Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network.

BACKGROUND: Adjuvant trastuzumab with chemotherapy is standard treatment for HER2-positive breast cancer, defined as either HER2 IHC3+ or IHC2+ and FISH amplified. The aim of this study was to investigate the degree to which HER2 amplification in terms of HER2 gene copy numbers in HER2+IHC2+ cancers affected the outcome in a community setting. METHODS: Case records of 311 consecutive patients with early breast cancer presenting between 1st January 2005 and 31st December 2008 were reviewed. Progression-free survival and overall survival were calculated with the Kaplan-Meier method using STATA 13. RESULTS: Among 3+ cases (n=230) 163 received T vs 67 no-T. Among 2+ cases (n=81) 59 received T vs 22 no-T. Among 59 IHC2+-treated cases n=28 had an average of >12, n=13 had >6 to <12, and n=18 had >2 to <6 HER2 gene copies, respectively. The time of progression and overall survival of high and low copy number patients was similar and better than the intermediate copy number and the untreated cohorts. CONCLUSIONS: High HER2 copy number (>12) appears to be associated with consistently better response compared with patients with intermediate HER2 copy numbers (6-12). In light of emerging data of patients showing insensivity to trastuzumab therapy, we propose that the HER2 gene copy number value should be included as an additional indicator for stratifying both the management and the follow-up of breast cancer patients.

Adapting to extreme events related to natural variability and climate change: the imperative of coupling technology with strong regulation and governance.

In recent years there has been an increase in extreme events related to natural variability (such as earthquakes, tsunamis and hurricanes) and climate change (such as flooding and more extreme weather). Developing innovative technologies is crucial in making society more resilient to such events. However, little emphasis has been placed on the role of human decision-making in maximizing the positive impacts of technological developments. This is exacerbated by the lack of appropriate adaptation options and the privatization of existing infrastructure, which can leave people exposed to increasing risk. This work examines the need for more robust government regulation and legislation to complement developments and innovations in technology in order to protect communities against such extreme events.

Intergenic disease-associated regions are abundant in novel transcripts.

BACKGROUND: Genotyping of large populations through genome-wide association studies (GWAS) has successfully identified many genomic variants associated with traits or disease risk. Unexpectedly, a large proportion of GWAS single nucleotide polymorphisms (SNPs) and associated haplotype blocks are in intronic and intergenic regions, hindering their functional evaluation. While some of these risk-susceptibility regions encompass cis-regulatory sites, their transcriptional potential has never been systematically explored. RESULTS: To detect rare tissue-specific expression, we employed the transcript-enrichment method CaptureSeq on 21 human tissues to identify 1775 multi-exonic transcripts from 561 intronic and intergenic haploblocks associated with 392 traits and diseases, covering 73.9 Mb (2.2%) of the human genome. We show that a large proportion (85%) of disease-associated haploblocks express novel multi-exonic non-coding transcripts that are tissue-specific and enriched for GWAS SNPs as well as epigenetic markers of active transcription and enhancer activity. Similarly, we captured transcriptomes from 13 melanomas, targeting nine melanoma-associated haploblocks, and characterized 31 novel melanoma-specific transcripts that include fusion proteins, novel exons and non-coding RNAs, one-third of which showed allelically imbalanced expression. CONCLUSIONS: This resource of previously unreported transcripts in disease-associated regions ( http://gwas-captureseq.dingerlab.org ) should provide an important starting point for the translational community in search of novel biomarkers, disease mechanisms, and drug targets.

Implementing intensified tuberculosis case-finding among street-connected youth and young adults in Kenya.

BACKGROUND: Street-connected youth and young adults (SCY) suffer a myriad of health problems. In Kenya, SCY are at high risk for tuberculosis (TB) due to their congregate living situations. TB screening is not routinely implemented in SCY and there has been no published literature on the burden of TB in SCY in western Kenya. PROGRAM DESCRIPTION: In 2011, the AMPATH TB Program, an experienced TB screening program, partnered with the Tumaini Center, a trusted street youth organization, to conduct intensified case finding (ICF) for pulmonary TB among SCY. Our program aimed to investigate the numbers of SCY who reported symptoms and those diagnosed with smear-positive pulmonary TB, and link SCY with TB to treatment. RESULTS: Of 116 SCY who were screened, 114 (98%) had a positive questionnaire; 104 (90%) provided a spot sputum sample, 39 (34%) provided a morning sputum sample, and 111 (97%) reported cough of >2 weeks. One street youth tested smear-positive for TB and was treated through to cure. CONCLUSIONS: Implementing TB ICF is feasible in low-resource settings through unique collaborations between health care programs and community-based organizations. In addition to identifying smear-positive TB, our program uncovered a high burden of respiratory symptoms among SCY in Eldoret, Kenya.

Contexte : Les jeunes et les adultes vivant dans la rue (SCY) souffrent d'une myriade de problèmes de santé. Au Kenya, les SCY ont un risque élevé de tuberculose (TB) à cause de la promiscuité de leur habitat. Le dépistage de la TB n'est pas mis en œuvre en routine parmi les SCY et il n'y a eu aucune littérature publiée sur le poids de la TB chez les SCY de l'ouest du Kenya.Description du programme : En 2011, le programme TB AMPATH, un programme de dépistage de TB expérimenté, a établi un partenariat avec le Tumaini Center, une organisation fiable de jeunes de la rue, afin de réaliser une recherche de cas intensifiée (ICF) de la TB pulmonaire parmi les SCY. Notre programme a eu pour but de rechercher le nombre de SCY qui présentaient des symptômes et ceux qui ont eu un diagnostic de TB pulmonaire à frottis positif, et enfin de mettre en contact les SCY avec un site de traitement de la TB.Résultats : De 116 SCY qui ont été dépistés, 114 (98%) ont remis un questionnaire positif, 104 (90%) ont fourni un échantillon de crachats, 39 (34%) un échantillon matinal et 111 (97%) ont fait état d'une toux de >2 semaines. Un jeune de la rue a eu un frottis positif pour la TB et a été traité avec succès.Conclusions: La mise en œuvre de l'ICF de TB est faisable dans un contexte de faibles ressources à travers une unique collaboration entre les programmes de soins de santé et les organisations communautaires. En plus d'identifier la TB à frottis positif, notre programme a révélé un lourd fardeau de symptômes respiratoires parmi les SCY d'Eldoret, au Kenya.

Marco de referencia: Los jóvenes y los adultos jóvenes en situación de calle (SCY) sufren de una miríada de problemas de salud. En Kenia, los SCY tienen un alto riesgo de contraer la tuberculosis (TB), dada la situación de su convivencia. La detección de la TB no se practica de manera sistemática en esta población y no existen publicaciones científicas sobre la carga de morbilidad por TB en los SCY en el oeste de Kenia.Descripción del programa: En el 2011, el Programa TB AMPATH, un programa con experiencia en la detección sistemática de la TB, creó una alianza con el Tumaini Center, que es una organización reconocida que se ocupa de los SCY; su objetivo fue realizar una búsqueda intensiva de casos de TB pulmonar en esta población de jóvenes. El presente estudio tuvo por objeto investigar el número de SCY que refirieron síntomas y la cantidad de casos de TB pulmonar con baciloscopia positiva que se diagnosticaron, y vincular los SCY diagnosticados con los centros de tratamiento.Resultados: Se practicó la detección sistemática en 116 SCY, de los cuales 114 tuvieron un cuestionario positivo (98%), 104 aportaron una muestra inmediata de esputo (90%) y 39 una muestra de esputo matinal (34%). De los SCY, 111 refirieron tos de >2 semanas de duración (97%). Un joven tuvo una baciloscopia de esputo positiva y recibió tratamiento hasta su curación.Conclusión: La ejecución de una búsqueda intensiva de casos de TB es factible en los entornos de bajos recursos, por conducto de colaboraciones especiales entre los programas de atención de salud y las organizaciones comunitarias. Además de detectar los casos de TB bacilífera, el programa reveló una alta carga de morbilidad por síntomas respiratorios en los SCY en la ciudad de Eldoret, en Kenia.

The utility of isokinetic dynamometry in the assessment of human muscle function.

Isokinetic dynamometry has become a favoured method for the assessment of dynamic muscle function in both clinical research and sports environments. Several indices, such as peak torque, are used in the literature to characterise individual, group or larger population performance via these sophisticated data acquisition systems. Research suggests that there are several competing demands on the design of the measurement protocol which may affect the measurement of isokinetic strength and subsequent suitability of data for meaningful evaluation and interpretation. There is a need to increase measurement rigour, reliability and sensitivity to a level which is commensurate with the intended application, via more elaborate multiple-trial protocols. However, this may be confounded by logistical and financial constraints or reduced individual compliance. The net effect of the interaction of such demands may be considered to be the utility of the isokinetic dynamometry protocol. Of the factors which impinge on utility, those which relate to reliability afford the most control by the test administrator. Research data suggest that in many measurement applications, the reliability and sensitivity associated with all frequently-used indices of isokinetic leg strength which are estimated via single-trial protocols, are not sufficient to differentiate either performance change within the same individual or between individuals within a homogeneous group. While such limitation may be addressed by the use of protocols based on 3 to 4 inter-day trials for the index of peak torque, other indices which demonstrate reduced reliability, for example the composite index of the ratio of knee flexion to extension peak torque, may require many more replicates to achieve the same level of sensitivity. Here, the measurement utility of the index may not be sufficient to justify its proper deployment.

Influence of acute endurance activity on leg neuromuscular and musculoskeletal performance.

PURPOSE: The purpose of this study was to investigate the effect of endurance activities designed to simulate the physiological demands of soccer match-play and training, on leg strength, electromechanical delay, and knee laxity. METHODS: Eight recreational soccer players completed four exercise trials in random order: 1) a prolonged intermittent high intensity shuttle run (PHISR) which required subjects to complete a total distance of 9600 m in a form simulating the pattern of physical activity in soccer match-play (activity mode; rest-to-work intervals; approximately 90 min duration), 2) a shuttle-run (SR), (3) a treadmill run (TR) which required subjects to complete an equivalent distance at a running speed corresponding to 70% VO2max, and 4) a control condition consisting of no exercise. RESULTS: Results from repeated measures ANOVA revealed significant condition (PHISR; SR; TR; control) by time (pre; mid; post) interactions for peak torque (PT: knee extension and flexion: 1.05 rad.s-1), EMD and anterior tibio-femoral displacement (TFD) (P < 0.05). Impairment to indices of knee joint performance was observed in PHISR, SR, and TR trials. The greatest decrement occurred in PHISR and SR trials (up to 44%). Knee extensor and flexor strength performance near to full knee extension (0.44 rad knee flexion) was not changed following the functionally-relevant endurance activities. CONCLUSIONS: Even though strength performance near to full knee extension was preserved following acute endurance activities, the risk of ligamentous injury may be increased by concomitant impairment to EMD and anterior TFD.

Nutritional status, functional capacity and exercise rehabilitation in end-stage renal disease.

A significant percentage of patients with end-stage renal disease are malnourished and/or muscle wasted. Uremia is associated with decreased protein synthesis and increased protein degradation. Fortunately, nutritional status has been shown to be a modifiable risk factor in the dialysis population. It has long been proposed that exercise could positively alter the protein synthesis-degradation balance. Resistance training had been considered as the only form of exercise likely to induce anabolism in renal failure patients. However, a small, but growing, body of evidence indicates that for some dialysis patients, favourable improvements in muscle atrophy and fibre hypertrophy can be achieved via predominantly aerobic exercise training. Moreover, some studies tentatively suggest that nutritional status, as measured by SGA, can also be modestly improved by modes and patterns of exercise training that have been shown to also increase muscle fibre cross-sectional area and improve functional capacity. Functional capacity tests can augment the information content of basic nutritional status assessments of dialysis patients and as such are recommended for routine inclusion as a feature of all nutritional status assessments.

Reliability of indices of neuromuscular leg performance in end-stage renal failure.

The purpose of this study was to examine the day-to-day reproducibility and single measurement reliability of peak force, time to half peak force and rate of force development indices of knee extension neuromuscular performance in patients with end-stage renal failure. Eleven self-selected patients (6 men, 5 women) receiving maintenance dialysis (dialysis history 67 +/- 42.8 month) completed 3 inter-day assessment sessions. Each comprised a standardized warm-up and 3 intermittent static maximal voluntary actions of the knee extensors of the preferred limb (45 degrees knee flexion angle [0 degrees = full knee extension]) using a specially-constructed dynamometer. Repeated measures ANOVA of coefficient of variation scores revealed significant differences between indices in their reproducibility across day-to-day trials. Post-hoc comparisons of group mean scores suggested that peak force (6.6 +/- 3.0%) offers significantly greater measurement reproducibility than time to half peak force (16.8 +/- 9.5%) or rate of force development (20.3 +/- 12.1%). Intraclass correlation coefficients and standard error of measurement scores showed that single-trial assessments of peak force, time to half peak force and rate of force development would demonstrate limited precision and capability to discriminate subtle intra-subject or inter-subject changes in neuromuscular performance.

Improvement in quality of life of dialysis patients during six months of exercise.

Quality of life (QOL) assessment has rapidly become an integral variable of outcome in clinical research; over 1,000 new articles each year are indexed under "quality of life" (1). Despite the proliferation of instruments and the burgeoning theoretical literature devoted to QOL evaluation, no unified approach has been derived for its measurement, and little agreement has been attained on what it means (2). Lack of clarity regarding the definition of QOL has led to several related concepts, namely functional status, life-satisfaction, well-being, and health status, being used interchangeably with QOL (3), further contributing to ambiguity. Compared to the general population, patients with end-stage renal disease (ESRD) experience a poorer QOL (4). Questionnaire-based QOL measurement in ESRD has demonstrated that QOL is best in renal transplantation and worst in unit-based haemodialysis. The main determinants of difference are the physical function domains. QOL in ESRD has traditionally been measured by a number of disease-specific, domain-specific and generic instruments, all exhibiting a fixed design. However, the fixed nature of the aforementioned instruments, is problematic in that what is measured is predetermined and hence may not represent the free choice of the individual whose QOL is assessed (5). Questionnaire-based instruments may not reflect individual priorities.

Evaluating the potential for environmental pollution from chromated copper arsenate (CCA)-treated wood waste: a new mass balance approach.

The potential for pollution from arsenic, chromium and copper in chromated copper arsenate (CCA) treated wood waste was assessed using two lysimeter studies. The first utilised lysimeters containing soil and CCA wood waste mulch exposed to natural conditions over a five month period. The second study used the same lysimeter setup in a regulated greenhouse setting with a manual watering regime. Woodchip, soil and leachate samples were evaluated for arsenic, chromium and copper concentrations. Resultant concentration data were used to produce mass balances, an approach thus far unused in such studies. This novel analysis revealed new patterns of mobility and distribution of the elements in the system. The results suggest that CCA wood waste tends to leach on initial exposure to a leachant and during weathering of the wood. When in contact with soil, metal(loid) transport is reduced due to complexation reactions. With higher water application or where the adsorption capacity of the soil is exceeded, the metal(loid)s are transported through the soil column as leachate. Overall, there was an unexplained loss of metal(loid)s from the system that might be attributed to volatilisation of arsenic and plant uptake. This suggests a hitherto unidentified risk to both the environment and human health.

Leaching characteristics of CCA-treated wood waste: a UK study.

CCA-treated wood is expected to increase in the UK waste stream over the next 20-50 years. The potential pollution from this waste has been evaluated through two leaching studies, one based upon batch leaching tests and another based upon a series of lysimeter tests. The aim of the studies was to characterise the behaviour of arsenic (As), chromium (Cr) and copper (Cu) from this wood when applied to soil as a mulch. Results demonstrate that all three elements leach from CCA waste wood, occasionally in concentrations exceeding regulatory thresholds by two to three orders of magnitude. In the lysimeter study, wood mulch monofills and wood mulch in combination with soil were used to monitor the leaching of As, Cr and Cu. Peak concentrations for As, Cr and Cu were 1885 µg/l, 1243 µg/l and 1261 µg/l, respectively. Freshly treated wood leached 11, 23 and 33 times more Cu, Cr and As, respectively than weathered wood. The toxic and mobile species of arsenic (As III, As V) were detected. Leaching in the CCA wood monofill was influenced by rainfall, with higher concentrations of metal(loid)s produced in lower intensity events. As and Cu were mobilised preferentially, with all metals exhibiting similar temporal trends. Retention of leached metal(loid)s was observed in lysimeters containing soil. Leaching processes appear to be favoured by the chipping process, diffusion and weathering. This study has shown that weathered waste wood mulch can cause significant pollution in soil water with potential impacts on both the environment and human health.