Both inadequate and excessive administration of oxygen to acutely unwell patients results in risk of harm. Guidelines recommend titration of oxygen to achieve a target oxygen saturation (SpO
) range. ...Information regarding whether this is being achieved is limited.
In this two-centre non-interventional study we used continuous pulse oximetry in acutely unwell medical patients over a 24-h period to determine the proportion of time spent with SpO
within the prescribed target range and whether this is influenced by the target range, age, care in a high-dependency area and the number of oxygen adjustments.
Eighty participants were included in the analysis. The mean (SD) proportion of time spent in target range was 55.6% (23.6), this was lower in those with a reduced hypercapnic target range (88-92% or below) compared to those with a range of 92-96%; difference - 13.1% (95% CI - 3.0 to - 23.2), P = 0.012. The proportion of time spent above range was 16.2% (22.9); this was higher in those with a reduced hypercapnic range; difference 21.6% (31.4 to 12), P < 0.001. The proportion of time below range was 28.4% (25.2); there was no difference between target ranges. The proportion of time spent in range was higher for those in a high dependency area in the multivariate model; difference 15.5% (95% CI 2.3 to 28.7), P = 0.02.
Medical patients receiving oxygen in a ward setting spend significant periods of time with SpO
both above and below the prescribed target range while receiving oxygen therapy.
Although the acetylation of histones has a well-documented regulatory role in transcription, its role in other chromosomal functions remains largely unexplored. Here we show that distinct patterns of ...histone H4 acetylation are essential in two separate pathways of double-strand break repair. A budding yeast strain with mutations in wild-type H4 acetylation sites shows defects in nonhomologous end joining repair and in a newly described pathway of replication-coupled repair. Both pathways require the ESA1 histone acetyl transferase (HAT), which is responsible for acetylating all H4 tail lysines, including ectopic lysines that restore repair capacity to a mutant H4 tail. Arp4, a protein that binds histone H4 tails and is part of the Esa1-containing NuA4 HAT complex, is recruited specifically to DNA double-strand breaks that are generated in vivo. The purified Esa1-Arp4 HAT complex acetylates linear nucleosomal arrays with far greater efficiency than circular arrays in vitro, indicating that it preferentially acetylates nucleosomes near a break site. Together, our data show that histone tail acetylation is required directly for DNA repair and suggest that a related human HAT complex may function similarly.
1. Understanding the effects of disease is critical to determining appropriate management responses, but estimating those effects in wildlife species is challenging. We used bovine tuberculosis (BTB) ...in the African buffalo Syncerus caffer population of Kruger National Park, South Africa, as a case study to highlight the issues associated with estimating chronic disease effects in a long-lived host. 2. We used known and radiocollared buffalo, aerial census data, and a natural gradient in pathogen prevalence to investigate if: (i) at the individual level, BTB infection reduces reproduction; (ii) BTB infection increases vulnerability to predation; and (iii) at the population level, increased BTB prevalence causes reduced population growth. 3. There was only a marginal reduction in calving success associated with BTB infection, as indexed by the probability of sighting a known adult female with or without a calf (P = 0·065). 4. Since 1991, BTB prevalence increased from 27 to 45% in the southern region and from 4 to 28% in the central region of Kruger National Park. The prevalence in the northern regions was only 1·5% in 1998. Buffalo population growth rates, however, were neither statistically different among regions nor declining over time. 5. Lions Panthera leo did not appear to preferentially kill test-positive buffalo. The best (Akaike's Information Criterion corrected for small sample size) AICc model with BTB as a covariate exp(β) = 0·49; 95% CI = (0·24-1·02) suggested that the mortality hazard for positive individuals was no greater than for test-negative individuals. 6. Synthesis and applications. Test accuracy, time-varying disease status, and movement among populations are some of the issues that make the detection of chronic disease impacts challenging. For these reasons, the demographic impacts of bovine tuberculosis in the Kruger National Park remain undetectable despite 6 years of study on known individuals and 40 years of population counts. However, the rainfall and forage conditions during this study were relatively good and the impacts of many chronic diseases may be a non-linear function of environmental conditions such that they are only detectable in stressful periods.
Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's ...esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T intronic, odds ratio 0.90, P = 0.0121, q = 0.3059, rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.
The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of ...human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.
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.
To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, ...there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study.
We studied 1,686 control subjects (mean age 66.1 ± 13.1 years) and 2,091 patients with PD (mean onset age 58.3 ± 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake.
A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 ± 8.6 heterozygous vs 58.5 ± 11.8 normal).
This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD.
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