Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

Increase in CFC-11 emissions from eastern China based on atmospheric observations.

The recovery of the stratospheric ozone layer relies on the continued decline in the atmospheric concentrations of ozone-depleting gases such as chlorofluorocarbons1. The atmospheric concentration of trichlorofluoromethane (CFC-11), the second-most abundant chlorofluorocarbon, has declined substantially since the mid-1990s2. A recently reported slowdown in the decline of the atmospheric concentration of CFC-11 after 2012, however, suggests that global emissions have increased3,4. A concurrent increase in CFC-11 emissions from eastern Asia contributes to the global emission increase, but the location and magnitude of this regional source are unknown3. Here, using high-frequency atmospheric observations from Gosan, South Korea, and Hateruma, Japan, together with global monitoring data and atmospheric chemical transport model simulations, we investigate regional CFC-11 emissions from eastern Asia. We show that emissions from eastern mainland China are 7.0 ± 3.0 (±1 standard deviation) gigagrams per year higher in 2014-2017 than in 2008-2012, and that the increase in emissions arises primarily around the northeastern provinces of Shandong and Hebei. This increase accounts for a substantial fraction (at least 40 to 60 per cent) of the global rise in CFC-11 emissions. We find no evidence for a significant increase in CFC-11 emissions from any other eastern Asian countries or other regions of the world where there are available data for the detection of regional emissions. The attribution of any remaining fraction of the global CFC-11 emission rise to other regions is limited by the sparsity of long-term measurements of sufficient frequency near potentially emissive regions. Several considerations suggest that the increase in CFC-11 emissions from eastern mainland China is likely to be the result of new production and use, which is inconsistent with the Montreal Protocol agreement to phase out global chlorofluorocarbon production by 2010.

Measurements of pulse rate using facial video cameras from smart devices in patients diagnosed with atrial fibrillation.

Clinical applications of passive long-term heart rate (HR) monitoring in patients with cardiac arrhythmias include adequate drug titration of atrioventricular (AV) nodal drugs and assessment of medical compliance with treatment. A majority of patients treated with beta-blockers, especially patients with atrial fibrillation (AF), require some degree of drug titration during the first 6 months of treatment to ensure that adequate HR control and medicine compliance has been achieved. Failing to achieve adequate rate control in patients with AF can lead to worsening symptoms, heart failure exacerbations, and potentially tachycardia-induced cardiomyopathy. Enabling video-based monitoring during telehealth patient visits could facilitate providers to measure heart rate (HR) without the need for a dedicated home device (smartwatch, SPO2 device, or others). Videoplethysmography (VPG) is a monitoring technology that measures pulse rate by utilizing front-facing cameras embedded in smart devices. VPG provides a remote and contactless cardiac monitoring solution. We conducted a clinical experiment to evaluate the accuracy of VPG in measuring HR while running on two portable devices: Samsung S10 smartphones and S3 tablets. We used a single­lead ECG to measure the heart rate at the time of the VPG recordings in AF patients. We employed the Bland-Altman method to measure the level of agreement between videoplethysmography and ECG-based measurements of HR. The findings reveal that the mean difference in videoplethysmography and ECG-based heart rate was inferior to 1 bpm across the 2 devices with confidence intervals ranging from 3 to 12 BPM. Our facial video-based HR monitoring solution could assist providers in measuring heart rates in their patients with AF during remote telehealth visits.

NIAID workshop on immunity to malaria: addressing immunological challenges.

The US National Institute of Allergy and Infectious Diseases convened a workshop of malaria investigators and immunologists to foster collaborations and attract more immunologists into malaria research. Discussions highlighted research gaps and underscored the incomplete understanding of basic immune mechanisms that contribute to the pathogenesis of or protection against malaria.

Second surgery for progressive glioblastoma: a multi-centre questionnaire and cohort-based review of clinical decision-making and patient outcomes in current practice.

PURPOSE: Glioblastoma prognosis is poor. Treatment options are limited at progression. Surgery may benefit, but no quality guidelines exist to inform patient selection. We sought to describe variations in surgical management at progression, highlight where further evidence is needed, and build towards a consensus strategy. METHODS: Current practice in selection of patients with progressive GBM for second surgery was surveyed online amongst specialists in the UK and Europe. We complemented this with an assessment of practice in a retrospective cohort study from six United Kingdom neurosurgical units. We used descriptive statistics to analyse the data. RESULTS: 234 questionnaire responses were received. Maintaining or improving patient quality of life was key to decision making, with variation as to whether patient age, performance status or intended extent of resection was relevant. MGMT methylation status was not important. Half considered no minimum time after first surgery. 288 patients were reported in the cohort analysis. Median time to second surgery from first surgery 390 days. Median overall survival 815 days, with no association between time to second surgery and time to death (p = 0.874). CONCLUSIONS: This is the most wide-ranging examination of contemporaneous practice in management of GBM progression. Without evidence-based guidelines, the variation is unsurprising. We propose consensus guidelines for consideration, to reduce heterogeneity in decision making, support data collection and analysis of factors influencing outcomes, and to inform clinical trials to establish whether second surgery improves patient outcomes, or simply selects to patients already performing well.

Knowledge and awareness of COVID-19 among Indonesian migrant workers in the Greater China Region.

OBJECTIVES: Migrant workers are one of the most vulnerable population groups during the coronavirus disease 2019 (COVID-19) pandemic. This study investigated knowledge and awareness of COVID-19 among Indonesian migrant workers (IMWs) in Macao (SAR), Hong Kong (SAR), and Taiwan. STUDY DESIGN: This was a cross-sectional study. METHODS: Data were collected through an online survey in February and March 2020 to gain information on (1) participants' sociodemographic characteristics, (2) experience and awareness regarding COVID-19 information, and (3) knowledge and understanding of COVID-19. A series of Chi-squared, t-test, and logistic regression analyses were conducted. RESULTS: The survey was completed by 491 participants (92.1% female). Knowledge of COVID-19 was obtained from multiple sources, including a large proportion from online social media. However, participants who obtained information from their employer, local social networks, and migrant organisations answered a greater number of questions correctly. One-third of participants reported receiving hoax, fake news, and incorrect information and obtained information from unverified sources. Participants were most interested in information about how to cure COVID-19, and 57.8% knew that no specific drug or vaccine was currently available. Almost all participants correctly identified fever and wearing a facemask as the main COVID-19 symptom and prevention strategy, respectively. Participants with senior high school or higher education and who worked as domestic or care workers had a greater knowledge of COVID-19 than their counterparts. CONCLUSIONS: Public health communication strategies using multiple channels, including employers and community organisations, would help to minimise COVID-19 knowledge gaps. In addition, it is recommended that digital literacy content is added to public health campaigns.

Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory.

Repeated presentations of a previously conditioned stimulus lead to a new form of learning known as extinction, which temporarily alters the response to the original stimulus. Previous studies have shown that the consolidation of extinction memory requires de novo protein synthesis. However, the role of specific nodes of translational control in extinction is unknown. Using auditory threat conditioning in mice, we investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and its effector p70 S6 kinase 1 (S6K1) in the extinction of auditory threat conditioning. We found that rapamycin attenuated the consolidation of extinction memory. In contrast, genetic deletion and pharmacological inhibition of S6K1, a downstream effector of mTORC1, blocked within-session extinction, indicating a role for S6K1 independent of protein synthesis. Indeed, the activation of S6K1 during extinction required extracellular signal-regulated kinase (ERK) activation in the basolateral nucleus of the amygdala (BLA) and was necessary for increased phosphorylation of the GluA1 (Thr840) subunit of the AMPA receptor following extinction training. Mice exposed to brief uncontrollable stress showed impaired within-session extinction as well as a downregulation of ERK and S6K1 signaling in the amygdala. Finally, using fiber photometry we were able to record calcium signals in vivo, and we found that inhibition of S6K1 reduces extinction-induced changes in neuronal activity of the BLA. These results implicate a novel ERK-S6K1-GluA1 signaling cascade critically involved in extinction.

Global Curriculum in Research Literacy for the Surgical Oncologist.

BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer-specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally.

Physical Functioning and Symptoms of Chronic Fatigue in Sarcoidosis Patients.

Scientific reports underscore the importance of measuring the health-related quality of life in sarcoidosis patients. The present study seeks to define how sarcoidosis patients' quality of life, daily physical activity, and physical performance are related to each other. Seventeen patients (mean age 46.8 ± 8.8 years) suffering from sarcoidosis completed the following questionnaires: the fatigue assessment scale (FAS), the quality of life scale (SF-36 questionnaire), and the Borg dyspnea scale. Physical activity (PA) was assessed using accelerometry. Respiratory function, consisting of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory volume in one second as a percentage of vital capacity (FEV1/%FVC), and diffusing capacity of the lungs for carbon monoxide (DLCO), were assessed. In addition, performance in 6-min walk test (MWT), aerobic capacity assessed from maximal oxygen uptake (VO2max), and the metabolic equivalent of task (MET) were evaluated. We found that daily PA (4566 ± 2378 steps/day) and VO2max (21.8 ± 5.9 ml/kg/min) were lower in sarcoidosis patients than the known predicted values in healthy age-matched individuals. There were significant inverse associations between the FAS score and 6MWT (r = -0.62; p < 0.01), and between SF-36 score and 6MWT (r = -0.55; p < 0.03). In contrast, SF-36 scores associated with fatigue and dyspnea scores (r = 0.72; p < 0.001 and r = 0.85; p < 0.001). These findings imply that sarcoidosis patients are less active compared with healthy subjects. The FAS and SF-36 scales seem to be effective tools for assessing the severity of fatigue in sarcoidosis patients.

malERA: An updated research agenda for malaria elimination and eradication.

Achieving a malaria-free world presents exciting scientific challenges as well as overwhelming health, equity, and economic benefits. WHO and countries are setting ambitious goals for reducing the burden and eliminating malaria through the "Global Technical Strategy" and 21 countries are aiming to eliminate malaria by 2020. The commitment to achieve these targets should be celebrated. However, the need for innovation to achieve these goals, sustain elimination, and free the world of malaria is greater than ever. Over 180 experts across multiple disciplines are engaged in the Malaria Eradication Research Agenda (malERA) Refresh process to address problems that need to be solved. The result is a research and development agenda to accelerate malaria elimination and, in the longer term, transform the malaria community's ability to eradicate it globally.

Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments.

Restoration of neuronal functions by outgrowths regenerating at ∼1 mm/day from the proximal stumps of severed peripheral nerves takes many weeks or months, if it occurs at all, especially after ablation of nerve segments. Distal segments of severed axons typically degenerate in 1-3 days. This study shows that Wallerian degeneration can be prevented or retarded, and lost behavioral function can be restored, following ablation of 0.5-1-cm segments of rat sciatic nerves in host animals. This is achieved by using 0.8-1.1-cm microsutured donor allografts treated with bioengineered solutions varying in ionic and polyethylene glycol (PEG) concentrations (modified PEG-fusion procedure), being careful not to stretch any portion of donor or host sciatic nerves. The data show that PEG fusion permanently restores axonal continuity within minutes, as initially assessed by action potential conduction and intracellular diffusion of dye. Behavioral functions mediated by the sciatic nerve are largely restored within 2-4 weeks, as measured by the sciatic functional index. Increased restoration of sciatic behavioral functions after ablating 0.5-1-cm segments is associated with greater numbers of viable myelinated axons within and distal to PEG-fused allografts. Many such viable myelinated axons are almost certainly spared from Wallerian degeneration by PEG fusion. PEG fusion of donor allografts may produce a paradigm shift in the treatment of peripheral nerve injuries.

Recent trends in global emissions of hydrochlorofluorocarbons and hydrofluorocarbons: reflecting on the 2007 adjustments to the Montreal Protocol.

Global-scale atmospheric measurements are used to investigate the effectiveness of recent adjustments to production and consumption controls on hydrochlorofluorocarbons (HCFCs) under the Montreal Protocol on Substances that Deplete the Ozone Layer (Montreal Protocol) and to assess recent projections of large increases in hydrofluorocarbon (HFC) production and emission. The results show that aggregate global HCFC emissions did not increase appreciably during 2007-2012 and suggest that the 2007 Adjustments to the Montreal Protocol played a role in limiting HCFC emissions well in advance of the 2013 cap on global production. HCFC emissions varied between 27 and 29 kt CFC-11-equivalent (eq)/y or 0.76 and 0.79 GtCO2-eq/y during this period. Despite slower than projected increases in aggregate HCFC emissions since 2007, total emissions of HFCs used as substitutes for HCFCs and chlorofluorocarbons (CFCs) have not increased more rapidly than rates projected [Velders, G. J. M.; Fahey, D. W.; Daniel, J. S.; McFarland, M.; Andersen, S. O. The Large Contribution of Projected HFC Emissions to Future Climate Forcing. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 10949-10954] for 2007-2012. HFC global emission magnitudes related to this substitution totaled 0.51 (-0.03, +0.04) GtCO2-eq/y in 2012, a magnitude about two times larger than emissions reported to the United Nations Framework Convention on Climate Change (UNFCCC) for these HFCs. Assuming accurate reporting to the UNFCCC, the results imply that developing countries (non-Annex I Parties) not reporting to the UNFCCC now account for nearly 50% of global HFC emissions used as substitutes for ozone-depleting substances (ODSs). Global HFC emissions (as CO2-eq) from ODS substitution can be attributed approximately equally to mobile air conditioning, commercial refrigeration, and the sum of all other applications.

Identification of coagulase-negative staphylococci in daily disposable contact lens wearers.

UNLABELLED: This study aimed to identify and quantify the number of contaminating organisms on daily disposable (DD) soft contact lenses, which may be responsible for mild cases of keratitis that occur with this lens wear modality. Ten participants wore DD lenses, and 10 participants wore planned replacement (PR) lenses. Lenses were collected aseptically and analysed for microbial contamination. Colony-forming units (CFU) were recorded, and representative colonies were used for identification using the API identification system. The DD lenses evaluated in this study were contaminated with coagulase-negative staphylococcus (CNS), ranging from 1 to 653 CFU. PR lenses showed more diversity in the types of contaminating micro-organisms and consisted of CNS, Gram-negative bacteria (Pseudomonas), a yeast (Candida) and a mould (Aspergillus), ranging from 1 to 230 CFU. CNS was the only type of micro-organism found on DD contact lenses and therefore may be the cause of any form of keratitis observed in DD lens wearers. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to determine the frequency and identify the contaminating organisms found on daily disposable (DD) soft contact lenses. The contaminating organisms identified on DD contact lenses were solely coagulase-negative staphylococcus (CNS), suggesting that CNS may be the causative organism associated with infectious keratitis that occurs with DD contact lens wear.

A unique Y gene in the Asian malaria mosquito Anopheles stephensi encodes a small lysine-rich protein and is transcribed at the onset of embryonic development.

In many organisms the Y chromosome initiates sex determination and regulates male fertility and mating behaviour. However, molecular characterization of Y genes is rare outside of a few model species because it is difficult to clone and analyse repeat-rich heterochromatic Y sequences. In insects, Y genes are only well characterized in a small number of Drosophila species. Here we report the discovery of GUY1 (gene unique to the Y), a gene unique to the Y chromosome in the Asian malaria mosquito, Anopheles stephensi, using an approach that compares Illumina sequences separately obtained from male and female genomic DNA. Experimental evidence confirmed that GUY1 is a single copy gene found only on the Y chromosome. GUY1 is transcribed at the very onset of zygotic transcription and encodes a small lysine-rich protein that forms two alpha helices and shows DNA-binding properties. Interestingly, three helix-loop-helix proteins are key factors that determine sex in the early embryo in Drosophila melanogaster. Single embryo analysis indicated that GUY1 is only transcribed in male embryos and that the GUY1 promoter is functional in the early embryos. GUY1 may be used as a paternally inherited molecular marker. Further investigation of GUY1 will contribute to the genetic approaches to control mosquito-borne diseases.

Isolation of a partial candidate gene for Menkes disease by positional cloning.

Menkes disease is an X-linked recessive disorder of copper metabolism resulting in death in early infancy. The gene has been mapped to band Xq13 based, in part, on a translocation breakpoint in a female with the disease, which was found to lie within 300 kilobases (kb) of the PGK-1 locus, allowing the isolation of a YAC clone spanning the breakpoint. Phage subclones from the breakpoint region were isolated and used to screen cDNA libraries. cDNA clones were found which detect an 8 kb transcript from normal individuals but show diminished or absent hybridization in Menkes disease patients. Partial sequence of the cDNA shows a unique open reading frame containing putative metal binding motifs which have been found in heavy metal resistance genes in bacteria. This gene is a strong candidate for the Menkes disease gene.

Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.

Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity.

War and disaster are forcing a major rethink around mass casualty management.

Mass casualty events (MASCAL) do not follow the same rules as typical major incidents. In the West at least, the latter often occur in stable, networked trauma systems, whereas MASCAL are characterised by overwhelming numbers of patients, compounded by protracted scene and transport times, decompensated response systems and significant disruption to infrastructure, command and control.This paper describes the 8Ds approach being taken by the UK Defence Medical Services and the North Atlantic Treaty Organization Emergency Medicine Panel framework to approach MASCAL. The eight domains were derived from literature about management of casualties in the World Wars, and also from approaches taken by civilian health systems as they struggle to manage increasing demand. They are: distribute; decompress; delay; delegate; deliver faster and deliver better; dynamic levels of care; and de-escalate These domains will allow a structured approach to research and innovate around MASCAL, informing better guidelines for their management.

Meeting Summary: Global Vaccine and Immunization Research Forum, 2021.

The 2021 Global Vaccine and Immunization Research Forum highlighted the considerable advances and recent progress in research and development for vaccines and immunization, critically reviewed lessons learned from COVID-19 vaccine programs, and looked ahead to opportunities for this decade. For COVID-19, decades of investments in basic and translational research, new technology platforms, and vaccines targeting prototype pathogens enabled a rapid, global response. Unprecedented global coordination and partnership have played an essential role in creating and delivering COVID-19 vaccines. More improvement is needed in product attributes such as deliverability, and in equitable access to vaccines. Developments in other priority areas included: the halting of two human immunodeficiency virus vaccine trials due to lack of efficacy in preventing infection; promising efficacy results in Phase 2 trials of two tuberculosis vaccines; pilot implementation of the most advanced malaria vaccine candidate in three countries; trials of human papillomavirus vaccines given in single-dose regimens; and emergency use listing of a novel, oral poliomyelitis type 2 vaccine. More systematic, proactive approaches are being developed for fostering vaccine uptake and demand, aligning on priorities for investment by the public and private sectors, and accelerating policy making. Participants emphasized that addressing endemic disease is intertwined with emergency preparedness and pandemic response, so that advances in one area create opportunities in the other. In this decade, advances made in response to the COVID-19 pandemic should accelerate availability of vaccines for other diseases, contribute to preparedness for future pandemics, and help to achieve impact and equity under Immunization Agenda 2030.

Protective effects of transgenic human endothelial protein C receptor expression in murine models of transplantation.

Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 µmol/L vs. 78.5 ± 10.0 µmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant-related thrombotic and inflammatory injury, without detrimental effects in the donor animal.