Multimorbidity and co-morbidity in atrial fibrillation and effects on survival: findings from UK Biobank cohort

Aims: To examine the number and type of co-morbid long-term health conditions (LTCs) and their associations with all-cause mortality in an atrial fibrillation (AF) population. Methods and results: Community cohort participants (UK Biobank n = 502 637) aged 37–73 years were recruited between 2006 and 2010. Self-reported LTCs (n = 42) identified in people with AF at baseline. All-cause mortality was available for a median follow-up of 7 years (interquartile range 76–93 months). Hazard ratios (HRs) examined associations between number and type of co-morbid LTC and all-cause mortality, adjusting for age, sex, socio-economic status, smoking, and anticoagulation status. Three thousand six hundred fifty-one participants (0.7% of the study population) reported AF; mean age was 61.9 years. The all-cause mortality rate was 6.7% (248 participants) at 7 years. Atrial fibrillation participants with ≥4 co-morbidities had a six-fold higher risk of mortality compared to participants without any LTC. Co-morbid heart failure was associated with higher risk of mortality [HR 2.96, 95% confidence interval (CI) 1.83–4.80], whereas the presence of co-morbid stroke did not have a significant association. Among non-cardiometabolic conditions, presence of chronic obstructive pulmonary disease (HR 3.31, 95% CI 2.14–5.11) and osteoporosis (HR 3.13, 95% CI 1.63–6.01) was associated with a higher risk of mortality. Conclusion: Survival in middle-aged to older individuals with self-reported AF is strongly correlated with level of multimorbidity. This group should be targeted for interventions to optimize their management, which in turn may potentially reduce the impact of their co-morbidities on survival. Future AF clinical guidelines need to place greater emphasis on the issue of co-morbidity

Sialic Acid Utilisation and Synthesis in the Neonatal Rat Revisited

Background: Milk is the sole source of nutrients for neonatal mammals and is generally considered to have co-evolved with the developmental needs of the suckling newborn. One evolutionary conserved constituent of milk and present on many glycoconjugates is sialic acid. The brain and colon are major sites of sialic acid display and together with the liver also of synthesis. Methodology/Principal Findings: In this study we examined in rats the relationship between the sialic acid content of milk and the uptake, utilization and synthesis of sialic acid in suckling pups. In rat milk sialic acid was found primarily as 39sialyllactose and at highest levels between 3 and 10 days postpartum and that decreased towards weaning. In the liver of suckling pups sialic acid synthesis paralleled the increase in milk sialic acid reaching and keeping maximum activity from postnatal day 5 onwards. In the colon, gene expression profiles suggested that a switch from sialic acid uptake and catabolism towards sialic acid synthesis and utilization occurred that mirrored the change of sialic acid in milk from high to low expression. In brain sialic acid related gene expression profiles did not change to any great extent during the suckling period. Conclusions/Significance: Our results support the views that (i) when milk sialic acid levels are high, in the colon this sialic acid is catabolized to GlcNAc that in turn may be used as such or used as substrate for sialic acid synthesis and (ii) when milk sialic acid levels are low the endogenous sialic acid synthetic machinery in colon is activated

High Gaussicity feedhorns for sub-/ millimeter wave applications

In feedhorn design, the power coupling to the fundamental free-space LG00 mode, or Gaussicity, is a good proxy for high performance, particularly the sidelobe and cross-polar levels and the near-field behavior. Gaussicity can be maximized by ensuring that the first few horn modes reach the aperture with the appropriate phase and amplitude relationship. We present two feedhorn designs for which the Gaussicity was maximized in order to achieve high performance. The first is a 94 GHz corrugated horn with a tanh-linear profile, manufactured by electroforming, which achieves a Gaussicity of 99.92% at band center and sidelobes at the -60 dB level. The second is a 340 GHz smooth-walled spline horn which achieves a Gaussicity of >99.2% over a 10% bandwidth, sidelobes below -30 dB and excellent near-field behavior. This design has been successfully fabricated in E-plane split block suitable for low volume manufacture, for example for imaging arrays.Postprin

Examining patterns of multimorbidity, polypharmacy and risk of adverse drug reactions in chronic obstructive pulmonary disease: a cross-sectional UK Biobank study

Objective: This study aims: (1) to describe the pattern and extent of multimorbidity and polypharmacy in UK Biobank participants with chronic obstructive pulmonary disease (COPD) and (2) to identify which comorbidities are associated with increased risk of adverse drug reactions (ADRs) resulting from polypharmacy. Design: Cross-sectional. Setting: Community cohort. Participants: UK Biobank participants comparing self-reported COPD (n=8317) with no COPD (n=494 323). Outcomes: Multimorbidity (≥4 conditions) and polypharmacy (≥5 medications) in participants with COPD versus those without. Risk of ADRs (taking ≥3 medications associated with falls, constipation, urinary retention, central nervous system (CNS) depression, bleeding or renal injury) in relation to the presence of COPD and individual comorbidities. Results: Multimorbidity was more common in participants with COPD than those without (17% vs 4%). Polypharmacy was highly prevalent (52% with COPD taking ≥5 medications vs 18% in those without COPD). Adjusting for age, sex and socioeconomic status, those with COPD were significantly more likely than those without to be prescribed ≥3 medications contributing to falls (OR 2.27, 95% CI 2.13 to 2.42), constipation (OR 3.42, 95% CI 3.10 to 3.77), urinary retention (OR 3.38, 95% CI 2.94 to 3.87), CNS depression (OR 3.75, 95% CI 3.31 to 4.25), bleeding (OR 4.61, 95% CI 3.35 to 6.19) and renal injury (OR 2.22, 95% CI 1.86 to 2.62). Concomitant cardiovascular disease was associated with the greatest risk of taking ≥3 medications associated with falls/renal injury. Concomitant mental health conditions were most strongly associated with medications linked with CNS depression/urinary retention/bleeding. Conclusions: Multimorbidity is common in COPD and associated with high levels of polypharmacy. Co-prescription of drugs with various ADRs is common. Future research should examine the effects on healthcare outcomes of co-prescribing multiple drugs with similar potential ADRs. Clinical guidelines should emphasise assessment of multimorbidity and ADR risk

Relationship between multimorbidity, demographic factors and mortality: findings from the UK Biobank Cohort

Background: Multimorbidity is associated with higher mortality, but the relationship with cancer and cardiovascular mortality is unclear. The influence of demographics and type of condition on the relationship of multimorbidity with mortality remains unknown. We examine the relationship between multimorbidity (number/type) and cause of mortality and the impact of demographic factors on this relationship. Methods: Data source: the UK Biobank; 500,769 participants; 37-73 years; 53.7% female. Exposure variables: number and type of long-term conditions (LTCs) (N = 43) at baseline, modelled separately. Cox regression models were used to study the impact of LTCs on all-cause/vascular/cancer mortality during median 7-year follow-up. All-cause mortality regression models were stratified by age/sex/socioeconomic status. Results: All-cause mortality is 2.9% (14,348 participants). Of all deaths, 8350 (58.2%) were cancer deaths and 2985 (20.8%) vascular deaths. Dose-response relationship is observed between the increasing number of LTCs and all-cause/cancer/vascular mortality. A strong association is observed between cardiometabolic multimorbidity and all three clinical outcomes; non-cardiometabolic multimorbidity (excluding cancer) is associated with all-cause/vascular mortality. All-cause mortality risk for those with ≥ 4 LTCs was nearly 3 times higher than those with no LTCs (HR 2.79, CI 2.61–2.98); for ≥ 4 cardiometabolic conditions, it was > 3 times higher (HR 3.20, CI 2.56–4.00); and for ≥ 4 non-cardiometabolic conditions (excluding cancer), it was 50% more (HR 1.50, CI 1.36–1.67). For those with ≥ 4 LTCs, morbidity combinations that included cardiometabolic conditions, chronic kidney disease, cancer, epilepsy, chronic obstructive pulmonary disease, depression, osteoporosis and connective tissue disorders had the greatest impact on all-cause mortality. In the stratified model by age/sex, absolute all-cause mortality was higher among the 60–73 age group with an increasing number of LTCs; however, the relative effect size of the increasing number of LTCs on higher mortality risk was larger among those 37–49 years, especially men. While socioeconomic status was a significant predictor of all-cause mortality, mortality risk with increasing number of LTCs remained constant across different socioeconomic gradients. Conclusions: Multimorbidity is associated with higher all-cause/cancer/vascular mortality. Type, as opposed to number, of LTCs may have an important role in understanding the relationship between multimorbidity and mortality. Multimorbidity had a greater relative impact on all-cause mortality in middle-aged as opposed to older populations, particularly males, which deserves exploration

Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493,737 UK Biobank participants

Background: Frailty is associated with older age and multimorbidity (two or more long-term conditions); however, little is known about its prevalence or effects on mortality in younger populations. This paper aims to examine the association between frailty, multimorbidity, specific long-term conditions, and mortality in a middle-aged and older aged population. Methods: Data were sourced from the UK Biobank. Frailty phenotype was based on five criteria (weight loss, exhaustion, grip strength, low physical activity, slow walking pace). Participants were deemed frail if they met at least three criteria, pre-frail if they fulfilled one or two criteria, and not frail if no criteria were met. Sociodemographic characteristics and long-term conditions were examined. The outcome was all-cause mortality, which was measured at a median of 7 years follow-up. Multinomial logistic regression compared sociodemographic characteristics and long-term conditions of frail or pre-frail participants with non-frail participants. Cox proportional hazards models examined associations between frailty or pre-frailty and mortality. Results were stratified by age group (37–45, 45–55, 55–65, 65–73 years) and sex, and were adjusted for multimorbidity count, socioeconomic status, body-mass index, smoking status, and alcohol use. Findings: 493 737 participants aged 37–73 years were included in the study, of whom 16 538 (3%) were considered frail, 185 360 (38%) pre-frail, and 291 839 (59%) not frail. Frailty was significantly associated with multimorbidity (prevalence 18% [4435/25 338] in those with four or more long-term conditions; odds ratio [OR] 27·1, 95% CI 25·3–29·1) socioeconomic deprivation, smoking, obesity, and infrequent alcohol consumption. The top five long-term conditions associated with frailty were multiple sclerosis (OR 15·3; 99·75% CI 12·8–18·2); chronic fatigue syndrome (12·9; 11·1–15·0); chronic obstructive pulmonary disease (5·6; 5·2–6·1); connective tissue disease (5·4; 5·0–5·8); and diabetes (5·0; 4·7–5·2). Pre-frailty and frailty were significantly associated with mortality for all age strata in men and women (except in women aged 37–45 years) after adjustment for confounders. Interpretation: Efforts to identify, manage, and prevent frailty should include middle-aged individuals with multimorbidity, in whom frailty is significantly associated with mortality, even after adjustment for number of long-term conditions, sociodemographics, and lifestyle. Research, clinical guidelines, and health-care services must shift focus from single conditions to the requirements of increasingly complex patient populations

Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes

Centrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar spindle assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET. We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HSET in vitro. The inhibitor induced multipolar mitoses only in cells containing supernumerary centrosomes. CW069 therefore constitutes a valuable tool for probing HSET function and, by reducing the growth of cells containing supernumerary centrosomes, paves the way for new cancer therapeutics

Statistical properties of SGR 1900+14 bursts

We study the statistics of soft gamma repeater (SGR) bursts, using a data base of 187 events detected with BATSE and 837 events detected with RXTE PCA, all from SGR 1900+14 during its 1998-1999 active phase. We find that the fluence or energy distribution of bursts is consistent with a power law of index 1.66, over 4 orders of magnitude. This scale-free distribution resembles the Gutenberg-Richter Law for earthquakes, and gives evidence for self-organized criticality in SGRs. The distribution of time intervals between successive bursts from SGR 1900+14 is consistent with a log-normal distribution. There is no correlation between burst intensity and the waiting times till the next burst, but there is some evidence for a correlation between burst intensity and the time elapsed since the previous burst. We also find a correlation between the duration and the energy of the bursts, but with significant scatter. In all these statistical properties, SGR bursts resemble earthquakes and solar flares more closely than they resemble any known accretion-powered or nuclear-powered phenomena. Thus our analysis lends support to the hypothesis that the energy source for SGR bursts is internal to the neutron star, and plausibly magnetic.Comment: 11 pages, 4 figures, accepted for publication in ApJ

Performance-based building and innovation: Balancing client and industry needs

One reason for the interest in performance-based building is that it is commonly advocated as a powerful way of enhancing innovation performance by articulating building performance outcomes, and by offering relevant procurement actors the discretion to innovate to meet these performance requirements more effectively and/or efficiently. The paper argues that the current approach to performance-based building assumes that relevant actors have the capacity, ability and motivation to innovate from a business perspective. It is proposed that the prevailing conceptualization of PBB is too restrictive and should be broadened explicitly to accommodate the required business logic that must be in place before actors will innovate. The relevant performance-based building and innovation literature is synthesized to support the assertion. The paper concludes with an innovation-focused definition of performance-based building