to control levels by exercising the obese dams (PI3K‐p110α and PI3K‐p110β). We have previously found that the exercise intervention improved maternal insulin sensitivity and glucose intolerance of obese dams  in the skeletal muscle of exercised obese dams compared to lean controls. This is in contrast to findings in nonpregnant animals, where exercise instead upregulates the abundance of several insulin signalling components in the skeletal muscle (Goodyear et al. In common with previous findings in rats (Vega et al. In conclusion, our data demonstrate that insulin sensitivity of the maternal white adipose is a key factor mediating the reduced glucose tolerance of the mother due to diet‐induced obesity. Furthermore, these data indicate that restoring insulin sensitivity of obese mothers during pregnancy using an exercise intervention (Fernandez‐Twinn et al. The authors have no conflicts of interest to declare.