Search

Utilizing external data from the real world, including data from historical clinical trials, has received increasing interest in drug development. The use of external data to support drug evaluation in clinical trials has mainly been through using various matching methods for baseline characteristics to form external control arms in single-arm trials or to augment control arms of randomized controlled trials in hybrid approaches. However, matching the baseline characteristics between the trial and the external subjects can only guarantee comparability on the level of baseline characteristics. Differences in outcomes between the two data sources may still exist due to contemporaneous and operational characteristics. Similarity between the outcomes in the trial control and the external subjects with similar baseline characteristics can be critical in leveraging the external subjects in the clinical trials. In this paper, a resampling method for augmenting control arms in randomized controlled trials is proposed under the conditional borrowing framework. The new method establishes empirical distributions for the hazard ratio in outcomes between the external and trial control subjects. The borrowing decision is then derived from this empirical distribution using a measure of similarity. Once the borrowing decision is established, the borrowing weights for the external subjects, based on the similarity measure, are incorporated in the weighted partial likelihood to evaluate the treatment effect. The operating characteristics of the hybrid control arm, under both the conditional borrowing and unconditional borrowing frameworks, are evaluated. Simulation is conducted to evaluate Type I error, bias, and power. An illustrative example using simulated data is also presented.

Increasing knowledge of the impacts of pesticides on soil ecological communities is fundamental to a comprehensive understanding of the functional changes in the global agroecosystem industry. In this study, we examined microbial community shifts in the gut of the soil-dwelling organism Enchytraeus crypticus and functional shifts in the soil microbiome (bacteria and viruses) after 21 d of exposure to difenoconazole, one of the main fungicides in intensified agriculture. Our results demonstrated reduced body weight and increased oxidative stress levels of E. crypticus under difenoconazole treatment. Meanwhile, difenoconazole not only altered the composition and structure of the gut microbial community, but also interfered with the soil-soil fauna microecology stability by impairing the abundance of beneficial bacteria. Using soil metagenomics, we revealed that bacterial genes encoding detoxification and viruses encoding carbon cycle genes exhibited a dependent enrichment in the toxicity of pesticides via metabolism. Taken together, these findings advance the understanding of the ecotoxicological impact of residual difenoconazole on the soil-soil fauna micro-ecology, and the ecological importance of virus-encoded auxiliary metabolic genes under pesticide stress.

Supplemental Digital Content is available in the text., Background: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score–matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment. Methods: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: 50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching. Results: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C 50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73–1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels

Tangential discontinuities known as cold fronts (CFs) are abundant in groups and clusters of galaxies (GCs). The relaxed, spiral-type CFs were initially thought to be isobaric, but a significant, $10\%$--$20\%$ jump in the thermal pressure $P_t$ was reported when deprojected CFs were stacked, interpreted as missing $P_t$ below the CFs (i.e. at smaller radii $r$) due to a locally-enhanced nonthermal pressure $P_{nt}$. We report a significant ($\sim4.3\sigma$) deprojected jump in $P_t$ across a single sharp CF in the Centaurus cluster. Additional seven CFs are deprojected in the GCs A2029, A2142, A2204, and Centaurus, all found to be consistent (stacked: $\sim1.9\sigma$) with similar pressure jumps. Combining our sample with high quality deprojected CFs from the literature indicates pressure jumps at significance levels ranging between $2.7\sigma$ and $5.0\sigma$, depending on assumptions. Our nominal results are consistent with $P_{nt}\simeq (0.1\mbox{--}0.3)P_t$ just below the CF. We test different deprojection and analysis methods to confirm that our results are robust, and show that without careful deprojection, an opposite pressure trend may incorrectly be inferred. Analysing all available deprojected data, we also find: (i) a nearly constant CF contrast $q$ of density and temperature within each GC, monotonically increasing with the GC mass $M_{200}$ as $q\propto M_{200}^{0.23\pm0.04}$; (ii) hydrostatic mass discontinuities indicating fast bulk tangential flows below all deprojected CFs, with a mean Mach number $\sim0.76$; and (iii) the newly deprojected CFs are consistent (stacked: $\sim2.9\sigma$) with a $1.25^{+0.09}_{-0.08}$ metallicity drop across the CF. These findings suggest that GCs quite generally harbor extended spiral flows., Comment: 29 pages, 20 figures, 6 tables

Background Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain. Objectives This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy. Methods A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non–high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were Results Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C Conclusions In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C NCT01663402 )

AimsProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50–60% and lipoprotein(a) (Lp(a)) by 20–30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab.MethodsThis is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%.ResultsOf the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance.ConclusionA high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance.

Personalized dialogue systems explore the problem of generating responses that are consistent with the user's personality, which has raised much attention in recent years. Existing personalized dialogue systems have tried to extract user profiles from dialogue history to guide personalized response generation. Since the dialogue history is usually long and noisy, most existing methods truncate the dialogue history to model the user's personality. Such methods can generate some personalized responses, but a large part of dialogue history is wasted, leading to sub-optimal performance of personalized response generation. In this work, we propose to refine the user dialogue history on a large scale, based on which we can handle more dialogue history and obtain more abundant and accurate persona information. Specifically, we design an MSP model which consists of three personal information refiners and a personalized response generator. With these multi-level refiners, we can sparsely extract the most valuable information (tokens) from the dialogue history and leverage other similar users' data to enhance personalization. Experimental results on two real-world datasets demonstrate the superiority of our model in generating more informative and personalized responses., Comment: Accepted by NAACL 2022 Main Conference

Objective: The aim of this study was to analyse the relationship between bone density derived from cone-beam computerized tomography (CBCT) scanning combined with the Simplant software at the implant site and primary implant stability.

In new drug development process, one of the most important milestones for a drug candidate is to establish Proof of Concept (PoC) at early Phase II stage. Among many challenges in PoC clinical trial design and analysis, the application of multiplicity comparison procedures (MCP) is frequently discussed when multiple doses or drugs are included in one PoC study. In such discussion, one fundamental question of applying multiplicity adjustment is which error one should consider to control and at what level. Should it be the experiment-wise error or the compound-wise error? In this paper, the multiplicity issues in two cases of PoC studies are used as examples to discuss the concept of different types of error and the level of the error rate control. With a clear understanding of the type of error and error rate control, the debate of applications of the multiplicity adjustment procedures in the PoC studies can be reconciled.

BackgroundPresently, there are limited reports in the literature on the post-operative (mid-term) clinical outcome for pure Aortic Regurgitation (AR) following Transcatheter Aortic Valve Replacement (TAVR).MethodsBetween March 2014 and June 2019, a total of 134 high-risk patients with pure, symptomatic severe AR patients were enrolled in the current study. The outcome was assessed according to the VARC-2 criteria. Procedural results, clinical outcomes, and the patients' hemodynamics for a period of 1-year were analyzed. ResultsPatient mean was 73.1±6.4 years and 25.4% were female. The average STS score was 9.8+5.3%. Procedural success was 97.1% (130/134), and the device success rate was 96.3% (129/134). Five cases were converted to open surgery, while two patients underwent valvular reinterventions (surgical aortic valve replacement for thrombosis and increasing paravalvular regurgitation). The mean aortic valve gradient was 10.2±4.1 mmHg, while the moderate and severe aortic regurgitation was 1.6% at 1 year. Paravalvular regurgitation was none/trivial in 79.8% and mild in 18.5%. The 1-year all-cause mortality rate was 7.4%. At 1-year, the stroke incidence rate was 2.2%. And pacemaker was implanted in 8.9% of the enrolled patients.ConclusionsIn high-risk patients undergoing transapical-TAVR for AR, the use of the J-Valve is safe and effective TAVR should be considered as a reasonable option for high-risk patients with pure AR.

Background New ESC/EAS guidelines advise a low-density lipoprotein cholesterol (LDL-C) target level Aim To overcome these limitations, we performed a propensity score-matching (PSM) analysis of the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in 18,924 patients with recent ACS. Methods Patients on alirocumab were classified in 1 of 3 pre-specified categories according to Month 4 LDL-C 50 mg/dL (n=2197). Within each category, MACE after Month 4 was compared with patients on placebo using 1:1 PSM on demographic, clinical, and adherence variables. Because the trial design involved blinded substitution of placebo for alirocumab when consecutive LDL-C levels were Results Patients in the three achieved LDL-C categories of the alirocumab group differed by baseline age, sex, geographic region; history of diabetes, smoking, peripheral artery disease, cerebrovascular disease, coronary revascularization, heart failure, obstructive pulmonary disease, or malignancy; type of index ACS event; baseline LDL-C, lipoprotein(a), estimated glomerular filtration rate, body mass index, systolic blood pressure; use of intensive statin therapy; and adherence with study medication. After PSM, patients in each LDL-C category on alirocumab were well matched to patients on placebo for these characteristics. Treatment hazard ratios (HRs) for MACE (Figure) were similar in those with achieved LDL-C 50 mg/dL achieved less benefit. Patients who achieved consecutive LDL-C levels Conclusion After accounting for differences in baseline characteristics and adherence, reduction in risk of MACE with alirocumab was similar in patients who achieved LDL-C Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi and Regeneron Pharmaceuticals, Inc

A dense seismological array and profile reveal the deep structure across the Longmenshan from the Songpan-Ganzi terrane of the Tibetan plateau to the Sichuan basin. Receiver function and tomographic images reveal that the Pengguan Complex which cores the Longmenshan in the region where the Ms. 8 Wenchuan earthquake of 2008 occurred, is marked by high velocities in the upper 15 km of the crust. At about 15 km depth both P- and S-wave velocities decrease at a flat-lying boundary around which the aftershock hypocentres of the Wenchuan earthquake are concentrated. Thus, this boundary may be a faulted interface or detachment, marking the base of the Pengguan Complex. Moho depths change significantly in going from the Tibetan plateau to the Sichuan basin. At the location of the dense profile a Moho step occurs, located about 50 km NW of the surface trace of the Yingxiu-Beichuan fault (YBF). The boundary at about 15 km depth below the Pengguan Complex seems to deepen at around the Wenchuan-Maoxian fault (WMF) by about 3 km and merge to the NW with another interface at about 18 km depth. This interface, NW of the WMF, which correlates with the top of a zone of high conductivity is interpreted to represent the top of the Tibetan mid-crustal low velocity, high conductivity zone. The tomographic image indicates that the boundary between the low velocities of the Songpan-Ganzi terrane and the high velocities of the Sichuan basin in the middle and lower crust occurs NW of the surface trace of the YBF. Thus, it is proposed that a zone extending from the WMF at about 15 km depth to the Moho step about 25 km further NW marks the boundary between the Tibetan plateau and the Sichuan basin in the middle and lower crust.

Background Recent guidelines for cholesterol management recognize uncertainty regarding long-term efficacy and safety of prolonged very low levels of LDL-C on treatment with a PCSK9 inhibitor, including risk of new-onset diabetes. ODYSSEY OUTCOMES used a treat-to-target approach to demonstrate reduction of coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina (MACE) with the PCSK9 inhibitor alirocumab (ALI) vs placebo (PBO) in 18,924 patients with recent acute coronary syndrome and elevated LDL-C despite intensive statin therapy. ALI was blindly adjusted (75 or 150 mg dose) to target LDL-C 0.6–1.3 mmol/L (25–50 mg/dL). To avoid sustained very low LDL-C, blind substitution of PBO for ALI was intended if 2 consecutive LDL-C levels were Purpose We report the efficacy and safety of ALI in patients who reached very low LDL-C (consecutively Methods Of 9462 patients randomized to receive ALI, 730 (7.7%) reached very low LDL-C and had substitution of PBO a median 8.3 months after randomization. Using propensity score matching, they were compared (3:1) with 2152 patients initially assigned to PBO. Propensity score matching was also used to compare the incidence of new-onset diabetes in 525 patients without diabetes at baseline who had very low LDL-C levels on ALI with 1675 matched patients in the PBO group. Neurocognitive events and haemorrhagic stroke were also evaluated in relation to very low LDL-C. Results Overall, ALI reduced the incidence of MACE (9.5% vs 11.1%; HR 0.85, 95% CI 0.78–0.93; P Conclusions The overall efficacy of ALI on cardiovascular outcomes was not diminished by the patients who had blinded substitution of PBO for sustained very low LDL-C. Despite a short duration of active treatment, these patients had fewer MACE than matched controls from the PBO group. No adverse consequence of very low LDL-C was identified. However, because patients with sustained very low LDL-C were switched to PBO, the long-term safety of more prolonged very low LDL-C, including risk of new-onset diabetes, deserves further study. Acknowledgement/Funding Funded by Sanofi and Regeneron Pharmaceuticals

Background Statins are a cornerstone of therapy for coronary heart disease. We describe the effects of alirocumab (ALI) in patients (pts) with recent acute coronary syndrome (ACS) and dyslipidaemia per category of statin use. Methods ODYSSEY OUTCOMES compared ALI with placebo (PBO) in 18,924 pts with recent ACS and dyslipidaemia despite high-intensity/maximum tolerated statin (atorvastatin 40–80 mg/d or rosuvastatin 20–40 mg/d). Lower doses could be used if there were symptoms, laboratory abnormalities, or contraindications with higher doses. In cases of documented intolerance to ≥2 statins, pts could qualify on no statin treatment. Pts were randomized to ALI (75 mg SC Q2W, with possible uptitration to 150 mg Q2W) or PBO. Median follow-up was 2.8 years. Primary endpoint was major adverse cardiovascular events (MACE: CHD death, non-fatal MI, ischaemic stroke, or unstable angina requiring hospitalization). Pts were categorized by statin therapy at baseline: high intensity (88.8%), low or moderate intensity (8.7%), or no statin use (2.4%). In each category we determined the relative (hazard ratio [HR]) and absolute risk reductions (ARR) for MACE with ALI. Results Overall, ALI reduced MACE (HR 0.85, 95% CI 0.78–0.93; P LDL-C values and MACE events All patients High-intensity statin Low-/moderate-intensity statin No statin Interaction P-value N=18,924 (100%) N=16,811 (88.8%) N=1653 (8.7%) N=460 (2.4%) (treatment x statin category) PBO (N=9462) ALI (N=9462) PBO (N=8431) ALI (N=8380) PBO (N=804) ALI (N=849) PBO (N=227) ALI (N=233) LDL-C at baseline, mmol/L, mean (SE)* 2.39 (0.01) 2.39 (0.01) 2.35 (0.01) 2.35 (0.01) 2.41 (0.03) 2.43 (0.03) 3.76 (0.08) 3.82 (0.08) Change in LDL-C from baseline to Month 4, mmol/L, mean (SE) 0.03 (0.01) −1.4 (0.01) 0.03 (0.01) −1.37 (0.01) 0.01 (0.02) −1.47 (0.02) −0.004 (0.06) −2.27 (0.06) Conclusions In ODYSSEY OUTCOMES, patients unable to receive high-intensity statin treatment showed greater ARRs with ALI, consistent with higher baseline LDL-C concentration and greater absolute LDL-C reduction. Patients unable to receive high-intensity statin treatment are an important group to consider for treatment with ALI after ACS. Acknowledgement/Funding Funded by Sanofi and Regeneron Pharmaceuticals

Background The 2018 ACC/AHA cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with LDL-C ≥1.8 mmol/L despite maximally tolerated statin therapy who are considered “very high-risk” on the basis of history of multiple ischaemic events or an ischaemic event and multiple high-risk conditions. Purpose We examined the frequency of major adverse cardiovascular events (MACE) and efficacy of PCSK9 inhibition with alirocumab to reduce MACE in patients with recent acute coronary syndrome (ACS) categorized as very high-risk or not very high-risk by guideline criteria. Methods Patients in ODYSSEY OUTCOMES (n=18,924) with recent ACS and residual dyslipidaemia despite optimal statin therapy were randomized to alirocumab or placebo and followed for median 2.8 years. The primary MACE outcome was a composite of coronary heart disease death, non-fatal myocardial infarction (MI), ischaemic stroke, or hospitalization for unstable angina. Results Of 18,924 randomized patients, 11,935 (63.1%) were categorized as very high-risk and 6989 (36.9%) as not very high risk (per ACC/AHA guidelines criteria). In the very high-risk category, 4450 (37.3%) had a prior ischaemic event plus the trial-qualifying index ACS (MI, 3633; stroke, 524; peripheral artery disease, 759); 7485 (62.7%) had no ischaemic event before the index ACS but had ≥2 high-risk conditions (diabetes, 3319; age ≥65 years, 3087; current smoking, 2371; chronic kidney disease, 1583). In the placebo group, the incidence of MACE was higher among those in the very high-risk category (14.4%) vs those not at very high-risk (5.6%). Overall, alirocumab reduced the risk of MACE vs placebo (9.5% vs 11.1%, hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.78–0.93; P=0.003), with consistent relative reductions in both risk categories (very high risk HR 0.84, 95% CI 0.76–0.92; not very high risk HR 0.86, 95% CI 0.70–1.06). However, the absolute reduction in MACE with alirocumab was greater among patients classified as very high-risk (2.1%) vs not very high risk (0.8%), and greater in particular among those classified as very high risk based on multiple ischaemic events (2.4%, Figure). Conclusions Application of 2018 ACC/AHA cholesterol guidelines criteria accurately identifies patients with ACS and dyslipidaemia who are at very high risk for recurrent MACE, and who derive a large absolute benefit from alirocumab treatment. Patients categorized as very high-risk based upon multiple ischaemic events derive a particularly large absolute benefit from treatment with alirocumab. Acknowledgement/Funding Supported by Sanofi and Regeneron Pharmaceuticals

The DarkSide project at Laboratori Nazionali del Gran Sasso (LNGS) is a dark matter direct search experiment based on the detection of rare nuclear recoils possibly induced by hypothetical dark matter particles, which are supposed to be neutral, massive (> 10 GeV) and weakly interact- ing (WIMP). DarkSide aims to perform background-free WIMP searches using a series of dual-phase liquid argon time projection chambers filled with ultra-pure liquid argon. The detector currently operat- ing at LNGS is DarkSide-50, a detector which holds 46 kg of active liquid argon and is now filled with argon extracted from underground and taking data in its final configuration. Combining the underground argon data with the preceding search made with atmospheric argon, a 90% C.L. upper limit on the WIMP-nucleon spin-independent cross section of 2.0 × 10−44 cm2 is set. The next phase of the experiment foresees the construction of a new detector with an active mass of ∼ 20 and equipped with silicon photomultipliers, called DarkSide-20k.

The objective of this study was to use surface-enhanced Raman spectroscopy (SERS) for rapid detection and characterization of trace amounts of forchlorfenuron extracted from fruits. Forchlorfenuron is a plant growth regulator widely used in grapes and has negative effects on human health. In this study, gold-coated nanosubstrates were used for SERS measurements. Partial least squares (PLS) analysis was used as a statistical method for quantitative analysis of the spectral data. Our results demonstrate that enhanced Raman signals acquired from samples exhibited characteristic spectral patterns. The PLS results for quantification of forchlorfenuron were obtained: R=0.96, RMSEP=9.336×10-6. The detection limit for forchlorfenuron by SERS is 3.15ppm for pure forchlorfenuron solutions and 4.43 ppm for forchlorfenuron extracted from grape skin. In addition, HPLC was also used to measure forchlorfenuron and verify SERS results. A good linear relationship was observed between 0 - 100 ppm with an R value of 0.999. These results demonstrate that SERS coupled with gold nanosubstrates is a rapid and simple method and it requires little sample preparation. It could be a practical approach to combine SERS with HPLC method to screen and analyze food samples for chemical contaminants and residues.

The application of an in-situ potential difference between carbon fibres and a graphite foil counter electrode (300 V, generating an electric field ca. 0.3 V μm-1 to 0.7 V μm-1) during the chemical vapour deposition synthesis of carbon nanotube (CNT) grafted carbon fibres, significantly improves the uniformity of growth without reducing the tensile properties of the underlying carbon fibres. Grafted carbon nanotubes with diameters around 55 nm and lengths around 10 μm were well attached to the carbon fibre surface, and were grown without the requirement for protective barrier coatings. The grafted CNTs increased the surface area to 185 m2 g-1 compared to the as-received sized carbon fibre 0.24 m2 g-1. The approach is not restricted to batch systems and has the potential to improve carbon nanotube grafted carbon fibre production for continuous processing.

© 2016 The Royal Society of Chemistry. Microalgae use various cellular mechanisms to detoxify both non-essential and excess essential metals or metalloids. There exists however, a threshold in intracellular metal(loid) concentrations beyond which detoxification mechanisms are no longer effective and inhibition of cell division inevitably occurs. It is therefore important to determine whether the availability of energy in the cell could constrain metal(loid) detoxification capacity and to better define the thresholds beyond which a metal(loid) becomes toxic. To do this we performed the first extensive bioenergetics analysis of intracellular metal(loid) detoxification mechanisms (e.g., metal-binding peptides, polyphosphate granules, metal efflux, metal and metalloid reduction, metalloid methylation, enzymatic and non-enzymatic antioxidants) in wild-type eukaryotic phytoplankton based on the biochemical mechanisms of each detoxification strategy and on experimental measurements of detoxifying biomolecules in the literature. The results show that at the onset of metal(loid) toxicity to growth, all the detoxification strategies considered required only a small fraction of the total cellular energy available for growth indicating that intracellular detoxification ability in wild-type eukaryotic phytoplankton species is not constrained by the availability of cellular energy. The present study brings new insights into metal(loid) toxicity mechanisms and detoxification strategies in wild-type eukaryotic phytoplankton.

The growth of carbon nanotubes (CNTs) on carbon fibres (CFs) to produce a hierarchical fibre with two differing reinforcement length scales, in this instance nanometre and micrometre respectively, is considered a route to improve current state-of-the-art fibre reinforced composites [1]. The scalable production of carbon nanotube-grafted-carbon fibres (CNT-g-CFs) has been limited due to high temperatures, the use of flammable gases and the requirement of inert conditions for CNT synthesis, whist (ideally) maintaining underlying original substrate mechanical properties. Here, the continuous production of CNT-g-CF is demonstrated in an open chemical vapour deposition (CVD) reactor, crucially, whilst retaining the tensile properties of the carbon fibres. As synthesised CNTs have a diameter of sub 20 nm and length ca. 120 nm, which are predicted to provide ideal fibre reinforcement in composites by retaining optimal composite fibre volume fraction (60%), whilst improving interfacial bonding of the matrix and reinforcement [1, 2]. Mild processing techniques enable this modified CVD process to be fully compatible with industrial practices, and have the potential to generate large volumes of hierarchical CNT-g-CF material.

A continuum model was proposed to simulate a biological cell adhering to a substrate surface domain with selectively coated ligands. Cell adhesion was modeled by a traction-separation law depending on the receptor-ligand distance and their densities. It was found that the obtained spreading patterns are consistent with published experimental data and that adhesion requires a nonuniform distribution of receptors at the spreading front with convex fronts requiring a much higher receptor density than concave fronts. Adhesion strength was also found to be more influential than adhesion energy on the spreading kinetics.

Often a treatment is assessed by co-primary endpoints so that a comprehensive picture of the treatment effect can be obtained. Co-primary endpoints can be different medical assessments angled at different aspects of a disease, therefore, are used collectively to strengthen evidence for the treatment effect. It is common sense that if a treatment is ineffective, the chance to show that the treatment is effective in all co-primary endpoints should be small. Therefore, it may not be necessary to require all the co-primary endpoints to be statistically significant at the 1-sided 0.025 level to control the error rate of wrongly approving an ineffective treatment. Rather it is reasonable to allow certain variation for the p -values within a range close to 0.025. In this paper, statistical methods are developed to derive decision rules to evaluate co-primary endpoints collectively. The decision rules control the error rate of wrongly accepting an ineffective treatment at the level of 0.025 for a study and the error rate at a slightly higher level for a treatment that works for all the co-primary endpoints except perhaps one. The decision rules also control the error rates for individual endpoints. Potential applications in clinical trials are presented.

Multiple doses, endpoints, and tests are used in several clinical studies to establish drug efficacy. Statistical evaluation relies heavily on multiplicity adjustments within one study to control the type I error rate. The use of multiplicity adjustment procedures (MAPs) sometimes leads to conclusions that may not seem logical. As drug efficacy evaluation involves aspects such as assessing efficacy, selecting optimal doses, and labeling claims, incorporating all the aspects under the umbrella of controlling type I error may not be an optimum strategy. Alternatively, a practical approach that uses collective evidence is proposed to evaluate multiple studies, doses, endpoints, and tests. Instead of controlling the type I error, specific types of errors are controlled, such as the error of wrongly approving an ineffective drug and the error of labeling false information. With the collective evidence approach, the need of MAPs in individual studies is debated when multiple studies are available.

A common statistical problem involves the testing of a K-dimensional parameter vector. In both parametric and semiparametric settings, two types of directional tests – linear combination and constrained tests – are frequently used instead of omnibus tests in hopes of achieving greater power for specific alternatives. In this paper, we consider the relationship between these directional tests, as well as their relationship to omnibus tests. Every constrained directional test is shown to be asymptotically equivalent to a specific linear combination test under a sequence of contiguous alternatives and vice versa. Even when the direction of the alternative is known, the constrained test in general will not be optimal unless the objective function used to derive it is efficient. For an arbitrary alternative, insight into the power characteristics of directional tests in comparison to omnibus tests can be gained by a chi-square partition of the omnibus test.

We investigate the properties of several statistical tests for comparing treatment groups with respect to multivariate survival data, based on the marginal analysis approach introduced by Wei, Lin and Weissfeld ["Regression Analysis of multivariate incomplete failure time data by modelling marginal distributions," JASA vol. 84 pp. 1065-1073]. We consider two types of directional tests, based on a constrained maximization and on linear combinations of the unconstrained maximizer of the working likelihood function, and the omnibus test arising from the same working likelihood. The directional tests are members of a larger class of tests, from which an asymptotically optimal test can be found. We compare the asymptotic powers of the tests under general contiguous alternatives for a variety of settings, and also consider the choice of the number of survival times to include in the multivariate outcome. We illustrate the results with simulations and with the results from a clinical trial examining recurring opportunistic infections in persons with HIV.

Usually, in applying for market approval of a new drug, more than one similarly designed clinical trial is conducted to support efficacy claims. How to evaluate these trials collectively and assess the overall type I error of a decision rule can be a challenging statistical issue. In this paper, we propose a decision rule to collectively evaluate p-values from several similarly designed and independently conducted trials. A concept of overall hypotheses, which is essentially union or intersection combinations of individual trials’ hypotheses, is used so that the overall type I error can be controlled at desired levels. We also discuss some important properties of the approach, including the selection of the overall type I error rates and power. Examples are presented.

We consider application of the Wei-Lin-Weissfeld (WLW) method for multiple failure time data when analysing a disease process consisting of a recurring outcome, such as clinical progression, and a terminating outcome, such as death. In order to adapt WLW for this situation, 'events' must be specified that define multiple failure times and whether these are censored. Various choices of events are possible, and each corresponds to inferences about a different aspect of the underlying disease process. Definitions which regard the terminating outcome as a censor of the recurring outcome focus on specific cause-specific hazard functions, while event definitions which make no distinction between a recurring and terminating outcome focus on hazard functions of the induced failure times. Some event definitions require strong statistical assumptions to yield valid inferences and are not recommended. The application of WLW for recurring/terminating processes is illustrated with the results of two recently conducted clinical trials in persons with HIV.

Over the past decade, concerns have been expressed increasingly regarding the difficulty for highly variable drugs and drug products (%CV greater than 30) to meet the standard bioequivalence (BE) criteria using a reasonable number of study subjects. The topic has been discussed on numerous occasions at national and international meetings. Despite the lack of a universally accepted solution for the issue, regulatory agencies generally agree that an adjustment of the traditional BE limits for these drugs or products may be warranted to alleviate the resource burden of studying relatively large numbers of subjects in bioequivalence trials. This report summarizes a careful examination of all the statistical methods available and extensive simulations for BE assessment of highly variable drugs/products. Herein, the authors present an approach of scaling an average BE criterion to the within-subject variability of the reference product in a crossover BE study, together with a point-estimate constraint imposed on the geometric mean ratio between the test and reference products. The use of a reference-scaling approach involves the determination of variability of the reference product, which requires replication of the reference treatment in each individual. A partial replicated-treatment design with this new data analysis methodology will thus provide a more efficient design for BE studies with highly variable drugs and drug products.

A rare drought occurred from 1998 to 2002 across much of the Northern Hemisphere midlatitude regions. Using observational data and numerical models, we analyze the impact of this event on terrestrial ecosystem and the global carbon cycle. The biological productivity in these regions was found to decrease by 0.9 PgC yr(-1) or 5% compared to the average of the previous two decades, in conjunction with significantly reduced vegetation greenness. The drought led to a land carbon release that is large enough to significantly modify the canonical tropically dominated ENSO response. An atmospheric inversion reveals that during the 1998 - 2002 drought period, Northern Hemisphere midlatitude changed from a 1980 1998 average of 0.7 PgC yr(-1) carbon sink to nearly neutral to the atmosphere, while a forward model suggests a change of 1.3 PgC yr(-1) in the same direction. This large CO2 source may explain the consecutive large increase in atmospheric CO2 growth rate of about 2 ppmv yr(-1) in recent years, as well as the anomalous timing of events. This Northern Hemisphere CO2 anomaly was largely caused by reduced vegetation growth due to less precipitation, but also with significant contribution from higher temperature that directly increases respiration loss and indirectly further reduces soil moisture. Since the Northern Hemisphere midlatitude landscape has been significantly modified by agriculture, grazing, irrigation and fire suppression, the strong signature in the global carbon cycle of a drought initiated by changes in tropical oceanic temperatures is a remarkable manifestation of climate variability, with implications for carbon cycle response and feedback to future climate change. [References: 14]

The polymer segmental dynamics is investigated in a series of silica-filled rubbers. The presence of inert fillers in polymers greatly affects the mechanical and physical performance of the final materials. For example, silica has been proposed as a reinforcing agent of elastomers in tire production. Results from quasielastic neutron scattering and Dynamic Mechanical Thermal Analysis (DMTA) measurements are presented on styrene-ran-butadiene rubber filled with silica. A clear indication is obtained of the existence of a bimodal dynamics, which can be rationalized in terms of the relaxation of bulk rubber and the much slower relaxation of the rubber adsorbed on the filler surface.

This article 'RFLP mapping of QTLs for yield and other related characters in rice' appeared in the International Rice Research Notes series, created by the International Rice Research Institute (IRRI) to expedite communication among scientists concerned with the development of improved technology for rice and rice-based systems. The series is a mechanism to help scientists keep each other informed of current rice research findings. The concise scientific notes are meant to encourage rice scientists to communicate with one another to obtain details on the research reported.

This article 'Screening RFLP probes for differentiating indicas and japonicas' appeared in the International Rice Research Notes series, created by the International Rice Research Institute (IRRI) to expedite communication among scientists concerned with the development of improved technology for rice and rice-based systems. The series is a mechanism to help scientists keep each other informed of current rice research findings. The concise scientific notes are meant to encourage rice scientists to communicate with one another to obtain details on the research reported.

International audience; DarkSide-50 is dual-phase liquid argon time projection chamber designed for WIMP search and installed at Gran Sasso underground laboratory. We present new constraints on dark matter particles scattering off nuclei and electrons from a 532.4 live-days exposure.

International audience; (The DarkSide Collaboration) The DarkSide program at Laboratori Nazionali del Gran Sasso aims to perform background-free WIMP searches using double phase liquid argon time projection chambers, with the ultimate goal of covering all parameters down to the so-called neutrino floor. One of the distinct features of the program is the use of underground argon with has a reduced content of the $radioactive^{39}$ Ar compared to atmospheric argon. The DarkSide Collaboration is currently operating the DarkSide-50 experiment, the first such WIMP detector using underground argon, resulting in the best WIMP limits obtained with argon. The results obtained with DarkSide-50 and the plans for the next steps of the DarkSide program, the 20 t fiducial mass DarkSide-20k detector and the 200 t fiducial Argo, are reviewed in this proceedings.

To clarify anatomy-related risk factors in the cervical spine with subsidence of titanium mesh cage (TMC) after one-level cervical corpectomy and fusion, we have assessed the radiological examinations and clinical outcomes for 236 patients. All the patients were underwent one-level corpectomy and TMC fusion between August 2003 and March 2006. The effects of the cervical posture, segmental curvature and endplate gradient on the postoperative phenomenon for these patients were evaluated. Our results suggested that in the patients who were followed up for 12 months, TMC subsidence occurred in 54 (28.6%) cases. C6 corpectomy had a significant higher risk (26/60, 43.3%) for TMC subsidence, which was correlated with the variation of the gradient of the vertebral endplates against cervical levels. Although the clinical outcome was comparable with those in the literature, the patients may have subsidence-related problems such as neck-shoulder pain, neurological deterioration and instrumental failure. In conclusion, to reduce the incidence of subsidence, TMC design should be optimized to be in line with anatomic characteristics of the cervical spine.

This study attempt to integrate the Wells-Riley equation and computational fluid dynamics for analyzing the risk of airborne transmission diseases in a building. The new method can predict the spatial distribution of the infection risk of the airborne transmission diseases in a large hospital ward, while the Wells-Riley equation alone can only predict the overall infection risk in the whole building assuming a uniform distribution of the droplet nuclei concentration. This new method is applied to analyze the transmission risk in the well documented 8A ward SARS outbreak in a Hong Kong hospital in 2003. This study attempt to integrate the Wells-Riley equation and computational fluid dynamics for analyzing the risk of airborne transmission diseases in a building. The new method can predict the spatial distribution of the infection risk of the airborne transmission diseases in a large hospital ward, while the Wells-Riley equation alone can only predict the overall infection risk in the whole building assuming a uniform distribution of the droplet nuclei concentration. This new method is applied to analyze the transmission risk in the well documented 8A ward SARS outbreak in a Hong Kong hospital in 2003.