617 research outputs found
The per-protocol effect of immediate versus deferred antiretroviral therapy initiation
OBJECTIVE: The START trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation. However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified. To supplement the published intention-to-treat effect estimates, here we estimate the per-protocol effect of immediate versus deferred ART initiation in START. DESIGN: The START trial randomized 4685 HIV-positive participants with CD4 counts > 500β/mm to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 count dropped below 350βcells/mm or an AIDS diagnosis (deferred initiation group). METHODS: We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate and deferred initiation groups had all the trial participants adhered to the protocol. RESULTS: We estimated that the 5-year risk of the composite outcome would have been 3.2% under immediate ART initiation and 7.0% under deferred initiation. The difference of 3.8% (95% confidence interval 1.5,6.5) was larger than the intention-to-treat effect estimate of 3.1%, corresponding to a difference in effect estimates of 0.72% (-0.35,2.35). CONCLUSIONS: The intention-to-treat effect estimate may underestimate the benefit of immediate ART initiation by 23%. This estimate can be used by patients and policy makers who need to understand the full extent of the benefit of changes in ART initiation policies
Viability of MSSM scenarios at very large tan(beta)
We investigate the MSSM with very large tan(beta) > 50, where the fermion
masses are strongly affected by loop-induced couplings to the "wrong" Higgs,
imposing perturbative Yukawa couplings and constraints from flavour physics.
Performing a low-energy scan of the MSSM with flavour-blind soft terms, we find
that the branching ratio of B->tau nu and the anomalous magnetic moment of the
muon are the strongest constraints at very large tan(beta) and identify the
viable regions in parameter space. Furthermore we determine the scale at which
the perturbativity of the Yukawa sector breaks down, depending on the
low-energy MSSM parameters. Next, we analyse the very large tan(beta) regime of
General Gauge Mediation (GGM) with a low mediation scale. We investigate the
requirements on the parameter space and discuss the implied flavour
phenomenology. We point out that the possibility of a vanishing Bmu term at a
mediation scale M = 100 TeV is challenged by the experimental data on B->tau nu
and the anomalous magnetic moment of the muon.Comment: 29 pages, 7 figures. v2: discussion in sections 1 and 4 expanded,
conclusions unchanged. Matches version published in JHE
Nitrides as ammonia synthesis catalysts and as potential nitrogen transfer reagents
In this article, an overview of the application of selected metal nitrides as ammonia synthesis catalysts is presented. The potential development of some systems into nitrogen transfer reagents is also described
Evaluation of a service intervention to improve awareness and uptake of bowel cancer screening in ethnically-diverse areas
The Policy
Research Unit in Cancer Awareness, Screening and Early Diagnosis
receives funding for a research programme from the UK
Department of Health Policy Research Programme (grant no.
106/0001). It is a collaboration between researchers from seven
institutions (the Queen Mary University of London, the UCL, the
Kingβs College London, the London School of Hygiene and
Tropical Medicine, the Hull York Medical School, the Durham
University and the Peninsula Medical School)
The mortality of colorectal cancer in relation to the initial symptom at presentation to primary care and to the duration of symptoms: a cohort study using medical records
The association between the staging of colorectal cancer and mortality is well known. Much less researched is the relationship between the duration of symptoms and outcome, and whether particular initial symptoms carry a different prognosis. We performed a cohort study of 349 patients with primary colorectal cancer in whom all their prediagnostic symptoms and investigation results were known. Survival data for 3β8 years after diagnosis were taken from the cancer registry. Six features were studied: rectal bleeding, abdominal pain, diarrhoea, constipation, weight loss, and anaemia. Two of these were significantly associated with different staging and mortality. Rectal bleeding as an initial symptom was associated with less advanced staging (odds ratio from one Duke's stage to the next 0.50, 95% confidence interval 0.31, 0.79; P=0.003) and with reduced mortality (Cox's proportional hazard ratio (HR) 0.56 (0.41, 0.79); P=0.001. Mild anaemia, with a haemoglobin of 10.0β12.9βgβdlβ1, was associated with more advanced staging (odds ratio 2.2 (1.2, 4.3); P=0.021) and worse mortality (HR 1.5 (0.98, 2.3): P=0.064). When corrected for emergency admission, sex, and the site of the tumour, the HR for mild anaemia was 1.7 (1.1, 2.6); P=0.015. No relationship was found between the duration of symptoms and staging or mortality
Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening
This is a summary of independent research funded by the National Institute for Health. Research (NIHR)βs Programme Grants for Applied Research Programme (RP-PG-0609β10106
Novel role for the innate immune receptor toll-like receptor 4 (TLR4) in the regulation of the wnt signaling pathway and photoreceptor apoptosis
Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFΞ± and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFΞ± antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFΞ± pathways. Β© 2012 Yi et al
Esophageal Cancer Related Gene-4 Is a Choroid Plexus-Derived Injury Response Gene: Evidence for a Biphasic Response in Early and Late Brain Injury
By virtue of its ability to regulate the composition of cerebrospinal fluid (CSF), the choroid plexus (CP) is ideally suited to instigate a rapid response to traumatic brain injury (TBI) by producing growth regulatory proteins. For example, Esophageal Cancer Related Gene-4 (Ecrg4) is a tumor suppressor gene that encodes a hormone-like peptide called augurin that is present in large concentrations in CP epithelia (CPe). Because augurin is thought to regulate senescence, neuroprogenitor cell growth and differentiation in the CNS, we evaluated the kinetics of Ecrg4 expression and augurin immunoreactivity in CPe after CNS injury. Adult rats were injured with a penetrating cortical lesion and alterations in augurin immunoreactivity were examined by immunohistochemistry. Ecrg4 gene expression was characterized by in situ hybridization. Cell surface augurin was identified histologically by confocal microscopy and biochemically by sub-cellular fractionation. Both Ecrg4 gene expression and augurin protein levels were decreased 24β72 hrs post-injury but restored to uninjured levels by day 7 post-injury. Protein staining in the supraoptic nucleus of the hypothalamus, used as a control brain region, did not show a decrease of auguin immunoreactivity. Ecrg4 gene expression localized to CPe cells, and augurin protein to the CPe ventricular face. Extracellular cell surface tethering of 14 kDa augurin was confirmed by cell surface fractionation of primary human CPe cells in vitro while a 6β8 kDa fragment of augurin was detected in conditioned media, indicating release from the cell surface by proteolytic processing. In rat CSF however, 14 kDa augurin was detected. We hypothesize the initial release and proteolytic processing of augurin participates in the activation phase of injury while sustained Ecrg4 down-regulation is dysinhibitory during the proliferative phase. Accordingly, augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation
The importance of anaemia in diagnosing colorectal cancer: a caseβcontrol study using electronic primary care records
Although anaemia is recognised as a feature of colorectal cancer, the precise risk is unknown. We performed a caseβcontrol study using electronic primary care records from the Health Improvement Network database, UK. A total of 6442 patients had a diagnosis of colorectal cancer, and were matched to 45β066 controls on age, sex, and practice. We calculated likelihood ratios and positive predictive values for colorectal cancer in both sexes across 1βgβdlβ1 haemoglobin and 10-year age bands, and examined the features of iron deficiency.In men, 178 (5.2%) of 3421 cases and 47 (0.2%) of 23β928 controls had a haemoglobin <9.0βgβdlβ1, giving a likelihood ratio (95% confidence interval) of 27 (19, 36). In women, the corresponding figures were 227 (7.5%) of 3021 cases and 58 (0.3%) of 21β138 controls, a likelihood ratio of 41 (30, 61). Positive predictive values increased with age and for each 1βgβdlβ1 reduction in haemoglobin. The risk of cancer for current referral guidance was quantified. For men over 60 years with a haemoglobin <11βgβdlβ1 and features of iron deficiency, the positive predictive value was 13.3% (9.7, 18) and for women with a haemoglobin <10βgβdlβ1 and iron deficiency, the positive predictive value was 7.7% (5.7, 11). Current guidance for urgent investigation of anaemia misses some patients with a moderate risk of cancer, particularly men
- β¦