Engineering geology and tunnelling in the Limmo Peninsula, East London

The Limmo Peninsula site has some of the most complex geology of London's Crossrail project and was the launching point for four tunnel boring machines (TBMs) to allow construction of Crossrail's eastern running tunnels. It is located in East London, c. 2 km east of the Canary Wharf business district, adjacent to the River Lea. It consists of a ventilation shaft, an auxiliary shaft, two sprayed concrete lining (SCL) tunnels interconnecting the shafts and four SCL adits for assisting in the launching of the TBMs. As part of the design requirements, some geological formations had to be depressurized from surface wells. The site is geologically complex: it is in the vicinity of a drift-filled hollow and it is located within the area of influence of several tectonic features. A geological ground model developed from important new information obtained during the design stage ground investigations and from direct observations conducted during construction stages reveals an inverted transtensional flower structure (i.e. it is now a transpressional restraining bend). Of special interest are the unusually low values of undrained shear strength of the London Clay associated with the tectonic setting

Determinants of muscle carnosine content

The main determinant of muscle carnosine (M-Carn) content is undoubtedly species, with, for example, aerobically trained female vegetarian athletes [with circa 13 mmol/kg dry muscle (dm)] having just 1/10th of that found in trained thoroughbred horses. Muscle fibre type is another key determinant, as type II fibres have a higher M-Carn or muscle histidine containing dipeptide (M-HCD) content than type I fibres. In vegetarians, M-Carn is limited by hepatic synthesis of β-alanine, whereas in omnivores this is augmented by the hydrolysis of dietary supplied HCD’s resulting in muscle levels two or more times higher. β-alanine supplementation will increase M-Carn. The same increase in M-Carn occurs with administration of an equal molar quantity of carnosine as an alternative source of β-alanine. Following the cessation of supplementation, M-Carn returns to pre-supplementation levels, with an estimated t1/2 of 5–9 weeks. Higher than normal M-Carn contents have been noted in some chronically weight-trained subjects, but it is unclear if this is due to the training per se, or secondary to changes in muscle fibre composition, an increase in β-alanine intake or even anabolic steroid use. There is no measureable loss of M-Carn with acute exercise, although exercise-induced muscle damage may result in raised plasma concentrations in equines. Animal studies indicate effects of gender and age, but human studies lack sufficient control of the effects of diet and changes in muscle fibre composition

Predictive feedback control and Fitts' law

Fitts’ law is a well established empirical formula, known for encapsulating the “speed-accuracy trade-off”. For discrete, manual movements from a starting location to a target, Fitts’ law relates movement duration to the distance moved and target size. The widespread empirical success of the formula is suggestive of underlying principles of human movement control. There have been previous attempts to relate Fitts’ law to engineering-type control hypotheses and it has been shown that the law is exactly consistent with the closed-loop step-response of a time-delayed, first-order system. Assuming only the operation of closed-loop feedback, either continuous or intermittent, this paper asks whether such feedback should be predictive or not predictive to be consistent with Fitts law. Since Fitts’ law is equivalent to a time delay separated from a first-order system, known control theory implies that the controller must be predictive. A predictive controller moves the time-delay outside the feedback loop such that the closed-loop response can be separated into a time delay and rational function whereas a non- predictive controller retains a state delay within feedback loop which is not consistent with Fitts’ law. Using sufficient parameters, a high-order non-predictive controller could approximately reproduce Fitts’ law. However, such high-order, “non-parametric” controllers are essentially empirical in nature, without physical meaning, and therefore are conceptually inferior to the predictive controller. It is a new insight that using closed-loop feedback, prediction is required to physically explain Fitts’ law. The implication is that prediction is an inherent part of the “speed-accuracy trade-off”

Etoricoxib-induced life-threatening hyperkalemia and acute kidney dysfunction against the background of telmisartan and a low sodium diet

Drug-induced hyperkalemia is not uncommon and may be life-threatening when presenting acutely in the emergency department. We present a case of severe hyperkalemia precipitated acutely by etoricoxib in a patient who was on telmisartan and a low sodium (potassium chloride-rich) diet. A 75-year-old male with a past medical history of well-controlled diabetes and hypertension was prescribed etoricoxib (90 mg daily) for 3 days for musculoskeletal backache. He had been taking his routine medications including telmisartan and a potassium-rich salt substitute for many years, without any recent change in dosage or quantity. There was evidence of microalbuminurea; however, the renal functions and electrolytes prior to starting etoricoxib were normal. He presented to the emergency department with signs and symptoms of life-threatening hyperkalemia (serum potassium 7.7 mEq/dl), accelerated hypertension, congestive heart failure, pulmonary edema and acute renal failure. Acute medical management and withholding all drugs that could cause hyperkalemia improved his serum potassium levels over 24 h and renal parameters within 5 days. All the other drugs except etoricoxib were restarted under observation over 8 weeks with no recurrence of the acute episode. Non-steroidal analgesics and other COX-2 inhibitors (rofecoxib and celecoxib) have been known to precipitate renal failure and hyperkalemia specially in patients at risk for the same; although not unexpected, this may be the first reported case of life-threatening hyperkalemia precipitated by etoricoxib in a previously stable patient having increased risk of renal failure and hyperkalemia

The effect of beta-alanine supplementation on neuromuscular fatigue in elderly (55–92 Years): a double-blind randomized study

<p>Abstract</p> <p>Background</p> <p>Ageing is associated with a significant reduction in skeletal muscle carnosine which has been linked with a reduction in the buffering capacity of muscle and in theory, may increase the rate of fatigue during exercise. Supplementing beta-alanine has been shown to significantly increase skeletal muscle carnosine. The purpose of this study, therefore, was to examine the effects of ninety days of beta-alanine supplementation on the physical working capacity at the fatigue threshold (PWC_FT) in elderly men and women.</p> <p>Methods</p> <p>Using a double-blind placebo controlled design, twenty-six men (n = 9) and women (n = 17) (age ± SD = 72.8 ± 11.1 yrs) were randomly assigned to either beta-alanine (BA: 800 mg × 3 per day; n = 12; CarnoSyn™) or Placebo (PL; n = 14) group. Before (pre) and after (post) the supplementation period, participants performed a discontinuous cycle ergometry test to determine the PWC_FT.</p> <p>Results</p> <p>Significant increases in PWC_FT(28.6%) from pre- to post-supplementation were found for the BA treatment group (p < 0.05), but no change was observed with PL treatment. These findings suggest that ninety days of BA supplementation may increase physical working capacity by delaying the onset of neuromuscular fatigue in elderly men and women.</p> <p>Conclusion</p> <p>We suggest that BA supplementation, by improving intracellular pH control, improves muscle endurance in the elderly. This, we believe, could have importance in the prevention of falls, and the maintenance of health and independent living in elderly men and women.</p

Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE(2), 6-keto-PGF1(α,) TxB(2)), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(−1) h(−1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE(2) excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB(2) excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users

Comparison of new forms of creatine in raising plasma creatine levels

<p>Abstract</p> <p>Background</p> <p>Previous research has shown that plasma creatine levels are influenced by extracellular concentrations of insulin and glucose as well as by the intracellular creatine concentration. However, the form of creatine administered does not appear to have any effect although specific data on this is lacking. This study examined whether the administration of three different forms of creatine had different effects on plasma creatine concentrations and pharmacokinetics.</p> <p>Methods</p> <p>Six healthy subjects (three female and three male subjects) participated in the study. Each subject was assigned to ingest a single dose of isomolar amounts of creatine (4.4 g) in the form of creatine monohydrate (CrM), tri-creatine citrate (CrC), or creatine pyruvate (CrPyr) using a balanced cross-over design. Plasma concentration curves, determined over eight hours after ingestion, were subject to pharmacokinetic analysis and primary derived data were analyzed by repeated measures ANOVA.</p> <p>Results</p> <p>Mean peak concentrations and area under the curve (AUC) were significantly higher with CrPyr (17 and 14%, respectively) in comparison to CrM and CrC. Mean peak concentration and AUC were not significantly different between CrM and CrC. Despite the higher peak concentration with CrPyr there was no difference between the estimated velocity constants of absorption (ka) or elimination (kel) between the three treatments. There was no effect of treatment with CrPyr on the plasma pyruvate concentration.</p> <p>Conclusion</p> <p>The findings suggest that different forms of creatine result in slightly altered kinetics of plasma creatine absorption following ingestion of isomolar (with respect to creatine) doses of CrM, CrC and CrPyr although differences in ka could not be detected due to the small number of blood samples taken during the absorption phase. Characteristically this resulted in higher plasma concentrations of creatine with CrPyr. Differences in bioavailability are thought to be unlikely since absorption of CrM is already close to 100%. The small differences in kinetics are unlikely to have any effect on muscle creatine elevation during periods of creatine loading.</p

Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines

Mathematical models are useful for assessing the potential epidemiological impact of future tuberculosis (TB) vaccines. We conducted a systematic review of mathematical models estimating the epidemiological impact of future human TB vaccines. PubMed, Embase and WHO Global Health Library were searched, 3-stage manual sifted, and citation- and reference-tracked, identifying 23 papers. An adapted quality assessment tool was developed, with a resulting median study quality score of 20/28. The literature remains divided as to whether vaccines effective pre- or post-infection would provide greatest epidemiological impact. However, all-age or adolescent/adult targeted prevention of disease vaccines achieve greater and more rapid impact than neonatal vaccines. Mass campaigns alongside routine neonatal vaccination can have profound additional impact. Economic evaluations found TB vaccines overwhelmingly cost-effective, particularly when targeted to adolescents/adults. The variability of impact by setting, age group and vaccine characteristics must be accounted for in the development and delivery of future TB vaccines

What predicts medical lethality of suicide attempts in Asian youths?

This study explores youth suicide attempts in Singapore using multiple databases of comprehensive archivalrecords. Three years of medical records related to suicide attempters (N = 666) who were admitted to theemergency department of a large teaching hospital in Singapore were subjected to retrospective analysis.Compared to other age groups, a peak in suicide attempts (n = 207) was observed in youths aged between 15and 24 years old (76.3% females; 23.7% males, mean age = 19.30, SD = 2.89). The model using recognized riskand protective factors was significant in predicting medical lethality, and correctly classified 62.8% of highlethality cases. Only resolution of precipitant made a unique statistical significant contribution. Analysis wasseparately conducted for males and females. Implications of the findings are discussed

New tuberculosis vaccines: advances in clinical development and modelling.

Tuberculosis remains a major source of morbidity and mortality worldwide, with 10 million cases and 1.5 million deaths in 2018. Achieving 'End TB' prevention and care goals by 2035 will likely require a new tuberculosis vaccine. The tuberculosis vaccine development pipeline has seen encouraging progress; however, questions around their population impact and implementation remain. Mathematical modelling investigates these questions to inform vaccine development and deployment strategies. We provide an update on the current vaccine development pipeline, and a systematic literature review of mathematical modelling of the epidemiological impact of new tuberculosis vaccines. Fourteen prophylactic tuberculosis vaccine candidates are currently in clinical trials. Two candidates have shown promise in phase II proof-of-concept efficacy trials: M72/AS01E demonstrated 49.7% (95% CI; 2.1, 74.2) protection against tuberculosis disease, and BCG revaccination demonstrated 45.4% (95% CI; 6.4, 68.1) protection against sustained Mycobacterium tuberculosis infection. Since the last modelling review, new studies have investigated the epidemiological impact of differential vaccine characteristics, age targeting and spatial/risk group targeting. Critical research priorities for M72/AS01E include completing the currently in-design trial, powered to improve the precision of efficacy estimates, include uninfected populations and further assess safety and immunogenicity in HIV-infected people. For BCG revaccination, the priority is completing the ongoing confirmation of efficacy trial. Critical modelling gaps remain on the full value proposition of vaccines, comparisons with other interventions and more realistic implementation strategies. Using carefully designed trials and modelling, we must prepare for success, to ensure that new vaccines will be promptly received by those most in need