Elliptic logarithms, diophantine approximation and the Birch and Swinnerton-Dyer conjecture

Most, if not all, unconditional results towards the abc-conjecture rely ultimately on classical Baker's method. In this article, we turn our attention to its elliptic analogue. Using the elliptic Baker's method, we have recently obtained a new upper bound for the height of the S-integral points on an elliptic curve. This bound depends on some parameters related to the Mordell-Weil group of the curve. We deduce here a bound relying on the conjecture of Birch and Swinnerton-Dyer, involving classical, more manageable quantities. We then study which abc-type inequality over number fields could be derived from this elliptic approach.Comment: 20 pages. Some changes, the most important being on Conjecture 3.2, three references added ([Mas75], [MB90] and [Yu94]) and one reference updated [BS12]. Accepted in Bull. Brazil. Mat. So

The Impact of Case Diagnosis Coverage and Diagnosis Delays on the Effectiveness of Antiviral Strategies in Mitigating Pandemic Influenza A/H1N1 2009

BACKGROUND: Neuraminidase inhibitors were used to reduce the transmission of pandemic influenza A/H1N1 2009 at the early stages of the 2009/2010 pandemic. Policies for diagnosis of influenza for the purposes of antiviral intervention differed markedly between and within countries, leading to differences in the timing and scale of antiviral usage. METHODOLOGY/PRINCIPAL FINDINGS: The impact of the percentage of symptomatic infected individuals who were diagnosed, and of delays to diagnosis, for three antiviral intervention strategies (each with and without school closure) were determined using a simulation model of an Australian community. Epidemic characteristics were based on actual data from the A/H1N1 2009 pandemic including reproduction number, serial interval and age-specific infection rate profile. In the absence of intervention an illness attack rate (AR) of 24.5% was determined from an estimated R(0) of 1.5; this was reduced to 21%, 16.5% or 13% by treatment-only, treatment plus household prophylaxis, or treatment plus household plus extended prophylaxis antiviral interventions respectively, assuming that diagnosis occurred 24 hours after symptoms arose and that 50% of symptomatic cases were diagnosed. If diagnosis occurred without delay, ARs decreased to 17%, 12.2% or 8.8% respectively. If 90% of symptomatic cases were diagnosed (with a 24 hour delay), ARs decreased to 17.8%, 11.1% and 7.6%, respectively. CONCLUSION: The ability to rapidly diagnose symptomatic cases and to diagnose a high proportion of cases was shown to improve the effectiveness of all three antiviral strategies. For epidemics with R(0)< = 1.5 our results suggest that when the case diagnosis coverage exceeds ∼70% the size of the antiviral stockpile required to implement the extended prophylactic strategy decreases. The addition of at least four weeks of school closure was found to further reduce cumulative and peak attack rates and the size of the required antiviral stockpile

The intertropical convergence zone modulates intense hurricane strikes on the western North Atlantic margin

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 6 (2016): 21728, doi:10.1038/srep21728Most Atlantic hurricanes form in the Main Development Region between 9°N to 20°N along the northern edge of the Intertropical Convergence Zone (ITCZ). Previous research has suggested that meridional shifts in the ITCZ position on geologic timescales can modulate hurricane activity, but continuous and long-term storm records are needed from multiple sites to assess this hypothesis. Here we present a 3000 year record of intense hurricane strikes in the northern Bahamas (Abaco Island) based on overwash deposits in a coastal sinkhole, which indicates that the ITCZ has likely helped modulate intense hurricane strikes on the western North Atlantic margin on millennial to centennial-scales. The new reconstruction closely matches a previous reconstruction from Puerto Rico, and documents a period of elevated intense hurricane activity on the western North Atlantic margin from 2500 to 1000 years ago when paleo precipitation proxies suggest that the ITCZ occupied a more northern position. Considering that anthropogenic warming is predicted to be focused in the northern hemisphere in the coming century, these results provide a prehistoric analog that an attendant northern ITCZ shift in the future may again return the western North Atlantic margin to an active hurricane interval.This research was supported by NSF Awards: OCE-1519578, OCE-1356708, BCS-1118340

Proteolytic cleavage of p53 mutants in response to mismatched DNA

Interaction of p53 with mismatched DNA induces proteolytic cleavage with release of a 35-kDa protein fragment from the p53–DNA complexes. The 35-kDa cleavage product is activated for specific biochemical function(s) and may play a role in the cellular response to DNA damage (Molinari et al (1996) Oncogene13: 2077–2086; Okorokov et al (1997) EMBO J16: 6008–6017). In the present study we have asked if mutants of p53 retain the ability to undergo similar proteolytic cleavage, and compared sequence-specific ‘DNA contact’ with ‘structural’ mutants commonly found in human cancer. In addition, a series of phosphorylation site mutants were generated to investigate the possible effects of phosphorylation/dephosphorylation on the proteolytic cleavage of p53. All mutants tested bound to a mismatched DNA target in vitro. Moreover, studies in vitro and in vivo indicate that p53 mutants with intact conformational structure (as determined by immunoreactivity with PAb246 and PAb1620) retain the ability to undergo proteolytic cleavage similar, if not identical, to the wild-type p53 protein. Our results suggest that the capacity for p53 to bind mismatched DNA is independent of structural conformation of the central core domain. Proteolytic cleavage, however, is crucially dependent upon a wild-type conformation of the protein. © 1999 Cancer Research Campaig

Immediate and short-term pain relief by acute sciatic nerve press: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Despite much research, an immediately available, instantly effective and harmless pain relief technique has not been discovered. This study describes a new manipulation: a "2-minute sciatic nerve press", for rapid short-term relief of pain brought on by various dental and renal diseases.</p> <p>Methods</p> <p>This randomized, single-blind, placebo-controlled trial ran in three hospitals in Anhui Province, China, with an enrollment of 66 out of 111 solicited patients aged 16 to 74 years. Patients were recruited sequentially, by specific participating physicians at their clinic visits to three independent hospitals. The diseases in enrolled dental patients included dental caries, periodontal diseases and dental trauma. Renal diseases in recruits included kidney infections, stones and some other conditions. Patients were randomly assigned to receive the "2-minute sciatic nerve press" or the "placebo press". For the "2-minute sciatic nerve press", pressure was applied simultaneously to the sciatic nerves at the back of the thighs, using the fists while patients lay prone. For the "placebo press", pressure was applied simultaneously to a parallel spot on the front of the thighs, using the fists while patients lay supine. Each fist applied a pressure of 11 to 20 kg for 2 minutes, after which, patients arose to rate pain.</p> <p>Results</p> <p>The "2-minute sciatic nerve press" produced greater pain relief than the "placebo press". Within the first 10 minutes after sciatic pressure, immediate pain relief ratings averaged 66.4% (p < 0.001) for the dental patients, versus pain relief of 20% for the placebo press, and, 52.2% (p < 0.01) for the renal patients, versus relief of 14% for the placebo press, in median. The method worked excellently for dental caries and periodontal diseases, but poorly for dental trauma. Forty percent of renal patients with renal colic did not report any pain relief after the treatment.</p> <p>Conclusion</p> <p>Two minutes of pressure on both sciatic nerves can produce immediate significant conduction analgesia, providing a convenient, safe and powerful way to overcome clinical pain brought on by dental diseases and renal diseases for short term purposes.</p> <p>Trial registration</p> <p>ACTR 12606000439549</p

A new analgesic method, two-minute sciatic nerve press, for immediate pain relief: a randomized trial

<p>Abstract</p> <p>Background</p> <p>Current analgesics have drawbacks such as delays in acquisition, lag-times for effect, and side effects. We recently presented a preliminary report of a new analgesic method involving a two-minute sciatic nerve press, which resulted in immediate short-term relief of pain associated with dental and renal diseases. The present study investigated whether this technique was effective for pain associated with other disease types, and whether the relief was effective for up to one hour.</p> <p>Methods</p> <p>This randomized, placebo-controlled, parallel-group trial was conducted in four hospitals in Anhui Province, China. Patients with pain were sequentially recruited by participating physicians during clinic visits, and 135 patients aged 15 – 80 years were enrolled. Dental disease patients included those with acute pulpitis and periapical abscesses. Renal disease patients included those with kidney infections and/or stones. Tumor patients included those with nose, breast, stomach and liver cancers, while Emergency Room patients had various pathologies. Patients were randomly assigned to receive a "sciatic nerve press" in which pressure was applied simultaneously to the sciatic nerves at the back of both thighs, or a "placebo press" in which pressure was applied to a parallel region on the front of the thighs. Each fist applied a pressure of 11 – 20 kg for 2 minutes. Patients rated their level of pain before and after the procedure.</p> <p>Results</p> <p>The "sciatic nerve press" produced immediate relief of pain in all patient groups. Emergency patients reported a 43.5% reduction in pain (p < 0.001). Significant pain relief for dental, renal and tumor patients lasted for 60 minutes (p < 0.001). The peak pain relief occurred at the 10 – 20^thminutes, and the relief decreased 47% by the 60^thminutes.</p> <p>Conclusion</p> <p>Two minutes of pressure on both sciatic nerves produced immediate significant short-term conduction analgesia. This technique is a convenient, safe and powerful method for the short-term treatment of clinical pain associated with a diverse range of pathologies.</p> <p>Trial registration</p> <p>Current Controlled Trials ACTRN012606000439549</p

Profiling the immune landscape in mucinous ovarian carcinoma

Objective: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. Methods: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. Results: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. Conclusion: In summary, MOCs are mostly immunogenically ‘cold’, suggesting they may have limited response to current immunotherapies

A General Framework for Formal Tests of Interaction after Exhaustive Search Methods with Applications to MDR and MDR-PDT

The initial presentation of multifactor dimensionality reduction (MDR) featured cross-validation to mitigate over-fitting, computationally efficient searches of the epistatic model space, and variable construction with constructive induction to alleviate the curse of dimensionality. However, the method was unable to differentiate association signals arising from true interactions from those due to independent main effects at individual loci. This issue leads to problems in inference and interpretability for the results from MDR and the family-based compliment the MDR-pedigree disequilibrium test (PDT). A suggestion from previous work was to fit regression models post hoc to specifically evaluate the null hypothesis of no interaction for MDR or MDR-PDT models. We demonstrate with simulation that fitting a regression model on the same data as that analyzed by MDR or MDR-PDT is not a valid test of interaction. This is likely to be true for any other procedure that searches for models, and then performs an uncorrected test for interaction. We also show with simulation that when strong main effects are present and the null hypothesis of no interaction is true, that MDR and MDR-PDT reject at far greater than the nominal rate. We also provide a valid regression-based permutation test procedure that specifically tests the null hypothesis of no interaction, and does not reject the null when only main effects are present. The regression-based permutation test implemented here conducts a valid test of interaction after a search for multilocus models, and can be applied to any method that conducts a search to find a multilocus model representing an interaction

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone.METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N = 31 and N = 18, respectively).RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk >= 2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk >= 2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases.CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening. British Journal of Cancer (2011) 104, 1656 -1663. doi: 10.1038/bjc.2011.118 www.bjcancer.com Published online 5 April 2011 (C) 2011 Cancer Research U

How and why are communities of practice established in the healthcare sector? A systematic review of the literature

Background: Communities of Practice (CoPs) are promoted in the healthcare sector as a means of generating and sharing knowledge and improving organisational performance. However CoPs vary considerably in the way they are structured and operate in the sector. If CoPs are to be cultivated to benefit healthcare organisations, there is a need to examine and understand their application to date. To this end, a systematic review of the literature on CoPs was conducted, to examine how and why CoPs have been established and whether they have been shown to improve healthcare practice. Methods. Peer-reviewed empirical research papers on CoPs in the healthcare sector were identified by searching electronic health-databases. Information on the purpose of establishing CoPs, their composition, methods by which members communicate and share information or knowledge, and research methods used to examine effectiveness was extracted and reviewed. Also examined was evidence of whether or not CoPs led to a change in healthcare practice. Results: Thirty-one primary research papers and two systematic reviews were identified and reviewed in detail. There was a trend from descriptive to evaluative research. The focus of CoPs in earlier publications was on learning and exchanging information and knowledge, whereas in more recently published research, CoPs were used more as a tool to improve clinical practice and to facilitate the implementation of evidence-based practice. Means by which members communicated with each other varied, but in none of the primary research studies was the method of communication examined in terms of the CoP achieving its objectives. Researchers are increasing their efforts to assess the effectiveness of CoPs in healthcare, however the interventions have been complex and multifaceted, making it difficult to directly attribute the change to the CoP. Conclusions: In keeping with Wenger and colleagues' description, CoPs in the healthcare sector vary in form and purpose. While researchers are increasing their efforts to examine the impact of CoPs in healthcare, cultivating CoPs to improve healthcare performance requires a greater understanding of how to establish and support CoPs to maximise their potential to improve healthcare