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Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029–2052) and median on-treatment follow-up was 1324 days (IQR 870–1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70–1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. Menarini, Ipsen, and Teijin Pharma Ltd.

Screening for food insecurity and other social determinants of health is being integrated into oncology practice. We performed a pilot randomized trial to investigate whether an unconditional cash transfer (UCT) could be used to address food insecurity among female breast and gynecological cancer survivors. Food-insecure cancer survivors completed a baseline survey and were randomly assigned to receive $100/month for 3 months (UCT) or usual care (UC). Participants (n = 14) completed a follow-up survey after 3 months, and we compared changes in health-related quality of life, indicators of food insecurity, diet quality, and whether a participant had to forgo, delay, or make changes to medical care because of cost. The UCT was associated with higher physical health scores, fewer indicators of food insecurity, better diet quality, and a lower likelihood of forgoing medical care than those who received UC. Our results suggest that UCTs can improve outcomes for food-insecure cancer survivors.

Standard models of taxpayer compliance have fallen short of predicting the degree of honesty found in the data. We contribute to the more recent literature assessing cultural factors in the decision to underreport. We find that there are two forms of possible misspecification in the current models of taxpayer compliance. First, we use econometric methods for detecting misclassification of the dependent variable in a probit model, applying them to a recent IRS-sponsored survey. We find evidence of misspecification, which may suggest that taxpayers are not fully truthful in their survey responses, a result that helps to reconcile findings from survey data with studies using other methods. Second, we divide the sample into those individuals who have an intense sense of \"tax morality\" and those who do not, in order to compare groups with differing tax cultures. We find that the two groups are indeed influenced differently by the factors that have been commonly found in the literature, such as opinions regarding the fairness of the tax system.

Racial disparities in health are well-documented and represent a significant public health concern in the US. Racism-related factors contribute to poorer health and higher mortality rates among Blacks compared to other racial groups. However, methods to measure racism and monitor its associations with health at the population-level have remained elusive. In this study, we investigated the utility of a previously developed Internet search-based proxy of area racism as a predictor of Black mortality rates. Area racism was the proportion of Google searches containing the \"N-word\" in 196 designated market areas (DMAs). Negative binomial regression models were specified taking into account individual age, sex, year of death, and Census region and adjusted to the 2000 US standard population to examine the association between area racism and Black mortality rates, which were derived from death certificates and mid-year population counts collated by the National Center for Health Statistics (2004-2009). DMAs characterized by a one standard deviation greater level of area racism were associated with an 8.2% increase in the all-cause Black mortality rate, equivalent to over 30,000 deaths annually. The magnitude of this effect was attenuated to 5.7% after adjustment for DMA-level demographic and Black socioeconomic covariates. A model controlling for the White mortality rate was used to further adjust for unmeasured confounders that influence mortality overall in a geographic area, and to examine Black-White disparities in the mortality rate. Area racism remained significantly associated with the all-cause Black mortality rate (mortality rate ratio = 1.036; 95% confidence interval = 1.015, 1.057; p = 0.001). Models further examining cause-specific Black mortality rates revealed significant associations with heart disease, cancer, and stroke. These findings are congruent with studies documenting the deleterious impact of racism on health among Blacks. Our study contributes to evidence that racism shapes patterns in mortality and generates racial disparities in health.

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1 −/− fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1 −/− tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor. Many age-related diseases are associated with chronic inflammation. Here Jurk et al . use a mouse model of chronic, low-grade inflammation to support a model by which such inflammation promotes a vicious cycle of oxidative stress, telomere dysfunction and cell senescence that accelerates the ageing process.

Our ability to predict invasions has been hindered by the seemingly idiosyncratic context-dependency of individual invasions. However, we argue that robust and useful generalisations in invasion science can be made by considering “invasion syndromes” which we define as “a combination of pathways, alien species traits, and characteristics of the recipient ecosystem which collectively result in predictable dynamics and impacts, and that can be managed effectively using specific policy and management actions”. We describe this approach and outline examples that highlight its utility, including: cacti with clonal fragmentation in arid ecosystems; small aquatic organisms introduced through ballast water in harbours; large ranid frogs with frequent secondary transfers; piscivorous freshwater fishes in connected aquatic ecosystems; plant invasions in high-elevation areas; tall-statured grasses; and tree-feeding insects in forests with suitable hosts. We propose a systematic method for identifying and delimiting invasion syndromes. We argue that invasion syndromes can account for the context-dependency of biological invasions while incorporating insights from comparative studies. Adopting this approach will help to structure thinking, identify transferrable risk assessment and management lessons, and highlight similarities among events that were previously considered disparate invasion phenomena.

Although invasive alien species have long been recognized as a major threat to nature and people, until now there has been no comprehensive global review of the status, trends, drivers, impacts, management and governance challenges of biological invasions. The Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) Thematic Assessment Report on Invasive Alien Species and Their Control (hereafter ‘IPBES invasive alien species assessment’) drew on more than 13,000 scientific publications and reports in 15 languages as well as Indigenous and local knowledge on all taxa, ecosystems and regions across the globe. Therefore, it provides unequivocal evidence of the major and growing threat of invasive alien species alongside ambitious but realistic approaches to manage biological invasions. The extent of the threat and impacts has been recognized by the 143 member states of IPBES who approved the summary for policymakers of this assessment. Here, the authors of the IPBES assessment outline the main findings of the IPBES invasive alien species assessment and highlight the urgency to act now. This Perspective highlights the global consensus on the urgency and growing threat of invasive alien species, and management needs, as found by the 2023 report on invasive alien species conducted by the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES).

5-Aminolevulinic acid (5-ALA) is a medical pro-drug used to induce the intracellular production of protoporphyrin IX (PpIX) via the heme synthesis pathway. Discoveries in mechanisms and developments in novel applications still continue with this uniquely endogenous intracellular optical system. Understanding and exploiting the growing uses can be advanced through a survey of knowledge on the mechanisms and biokinetics of 5-ALA administration, partitioning, PpIX production, localization changes, clearance mechanisms, biological interactions, and methods for unique activation methods in both diagnostic and therapeutic applications. The current medical uses of PpIX are reviewed, separating into therapeutic and diagnostic areas, and the expansion and lateral growth areas are outlined. Initially approved for photodynamic therapy of skin lesions, fluorescence diagnostic indications later developed to guide surgical resection in bladder cancer and glioma. Today, the 5-ALA-PpIX system's spatial-temporal complexity in photophysics and pharmacokinetics continues to lead to more uses, such as photodynamic priming to alter tissue, fast intracellular tissue oxygen sensing, infection, and burn imaging and therapy. The 5-ALA-PpIX system has broad potential partly because of the ubiquity of the heme synthesis across many cell/tissue types, combined with natural selectivity, unique pharmacokinetics, bright fluorescence, and sufficiently strong singlet oxygen production.

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45–6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99–3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07–2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28–0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25–2.21]) and Asian (1.51 [1.28–1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34–3.15]).