Comparing trends in mid-life ‘deaths of despair’ in the USA, Canada and UK, 2001–2019: is the USA an anomaly?

Objectives In recent years, ‘deaths of despair’ due to drugs, alcohol and suicide have contributed to rising mid-life mortality in the USA. We examine whether despair-related deaths and mid-life mortality trends are also changing in peer countries, the UK and Canada. Design Descriptive analysis of population mortality rates. Setting The USA, UK (and constituent nations England and Wales, Northern Ireland and Scotland) and Canada, 2001–2019. Participants Full population aged 35–64 years. Outcome measures We compared all-cause and ‘despair’-related mortality trends at mid-life across countries using publicly available mortality data, stratified by three age groups (35–44, 45–54 and 55–64 years) and by sex. We examined trends in all-cause mortality and mortality by causes categorised as (1) suicides, (2) alcohol-specific deaths and (3) drug-related deaths. We employ several descriptive approaches to visually inspect age, period and cohort trends in these causes of death. Results The USA and Scotland both saw large relative increases and high absolute levels of drug-related deaths. The rest of the UK and Canada saw relative increases but much lower absolute levels in comparison. Alcohol-specific deaths showed less consistent trends that did not track other ‘despair’ causes, with older groups in Scotland seeing steep declines over time. Suicide deaths trended slowly upward in most countries. Conclusions In the UK, Scotland has suffered increases in drug-related mortality comparable with the USA, while Canada and other UK constituent nations did not see dramatic increases. Alcohol-specific and suicide mortalities generally follow different patterns to drug-related deaths across countries and over time, questioning the utility of a cohesive ‘deaths of despair’ narrative

The A component (SmhA) of a tripartite pore-forming toxin from Serratia marcescens: expression, purification and crystallographic analysis

Tripartite α-pore-forming toxins are constructed of three proteins (A, B and C) and are found in many bacterial pathogens. While structures of the B and C components from Gram-negative bacteria have been described, the structure of the A component of a Gram-negative α-pore-forming toxin has so far proved elusive. SmhA, the A component from the opportunistic human pathogen Serratia marcescens, has been cloned, overexpressed and purified. Crystals were grown of selenomethionine-derivatized protein and anomalous data were collected. Phases were calculated and an initial electron-density map was produced

Critical discussion of Daniel C. Dennett, The Intentional Stance.

Daniel Dennett spends a good bit of time defending the possibility of a compromise position on the reality of beliefs and desires. It will be claimed that a puzzle remains in the interpretation of Dennett's position. In earlier works one finds a theme, which we can call 'near-fatalism', which has not been integrated with the kind of middle ground he describes. But the near-fatalism theme is dropped in later work. Is it because it is felt to be incompatible with that middle ground compromise? It is not obviously so

Osteoarthritis and other long-term health conditions in former elite cricketers

Objectives This study aimed to describe the prevalence and risk of chronic conditions in former elite cricketers compared to a normal population, and describe wellbeing in former elite cricketers. Design Cross-sectional study. Methods Former elite cricketers, recruited from the Professional Cricketers’ Association, completed a self-report cross-sectional questionnaire. The English Longitudinal Study of Ageing (ELSA) served as the normal population. The prevalence of self-reported, GP-diagnosed conditions (heart problems, hyper-tension, stroke, diabetes, asthma, dementia, osteoarthritis (OA), total hip replacement (THR), total knee replacement (TKR), anxiety, depression) were reported for both population samples. Standardised mor-bidity ratios (SMRs) compared chronic conditions in sex-, age- and BMI-matched former cricketers(n = 113) and normal population (n = 4496). Results Heart problems were reported by 13.3% of former cricketers, significantly lower than the normal population, SMR 0.55 (0.33–0.91). Former cricketers reported 31.9% hypertension, 1.8% stroke, 6.2% diabetes, 15.0% asthma, and no dementia, none significantly different to the normal population. OA, THR,and TKR were reported by 51.3%, 14.7% and 10.7% of former cricketers, respectively, significantly higher than the normal population, SMRs 3.64 (2.81–4.71), 3.99 (2.21–7.20) and 3.84 (1.92–7.68). Anxiety and depression were reported by 12.4% and 8.8% of former cricketers, respectively, SMRs 3.95 (2.34–6.67)and 2.22 (1.20–4.14). 97% of former cricketers reflected they would undertake their cricket career again, 98% agreed that cricket enriched their lives. Conclusions Heart problems were significantly lower, while OA, THR, TKR, anxiety, and depression were significantly higher in the former cricketers compared to the normal population (ELSA). Most former cricketers reflected positively on their career.</p

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

When Do Stalled Stars Resume Spinning Down? Advancing Gyrochronology with Ruprecht 147

Recent measurements of rotation periods () in the benchmark open clusters Praesepe (670 Myr), NGC 6811 (1 Gyr), and NGC 752 (1.4 Gyr) demonstrate that, after converging onto a tight sequence of slowly rotating stars in mass-period space, stars temporarily stop spinning down. These data also show that the duration of this epoch of stalled spin-down increases toward lower masses. To determine when stalled stars resume spinning down, we use data from the K2 mission and the Palomar Transient Factory to measure for 58 dwarf members of the 2.7 Gyr old cluster Ruprecht 147, 39 of which satisfy our criteria designed to remove short-period or near-equal-mass binaries. Combined with the Kepler data for the approximately coeval cluster NGC 6819 (30 stars with M ∗ > 0.85, our new measurements more than double the number of ≈2.5 Gyr benchmark rotators and extend this sample down to ≈0.55. The slowly rotating sequence for this joint sample appears relatively flat (22 ± 2 days) compared to sequences for younger clusters. This sequence also intersects the Kepler intermediate-period gap, demonstrating that this gap was not created by a lull in star formation. We calculate the time at which stars resume spinning down and find that 0.55 stars remain stalled for at least 1.3 Gyr. To accurately age-date low-mass stars in the field, gyrochronology formulae must be modified to account for this stalling timescale. Empirically tuning a core-envelope coupling model with open cluster data can account for most of the apparent stalling effect. However, alternative explanations, e.g., a temporary reduction in the magnetic braking torque, cannot yet be ruled out

FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy

Simulating rewetting events in intermittent rivers and ephemeral streams: A global analysis of leached nutrients and organic matter

Climate change and human pressures are changing the global distribution and the ex‐ tent of intermittent rivers and ephemeral streams (IRES), which comprise half of the global river network area. IRES are characterized by periods of flow cessation, during which channel substrates accumulate and undergo physico‐chemical changes (precon‐ ditioning), and periods of flow resumption, when these substrates are rewetted and release pulses of dissolved nutrients and organic matter (OM). However, there are no estimates of the amounts and quality of leached substances, nor is there information on the underlying environmental constraints operating at the global scale. We experi‐ mentally simulated, under standard laboratory conditions, rewetting of leaves, river‐ bed sediments, and epilithic biofilms collected during the dry phase across 205 IRES from five major climate zones. We determined the amounts and qualitative character‐ istics of the leached nutrients and OM, and estimated their areal fluxes from riverbeds. In addition, we evaluated the variance in leachate characteristics in relation to selected environmental variables and substrate characteristics. We found that sediments, due to their large quantities within riverbeds, contribute most to the overall flux of dis‐ solved substances during rewetting events (56%–98%), and that flux rates distinctly differ among climate zones. Dissolved organic carbon, phenolics, and nitrate contrib‐ uted most to the areal fluxes. The largest amounts of leached substances were found in the continental climate zone, coinciding with the lowest potential bioavailability of the leached OM. The opposite pattern was found in the arid zone. Environmental vari‐ ables expected to be modified under climate change (i.e. potential evapotranspiration, aridity, dry period duration, land use) were correlated with the amount of leached sub‐ stances, with the strongest relationship found for sediments. These results show that the role of IRES should be accounted for in global biogeochemical cycles, especially because prevalence of IRES will increase due to increasing severity of drying event

Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study

A41 Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study In: Addiction Science & Clinical Practice 2017, 12(Suppl 1): A4