Height-related risk factors for prostate cancer

Previous studies have reported that adult height is positively associated with the risk of prostate cancer. The authors carried out a population-based case–control study involving 317 prostate cancer cases and 480 controls to further investigate the possibility that height is more strongly associated with advanced, compared with localized forms of this disease. Since the inherited endocrine factors, which in part determine height attained during the growing years, may influence the risk of familial prostate cancer later in life, the relationship with height was also investigated for familial versus sporadic prostate cancers. Adult height was not related to the risk of localized prostate cancer, but there was a moderate positive association between increasing height and the risk of advanced cancer (relative risk (RR) = 1.62; 95% confidence interval (CI) 0.97–2.73, upper versus lowest quartile, P -trend = 0.07). Height was more strongly associated with the risk of prostate cancer in men with a positive family history compared with those reporting a negative family history. The RR of advanced prostate cancer for men in the upper height quartile with a positive family history was 7.41 (95% CI 1.68–32.67, P -trend = 0.02) compared with a reference group comprised of men in the shortest height quartile with a negative family history. Serum insulin-like growth factor-1 levels did not correlate with height amongst men with familial or sporadic prostate cancers. These findings provide evidence for the existence of growth-related risk factors for prostate cancer, particularly for advanced and familial forms of this disease. The possible existence of inherited mechanisms affecting both somatic and tumour growth deserves further investigation. © 2000 Cancer Research Campaig

Engineering with logic: Rigorous test-oracle specification and validation for TCP/IP and the Sockets API

Conventional computer engineering relies on test-and-debug development processes, with the behavior of common interfaces described (at best) with prose specification documents. But prose specifications cannot be used in test-and-debug development in any automated way, and prose is a poor medium for expressing complex (and loose) specifications. The TCP/IP protocols and Sockets API are a good example of this: they play a vital role in modern communication and computation, and interoperability between implementations is essential. But what exactly they are is surprisingly obscure: their original development focused on “rough consensus and running code,” augmented by prose RFC specifications that do not precisely define what it means for an implementation to be correct. Ultimately, the actual standard is the de facto one of the common implementations, including, for example, the 15 000 to 20 000 lines of the BSD implementation—optimized and multithreaded C code, time dependent, with asynchronous event handlers, intertwined with the operating system, and security critical. This article reports on work done in the Netsem project to develop lightweight mathematically rigorous techniques that can be applied to such systems: to specify their behavior precisely (but loosely enough to permit the required implementation variation) and to test whether these specifications and the implementations correspond with specifications that are executable as test oracles . We developed post hoc specifications of TCP, UDP, and the Sockets API, both of the service that they provide to applications (in terms of TCP bidirectional stream connections) and of the internal operation of the protocol (in terms of TCP segments and UDP datagrams), together with a testable abstraction function relating the two. These specifications are rigorous, detailed, readable, with broad coverage, and rather accurate. Working within a general-purpose proof assistant (HOL4), we developed language idioms (within higher-order logic) in which to write the specifications: operational semantics with nondeterminism, time, system calls, monadic relational programming, and so forth. We followed an experimental semantics approach, validating the specifications against several thousand traces captured from three implementations (FreeBSD, Linux, and WinXP). Many differences between these were identified, as were a number of bugs. Validation was done using a special-purpose symbolic model checker programmed above HOL4. Having demonstrated that our logic-based engineering techniques suffice for handling real-world protocols, we argue that similar techniques could be applied to future critical software infrastructure at design time, leading to cleaner designs and (via specification-based testing) more robust and predictable implementations. In cases where specification looseness can be controlled, this should be possible with lightweight techniques, without the need for a general-purpose proof assistant, at relatively little cost.EPSRC Programme Grant EP/K008528/1 REMS: Rigorous Engineering for Mainstream Systems EPSRC Leadership Fellowship EP/H005633 (Sewell) Royal Society University Research Fellowship (Sewell) St Catharine's College Heller Research Fellowship (Wansbrough), EPSRC grant GR/N24872 Wide-area programming: Language, Semantics and Infrastructure Design EPSRC grant EP/C510712 NETSEM: Rigorous Semantics for Real Systems EC FET-GC project IST-2001-33234 PEPITO Peer-to-Peer Computing: Implementation and Theory CMI UROP internship support (Smith) EC Thematic Network IST-2001-38957 APPSEM 2 NICTA was funded by the Australian Government's Backing Australia's Ability initiative, in part through the Australian Research Council

La relación personal en el tratamiento de la diversidad

El autor centra su aportación en diferentes características de los organismos vivos, para incorporarlas a las perspectivas interpretativas y operativas, y de los métodos actuales de intervención educativa. En el texto también se trata el enfoque positivo desde la dimensión técnica y no «voluntarista», teniendo en cuenta que los especialistas que adoptan la perspectiva del enfoque positivo dan mucha importancia al tema de la calidad de vida.L'autor centra la seva aportació en diferents característiques dels organismes vius, per incorporar- les a les perspectives interpretatives i operatives, i dels mètodes actuals d'intervenció educativa. Al text també es tracta l'enfocament positiu des de la seva dimensió tècnica i no «voluntarista», tenint en compte que els especialistes que adopten la perspectiva de l'enfocament positiu donen molta importància al tema de la qualitat de vida.The author focuses on the different characteristics of the alive organisms in order to include them into the interpretative and operative views of the current methods of educational intervention. He also deals with the positive focus, from the technical and «no voluntary» dimension, taking into account that those specialists having this kind of view do emphasize a lot on the quality of life issue

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. DESIGN AND SETTING: Retrospective, longitudinal cohort study of children with FA-HCM from the UK. PATIENTS: 78 children (<18 years) with FA-HCM diagnosed over four decades. INTERVENTION: Anonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up. MAIN OUTCOME MEASURES: The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. RESULTS: The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). CONCLUSIONS: This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly

Effect of dietary omega-3 fatty acids on castrate-resistant prostate cancer and tumor-associated macrophages.

BackgroundM2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages.MethodsMycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm2. To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay.ResultsThe ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm3) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3).ConclusionsDietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC

A formalized general theory of syntax with bindings

We present the formalization of a theory of syntax with bindings that has been developed and refined over the last decade to support several large formalization efforts. Terms are defined for an arbitrary number of constructors of varying numbers of inputs, quotiented to alpha-equivalence and sorted according to a binding signature. The theory includes a rich collection of properties of the standard operators on terms, such as substitution and freshness. It also includes induction and recursion principles and support for semantic interpretation, all tailored for smooth interaction with the bindings and the standard operators

Longitudinal assessment of symptoms and risk of SARS-CoV-2 infection in healthcare workers across 5 hospitals to understand ethnic differences in infection risk.

BACKGROUND: Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. We aimed to understand ethnic differences in SARS-CoV-2 seropositivity among hospital healthcare workers depending on their hospital role, socioeconomic status, Covid-19 symptoms and basic demographics. METHODS: A prospective longitudinal observational cohort study. 1364 HCWs at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals between March 20 and July 10 2020. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Registration number: NCT04318314. FINDINGS: 272 of 1364 HCWs (mean age 40.7 years, 72% female, 74% White, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in Intensive Therapy Unit (ITU) workers (OR=0.44 95%CI 0.24, 0.77; p=0.0035). Seropositivity was higher in Black (compared to White) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen between White HCWs and other minority ethnic groups. INTERPRETATION: In the UK first wave, Black ethnicity (but not other ethnicities) more than doubled HCWs likelihood of seropositivity, independent of age, sex, measured socio-economic factors and hospital role

Prostate cancer risk and consumption of fish oils: a dietary biomarker-based case–control study

Experimental studies suggest that the risk of prostate cancer is reduced with the intake of long-chain n-3 polyunsaturated fatty acids derived from marine foods, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, few human studies have been conducted due to difficulties in assessing the dietary intake of these fatty acids. The authors examined the relationship between prostate cancer risk and EPA and DHA in erythrocyte biomarkers in a population-based case–control study in Auckland, New Zealand during 1996–1997 involving 317 prostate cancer cases and 480 age-matched community controls. Reduced prostate cancer risk was associated with high erythrocyte phosphatidylcholine levels of EPA (multivariate relative risk = 0.59; 95% confidence interval 0.37–0.95, upper vs lowest quartile) and DHA (multivariate relative risk = 0.62; 95% confidence interval 0.39–0.98, upper vs lowest quartile). These analyses support evidence from in vitro experiments for a reduced risk of prostate cancer associated with dietary fish oils, possibly acting via inhibition of arachidonic acid-derived eicosanoid biosynthesis. © 1999 Cancer Research Campaig

A mechanized semantics for C++ object construction and destruction, with applications to resource management

International audienceWe present a formal operational semantics and its Coq mechanization for the C++ object model, featuring object construction and destruction, shared and repeated multiple inheritance, and virtual function call dispatch. These are key C++ language features for high-level system programming, in particular for predictable and reliable resource management. This paper is the first to present a formal mechanized account of the metatheory of construction and destruction in C++, and applications to popular programming techniques such as "resource acquisition is initialization." We also report on irregularities and apparent contradictions in the ISO C++03 and C++11 standards