Myeloid cells expressing VEGF and arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice

Whilst data recognise both myeloid cell accumulation during choroidal neovascularisation (CNV) as well as complement activation, none of the data has presented a clear explanation for the angiogenic drive that promotes pathological angiogenesis. One possibility that is a pre-eminent drive is a specific and early conditioning and activation of the myeloid cell infiltrate. Using a laser-induced CNV murine model, we have identified that disruption of retinal pigment epithelium (RPE) and Bruch's membrane resulted in an early recruitment of macrophages derived from monocytes and microglia, prior to angiogenesis and contemporaneous with lesional complement activation. Early recruited CD11b(+) cells expressed a definitive gene signature of selective inflammatory mediators particularly a pronounced Arg-1 expression. Accumulating macrophages from retina and peripheral blood were activated at the site of injury, displaying enhanced VEGF expression, and notably prior to exaggerated VEGF expression from RPE, or earliest stages of angiogenesis. All of these initial events, including distinct VEGF (+) Arg-1(+) myeloid cells, subsided when CNV was established and at the time RPE-VEGF expression was maximal. Depletion of inflammatory CCR2-positive monocytes confirmed origin of infiltrating monocyte Arg-1 expression, as following depletion Arg-1 signal was lost and CNV suppressed. Furthermore, our in vitro data supported a myeloid cell uptake of damaged RPE or its derivatives as a mechanism generating VEGF (+) Arg-1(+) phenotype in vivo. Our results reveal a potential early driver initiating angiogenesis via myeloid-derived VEGF drive following uptake of damaged RPE and deliver an explanation of why CNV develops during any of the stages of macular degeneration and can be explored further for therapeutic gain

Vaccination with M2e-Based Multiple Antigenic Peptides: Characterization of the B Cell Response and Protection Efficacy in Inbred and Outbred Mice

The extracellular domain of the influenza A virus protein matrix protein 2 (M2e) is remarkably conserved between various human isolates and thus is a viable target antigen for a universal influenza vaccine. With the goal of inducing protection in multiple mouse haplotypes, M2e-based multiple antigenic peptides (M2e-MAP) were synthesized to contain promiscuous T helper determinants from the Plasmodium falciparum circumsporozoite protein, the hepatitis B virus antigen and the influenza virus hemagglutinin. Here, we investigated the nature of the M2e-MAP-induced B cell response in terms of the distribution of antibody (Ab) secreting cells (ASCs) and Ab isotypes, and tested the protective efficacy in various mouse strains.Immunization of BALB/c mice with M2e-MAPs together with potent adjuvants, CpG 1826 oligonucleotides (ODN) and cholera toxin (CT) elicited high M2e-specific serum Ab titers that protected mice against viral challenge. Subcutaneous (s.c.) and intranasal (i.n.) delivery of M2e-MAPs resulted in the induction of IgG in serum and airway secretions, however only i.n. immunization induced anti-M2e IgA ASCs locally in the lungs, correlating with M2-specific IgA in the bronchio-alveolar lavage (BAL). Interestingly, both routes of vaccination resulted in equal protection against viral challenge. Moreover, M2e-MAPs induced cross-reactive and protective responses to diverse M2e peptides and variant influenza viruses. However, in contrast to BALB/c mice, immunization of other inbred and outbred mouse strains did not induce protective Abs. This correlated with a defect in T cell but not B cell responsiveness to the M2e-MAPs.Anti-M2e Abs induced by M2e-MAPs are highly cross-reactive and can mediate protection to variant viruses. Although synthetic MAPs are promising designs for vaccines, future constructs will need to be optimized for use in the genetically heterogeneous human population

Global, regional, and national burden of respiratory tract cancers and associated risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Prevention, control, and treatment of respiratory tract cancers are important steps towards achieving target 3.4 of the UN Sustainable Development Goals (SDGs)—a one-third reduction in premature mortality due to non-communicable diseases by 2030. We aimed to provide global, regional, and national estimates of the burden of tracheal, bronchus, and lung cancer and larynx cancer and their attributable risks from 1990 to 2019. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 methodology, we evaluated the incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) of respiratory tract cancers (ie, tracheal, bronchus, and lung cancer and larynx cancer). Deaths from tracheal, bronchus, and lung cancer and larynx cancer attributable to each risk factor were estimated on the basis of risk exposure, relative risks, and the theoretical minimum risk exposure level input from 204 countries and territories, stratified by sex and Socio-demographic Index (SDI). Trends were estimated from 1990 to 2019, with an emphasis on the 2010-19 period. Findings Globally, there were 2·26 million (95% uncertainty interval 2·07 to 2·45) new cases of tracheal, bronchus, and lung cancer, and 2·04 million (1·88 to 2·19) deaths and 45·9 million (42·3 to 49·3) DALYs due to tracheal, bronchus, and lung cancer in 2019. There were 209 000 (194 000 to 225 000) new cases of larynx cancer, and 123 000 (115 000 to 133 000) deaths and 3·26 million (3·03 to 3·51) DALYs due to larynx cancer globally in 2019. From 2010 to 2019, the number of new tracheal, bronchus, and lung cancer cases increased by 23·3% (12·9 to 33·6) globally and the number of larynx cancer cases increased by 24·7% (16·0 to 34·1) globally. Global age-standardised incidence rates of tracheal, bronchus, and lung cancer decreased by 7·4% (−16·8 to 1·6) and age-standardised incidence rates of larynx cancer decreased by 3 ·0% (−10·5 to 5·0) in males over the past decade; however, during the same period, age-standardised incidence rates in females increased by 0·9% (−8·2 to 10·2) for tracheal, bronchus, and lung cancer and decreased by 0·5% (−8·4 to 8·1) for larynx cancer. Furthermore, although age-standardised incidence and death rates declined in both sexes combined from 2010 to 2019 at the global level for tracheal, bronchus, lung and larynx cancers, some locations had rising rates, particularly those on the lower end of the SDI range. Smoking contributed to an estimated 64·2% (61·9–66·4) of all deaths from tracheal, bronchus, and lung cancer and 63·4% (56·3–69·3) of all deaths from larynx cancer in 2019. For males and for both sexes combined, smoking was the leading specific risk factor for age-standardised deaths from tracheal, bronchus, and lung cancer per 100 000 in all SDI quintiles and GBD regions in 2019. However, among females, household air pollution from solid fuels was the leading specific risk factor in the low SDI quintile and in three GBD regions (central, eastern, and western sub-Saharan Africa) in 2019. Interpretation The numbers of incident cases and deaths from tracheal, bronchus, and lung cancer and larynx cancer increased globally during the past decade. Even more concerning, age-standardised incidence and death rates due to tracheal, bronchus, lung cancer and larynx cancer increased in some populations—namely, in the lower SDI quintiles and among females. Preventive measures such as smoking control interventions, air quality management programmes focused on major air pollution sources, and widespread access to clean energy should be prioritised in these settings

Cancer recurrence times from a branching process model

As cancer advances, cells often spread from the primary tumor to other parts of the body and form metastases. This is the main cause of cancer related mortality. Here we investigate a conceptually simple model of metastasis formation where metastatic lesions are initiated at a rate which depends on the size of the primary tumor. The evolution of each metastasis is described as an independent branching process. We assume that the primary tumor is resected at a given size and study the earliest time at which any metastasis reaches a minimal detectable size. The parameters of our model are estimated independently for breast, colorectal, headneck, lung and prostate cancers. We use these estimates to compare predictions from our model with values reported in clinical literature. For some cancer types, we find a remarkably wide range of resection sizes such that metastases are very likely to be present, but none of them are detectable. Our model predicts that only very early resections can prevent recurrence, and that small delays in the time of surgery can significantly increase the recurrence probability.Comment: 26 pages, 9 figures, 4 table

Effect of Exercise Interventions on Health-Related Quality of Life After Stroke and Transient Ischemic Attack: A Systematic Review and Meta-Analysis

Exercise interventions have been shown to help physical fitness, walking and balance after stroke, but data is lacking on whether such interventions lead to improvements in health-related quality of life (HRQoL). In this systematic review and meta-analysis, thirty randomised controlled trials (n=1,836 patients) were found from PubMed, OVID MEDLINE, Web of Science, CINAHL, SCOPUS, The Cochrane Library and TRIP databases when searched from 1966 to Feb 2020, that examine the effects of exercise interventions on HRQoL after strokem or transient ischaemic attack (TIA). Exercise interventions resulted in small to moderate beneficial effects on HRQoL at intervention end (standardised mean difference (SMD) -0.23; 95% CI -0.40 to -0.07) that appeared to diminish at longer term follow up (SMD -0.11; 95%CI -0.26 to 0.04). Exercise was associated with moderate improvements in physical health (SMD -0.33; 95% CI -0.61 to -0.04) and mental health (SMD -0.29; 95% CI -0.49 to -0.09) domains of HRQoL while effects on social or cognitive composites showed little difference. Interventions that were initiated within 6 months, lasted at least 12 weeks in duration, involved at least 150 minutes per week, and included resistance training appeared most effective. Exercise can lead to moderate beneficial effects on HRQoL and should be considered an integral part of stroke rehabilitatio

Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants

Background Diabetes can be detected at the primary health-care level, and effective treatments lower the risk of complications. There are insufficient data on the coverage of treatment for diabetes and how it has changed. We estimated trends from 1990 to 2022 in diabetes prevalence and treatment for 200 countries and territories. Methods We used data from 1108 population-representative studies with 141 million participants aged 18 years and older with measurements of fasting glucose and glycated haemoglobin (HbA1c), and information on diabetes treatment. We defined diabetes as having a fasting plasma glucose (FPG) of 7·0 mmol/L or higher, having an HbA1c of 6·5% or higher, or taking medication for diabetes. We defined diabetes treatment as the proportion of people with diabetes who were taking medication for diabetes. We analysed the data in a Bayesian hierarchical meta-regression model to estimate diabetes prevalence and treatment. Findings In 2022, an estimated 828 million (95% credible interval [CrI] 757–908) adults (those aged 18 years and older) had diabetes, an increase of 630 million (554–713) from 1990. From 1990 to 2022, the age-standardised prevalence of diabetes increased in 131 countries for women and in 155 countries for men with a posterior probability of more than 0·80. The largest increases were in low-income and middle-income countries in southeast Asia (eg, Malaysia), south Asia (eg, Pakistan), the Middle East and north Africa (eg, Egypt), and Latin America and the Caribbean (eg, Jamaica, Trinidad and Tobago, and Costa Rica). Age-standardised prevalence neither increased nor decreased with a posterior probability of more than 0·80 in some countries in western and central Europe, sub-Saharan Africa, east Asia and the Pacific, Canada, and some Pacific island nations where prevalence was already high in 1990; it decreased with a posterior probability of more than 0·80 in women in Japan, Spain, and France, and in men in Nauru. The lowest prevalence in the world in 2022 was in western Europe and east Africa for both sexes, and in Japan and Canada for women, and the highest prevalence in the world in 2022 was in countries in Polynesia and Micronesia, some countries in the Caribbean and the Middle East and north Africa, as well as Pakistan and Malaysia. In 2022, 445 million (95% CrI 401–496) adults aged 30 years or older with diabetes did not receive treatment (59% of adults aged 30 years or older with diabetes), 3·5 times the number in 1990. From 1990 to 2022, diabetes treatment coverage increased in 118 countries for women and 98 countries for men with a posterior probability of more than 0·80. The largest improvement in treatment coverage was in some countries from central and western Europe and Latin America (Mexico, Colombia, Chile, and Costa Rica), Canada, South Korea, Russia, Seychelles, and Jordan. There was no increase in treatment coverage in most countries in sub-Saharan Africa; the Caribbean; Pacific island nations; and south, southeast, and central Asia. In 2022, age-standardised treatment coverage was lowest in countries in sub-Saharan Africa and south Asia, and treatment coverage was less than 10% in some African countries. Treatment coverage was 55% or higher in South Korea, many high-income western countries, and some countries in central and eastern Europe (eg, Poland, Czechia, and Russia), Latin America (eg, Costa Rica, Chile, and Mexico), and the Middle East and north Africa (eg, Jordan, Qatar, and Kuwait). Interpretation In most countries, especially in low-income and middle-income countries, diabetes treatment has not increased at all or has not increased sufficiently in comparison with the rise in prevalence. The burden of diabetes and untreated diabetes is increasingly borne by low-income and middle-income countries. The expansion of health insurance and primary health care should be accompanied with diabetes programmes that realign and resource health services to enhance the early detection and effective treatment of diabetes. Funding UK Medical Research Council, UK Research and Innovation (Research England), and US Centers for Disease Control and Prevention

General and abdominal adiposity and hypertension in eight world regions: a pooled analysis of 837 population-based studies with 7•5 million participants

Background Adiposity can be measured using BMI (which is based on weight and height) as well as indices of abdominal adiposity. We examined the association between BMI and waist-to-height ratio (WHtR) within and across populations of different world regions and quantified how well these two metrics discriminate between people with and without hypertension. Methods We used data from studies carried out from 1990 to 2023 on BMI, WHtR and hypertension in people aged 20–64 years in representative samples of the general population in eight world regions. We graphically compared the regional distributions of BMI and WHtR, and calculated Pearson's correlation coefficients between BMI and WHtR within each region. We used mixed-effects linear regression to estimate the extent to which WHtR varies across regions at the same BMI. We graphically examined the prevalence of hypertension and the distribution of people who have hypertension both in relation to BMI and WHtR, and we assessed how closely BMI and WHtR discriminate between participants with and without hypertension using C-statistic and net reclassification improvement (NRI). Findings The correlation between BMI and WHtR ranged from 0·76 to 0·89 within different regions. After adjusting for age and BMI, mean WHtR was highest in south Asia for both sexes, followed by Latin America and the Caribbean and the region of central Asia, Middle East and north Africa. Mean WHtR was lowest in central and eastern Europe for both sexes, in the high-income western region for women, and in Oceania for men. Conversely, to achieve an equivalent WHtR, the BMI of the population of south Asia would need to be, on average, 2·79 kg/m2 (95% CI 2·31–3·28) lower for women and 1·28 kg/m2 (1·02–1·54) lower for men than in the high-income western region. In every region, hypertension prevalence increased with both BMI and WHtR. Models with either of these two adiposity metrics had virtually identical C-statistics and NRIs for every region and sex, with C-statistics ranging from 0·72 to 0·81 and NRIs ranging from 0·34 to 0·57 in different region and sex combinations. When both BMI and WHtR were used, performance improved only slightly compared with using either adiposity measure alone. Interpretation BMI can distinguish young and middle-aged adults with higher versus lower amounts of abdominal adiposity with moderate-to-high accuracy, and both BMI and WHtR distinguish people with or without hypertension. However, at the same BMI level, people in south Asia, Latin America and the Caribbean, and the region of central Asia, Middle East and north Africa, have higher WHtR than in the other regions. Funding UK Medical Research Council and UK Research and Innovation (Innovate UK)