Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: evidence from secondary analysis of an English primary care audit survey

Objectives: To explore whether women experience greater delays in the diagnosis of bladder and renal cancer when first presenting to a general practitioner with symptoms caused by those cancers and potential reasons for such gender inequalities. Design: Prospective national audit survey of cancer diagnosis. Setting: English primary care (2009–2010). Participants: 920 patients with bladder and 398 patients with renal cancer (252 (27%) and 165 (42%), respectively, were women). Primary and secondary outcome measures: Proportion of patients with three or more pre-referral consultations; number of days from first presentation to referral; proportion of patients who presented with haematuria and proportion of patients investigated in primary care. Results: Women required three or more prereferral consultations more often than men (27% (95% CI 21% to 33%) vs 11% (9% to 14%) for bladder (p<0.001); and 30% (22% to 39%) vs 18% (13% to 25%) for renal cancer (p=0.025)) and had a greater number of days from presentation to referral. In multivariable analysis (adjusting for age, haematuria status and use of primary care-led investigations), being a woman was independently associated with higher odds of three or more pre-referral consultations (OR=3.29 (2.06 to 5.25, p<0.001) for bladder cancer; and OR=1.90 (1.06 to 3.42, p=0.031) for renal cancer). Although presentation with haematuria was associated with more timely diagnosis of bladder cancer, gender inequalities did not vary by haematuria status for either cancer (p=0.18 for bladder and p=0.27 for renal). Each year in the UK, approximately 700 women with either bladder or renal cancer experience a delayed diagnosis because of their gender, of whom more than a quarter (197, or 28%) present with haematuria. Conclusions: There are notable gender inequalities in the timeliness of diagnosis of urological cancers. There is a need to both reinforce existing guidelines on haematuria investigation and develop new diagnostic decision aids and tests for patients who present without haematuria

Measures of promptness of cancer diagnosis in primary care: Secondary analysis of national audit data on patients with 18 common and rarer cancers

Background: Evidence is needed about the promptness of cancer diagnosis and associations between its measures. Methods: We analysed data from the National Audit of Cancer Diagnosis in Primary Care 2009–10 exploring the association between the interval from first symptomatic presentation to specialist referral (the primary care interval, or ‘interval’ hereafter) and the number of pre-referral consultations. Results: Among 13 035 patients with any of 18 different cancers, most (82%) were referred after 1 (58%) or 2 (25%) consultations (median intervals 0 and 15 days, respectively) while 9%, 4% and 5% patients required 3, 4 or 5 þ consultations (median intervals 34, 47 and 97 days, respectively) (Spearman’s r ¼ 0.70). The association was at least moderate for any cancer (Spearman’s r range: 0.55 (prostate) 0.77 (brain)). Patients with cancers with a higher proportion of three or more pre-referral consultations typically also had longer median intervals (e.g., multiple myeloma) and vice versa (e.g., breast cancer). Conclusion: The number of pre-referral consultations has construct validity as a measure of the primary care interval. Developing interventions to reduce the number of pre-referral consultations can help improve the timeliness of cancer diagnosis, and constitutes a priority for early diagnosis initiatives and research

CP asymmetries in the supersymmetric trilepton signal at the LHC

In the CP-violating Minimal Supersymmetric Standard Model, we study the production of a neutralino-chargino pair at the LHC. For their decays into three leptons, we analyze CP asymmetries which are sensitive to the CP phases of the neutralino and chargino sector. We present analytical formulas for the entire production and decay process, and identify the CP-violating contributions in the spin correlation terms. This allows us to define the optimal CP asymmetries. We present a detailed numerical analysis of the cross sections, branching ratios, and the CP observables. For light neutralinos, charginos, and squarks, the asymmetries can reach several 10%. We estimate the discovery potential for the LHC to observe CP violation in the trilepton channel.Comment: 39 pages, 8 figures, version to appear in EPJC, discussion(s) added, typo in (D.79), (D.118) corrected, new Fig. 7; The European Physical Journal C, Volume 72, Issue 3, 201

Multidecadal variability in Atlas cedar growth in northwest Africa during the last 850 years: implications for dieback and conservation of an endangered species

Widespread forest dieback is a phenomenon of global concern that requires an improved understanding of the relationship between tree growth and climate to support conservation efforts. One priority for conservation is the Atlas cedar (Cedrus atlantica), an endangered species exhibiting dieback throughout its North African range. In this study, we evaluate the long-term context for recent dieback and develop a projection of future C. atlantica growth by exploring the periodic variability of its growth through time. First, we present a new C. atlantica tree- ring chronology (1150–2013 CE) from the Middle Atlas mountains, Morocco. We then compare the new chronology to existing C. atlantica chronologies in Morocco and use principal components analysis (PCA) to isolate the common periodic signal from the seven longest available records (PCA7, 1271–1984 CE) in the Middle and High Atlas portions of the C. atlantica range. PCA7 captures 55.7% of the variance and contains significant multidecadal ( ̃95yr, ̃57yr, ̃21yr) periodic components, revealed through spectral and wavelet analyses. Parallel analyses of historical climate data (1901–2016 CE) suggests that the multidecadal growth signal ori- ginates primarily in growing season (spring and summer) precipitation variability, compounded by slow- changing components of summer and winter temperatures. Finally, we model the long-term growth patterns between 1271–1984 CE using a small number (three to four) of harmonic components, illustrating that sup- pressed growth since the 1970s – a factor implicated in the dieback of this species – is consistent with recurrent climatically-driven growth declines. Forward projection of this model suggests two climatically-favourable periods for growth in the 21st century that may enhance current conservation actions for the long-term survival of the C. atlantica in the Middle and High Atlas mountains

Evolutionary Heritage Influences Amazon Tree Ecology

Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life-history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant life-history strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability

Mapping and characterization of structural variation in 17,795 human genomes

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0–11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing

Accelarated immune ageing is associated with COVID-19 disease severity

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01). Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease