MNiSb  compounds and guide the band engineering to enhance TE performance in p-type FeRSb  based systems. The calculations on electrical transport properties, especially the scattering time, and lattice thermal conductivities are also demonstrated. The outlook for future research directions of first-principles calculations on HH TE materials is also discussed.Half-Heusler (HH) compounds, with a valence electron count of 8 or 18, have gained popularity as promising high-temperature thermoelectric (TE) materials due to their excellent electrical properties, robust mechanical capabilities, and good high-temperature thermal stability. With the help of first-principles calculations, great progress has been made in half-Heusler thermoelectric materials. In this review, we summarize some representative theoretical work on band structures and transport properties of HH compounds. We introduce how basic band-structure calculations are used to investigate the atomic disorder in n-type  These environmentally friendly and extremely reliable solid state devices have no moving parts, hazardous liquids, or greenhouse emissions. A key challenge is to improve the TE conversion efficiency in order to expand the role of TE materials and, in turn, enable new practical applications. The efficiency of TE materials depends on the dimensionless figure of merit ectively .α, σ, and κe are related to the electronic structure of the material. The three parameters are intercorrelated and cannot be optimized independently. For instance, increasing α is usually accompanied by a decreasing σ; an increase in σ concomitantly leads to an increase in κe via the Wiedemann-Franz law κe = LσT (L is the Lorenz number). One possible way to optimize zT is to maximize the power factor (α2σ), which can be achieved by the band engineering [Among those quantities,  factor ασ, which ineering . Once thα under parabolic band approximation is a function of the density of states (DOS) effective mass *m [m* = Nv2/3mb* (Nv is the band degeneracy and mb* is the band effective mass), increasing both Nv and mb* contributes to a enhanced m* and, consequently, α [mb* always leads to a low carrier mobility μ due to μmb*. It has been proved that increasing Nv is beneficial to large m* without deterioration of μ, and is an efficient strategy to improve TE performance for many materials [For TE materials, the main characters of the band are reflected by the effective mass . In dege mass m* . Accordiently, α . Howeveraterials ,8,9,10.κL, related to its phonon vibration, is more or less independent of the electronic transport properties. However, defects that reduce κL, such as forming solid solutions or making composite structures, are likely to reduce μ [κLMV1/3θD3/γ2  [M, V, θD, and high γ contribute a low κL. Starting with this viewpoint, many good TE materials with intrinsically low κL have been reported [The lattice thermal conductivity reduce μ . Neverthreduce μ . Alternareduce μ ,13,14. Orameter) . Accordireported ,17,18.2X is obtained by filling the vacant sublattice with B atoms, as shown in Half-Heusler (HH) compounds are ternary intermetallics with a general formula ABX, where A and B are usually transition metals and X is a main group element , as showblattice . The HeuMNiSn  HH compounds have profound effects on TE properties [RSb  HH compounds are expected to exhibit attractive TE performance [zT has been obtained in these heavy-band semiconductors via a band engineering approach [As is known, the fabrication of single-phase HH compounds is difficult, which is mainly due to the distinct differences in the specific gravity and melting point of the constituent elements . Note thoperties ,24. In toperties . The chaoperties . Recentloperties ,27, instformance . A high approach .MNiSn [It is also worth mentioning that first-principles calculations have provided the guideline for developing new promising HH-based TE materials. Up to now, experimental investigations on HH compounds have mainly focused on n-type MNiSn ,32,33,34MNiSn ,36. ActuMNiSn . Even usMNiSn . There iIn this paper, we focus on the recent significant progress in theoretical investigation on HH-based TE materials. In Band structures, which reside in reciprocal space due to the periodicity of the lattice, directly determine the electrical transport properties of materials. The accurate band structures are beneficial for understanding the underlying transport physics and designing new TE materials. Therefore, it is crucial to establish the connections between the electrical transport properties in real space and the band structures in reciprocal space. The calculation of band structures became accessible with the development of density functional theory (DFT) ,40, whicMNiSn alloys using DFT methods. The indirect band gaps of ~0.5 eV were found between the Γ and X points, which are larger than experimental ones  [In 1995, Öğüt and Rabe  calculatctively) . Öğüt anctively) . The calctively) . Qiu et ctively) . By chanMNiSn compounds [b site [MNiSn compounds tend to stay close to each other to form nanoclusters and showed the in-gap states from interstitial Ni near the conduction band edge in the calculated band structures 4− orbitals to Sn as Sn4−). In this case, non-stoichiometry in the form of ZrNi1+xSn may be expected to not move the Fermi level outside the band gap [However, Larson et al. suggested that antisite defects of Ni atoms occupying the vacant sites also exist in ompounds . An analompounds ,44. Xie  [b site . Douglas [b site  and Do e [b site  suggesteructures . The banr TiNiSn . Recentlband gap .GW0 method are 0.45, 0.62, and 0.75 eV, respectively [d levels in the transition metal atoms vary among the different methods. However, considering that calculations using the GW0 method are very computationally expensive for defect calculations due to the large supercells, more precise and computationally-tractable methods should be applied to the MNi1+xSn systems.Here we have to point out that the band structure calculations by Douglas et al.  and Do eectively . The difRSb -based HH compounds, with abundantly available constituent elements, have attracted signfiicant attention due to a high Seebeck coefficient (approximately –200 μV K−1 at 300 K) and a large power factor (4.5 × 10−3 W m−1 K−2 at 300 K) [−1 K−1 at 300 K), earlier studies have been focused on improving the TE performance of n-type FeRSb by alloying [zT (≈0.33 at 650 K) was obtained.Fet 300 K) . Howeveralloying ,50 or naalloying , but onlRSb 1−xTixSb compounds, which resulted in a high Seebeck coefficient. Although the heavy mb* led to a low µ, the low deformation potential and alloy scattering potential were both beneficial for a reasonably high mobility in this system. Therefore, a high power factor of about 3 × 10−3 W m−1 K−2 was available at 900 K for Fe(V0.6Nb0.4)0.8Ti0.2Sb. Mainly due to the high power factor, in addition to the relatively low lattice thermal conductivity among the FeRSb system, a high zT of ≈0.8 at 900 K was achieved.Recently, band structure calculations showed that the characteristic of the valence band shows great disparity from that of conduction band in FeRSb . The conf Nv = 8 ,53, whicaterials ,7. Accorstigated . Combinemb* leads to a low µ in Fe(V0.6Nb0.4)1−xTixSb. Based on the band structures, the mb* of 0.16 me for p-type FeNbSb is lower than that of 0.25 me for p-type FeVSb, indicating that increasing Nb content may lead to a lower mb* and, hence, higher µ Sb was about 20%. The optimized power factor may be realized within the solubility limit of Ti by decreasing the optimal carrier concentration (0.6Nb0.4)1−xTixSb will broaden the band gap and consequently increases the temperature at which bipolar diffusion begins to diminish TE performance. The enhanced carrier mobility and reduced optimal carrier concentration result in the optimal power factor. The power factor of p-type FeNb0.8Ti0.2Sb was about 4.5× 10−3 W m−1 K−2 at 1100 K, ~50% higher than the Fe(V0.6Nb0.4)1−xTixSb solid solutions. A higher zT value of 1.1 at 1100 K was achieved for FeNb0.8Ti0.2Sb due to the enhanced power factor [It is obvious that the heavy higher µ a. Moreovntration . The solntration b. The bar factor .m* of 6.9 me for FeNb1−xTixSb is also higher than that of 0.3 me and 1.3 me for conventional PbTe-based and Bi2Te3-based materials, respectively [mb* in these Fe-containing p-type TE materials is due to the spatially localized nature of transition metal 3d orbitals [d transition metal, such as Ru, possess low mb* at the valence band [mb* and hence higher µ  are ultimately determined by the transport distribution function [E) = v2τg . Currently, the greatest challenge for computations is to capture the relaxation time τ, which is affected by many scattering mechanisms and difficult to calculate accurately [τ impedes the direct evaluation for large sets of TE materials. Thus, several approximations for τ have been proposed for quantifying the TE performance of materials.The Boltzmann transport theory is usually an appropriate description for electrical transport in TE materials, due to their relatively high operating temperatures and macroscopic sizes of the samples . The elefunction , Σ(E) = curately . The eneτ is assumed to be energy independent, leading to a computationally manipulable form of the equations for electronic transport coefficients. The calculations of electronic transport properties within the CRT approximation are most commonly performed using the BoltzTraP code [Constant relaxation time (CRT) approximation is the most common approach in solving the Boltzmann transport equations . In thisraP code , which cd-states are the dominant electronic states around band gaps. Therefore, changing elements at X positions does not substantially affect the gap value. Additionally, there is no strong correlation between the band gap and the corresponding elemental electronegativity differences. The maximum power factor and the corresponding optimal n-type and p-type doping levels were also determined. The calculated optimal doping levels and the corresponding Seebeck coefficients exhibited reasonable agreement with experiments for five previously-studied HH compounds. 21 cm−3. Based on the estimated n-type power factors, IIIB- and some Co-containing HH compounds show reasonable n-type performance and their carrier concentrations fall in the range of 1020–1021 cm−3  approximation (CMFP) [τ becomes energy-dependent (v(E)τ(E) = λ) and λ is constant for different material systems. To ensure the same λ, it is necessary to assume that materials are nanostructured, with λ limited by the grain size. Furthermore, the grain size needs to be smaller than the smallest λ in the considered materials. Although this approach is not suitable for materials with intrinsically long λ, it may be able to evaluate the electrical transport properties for systems with naturally low µ and, hence, λ.An alternative approach is the constant mean free path (n (CMFP) . Within zT was performed for 75 nanograined compounds. The calculated zT values of many HH compounds are higher than those of nanograined IV and III-V semiconductors. Especially remarkable are the values of zT in excess of 2 achieved for about 15% of them at T > 600 K. Although the zT values of best n-type doped compounds are comparable with those of the best p-type doped ones, the general trend is that a typical p-type doped HH shows a higher zT than a typical n-type doped HH. This phenomenon is mainly due to the fact that for 65% of compounds the effective mass of holes (mh*) is higher than that of electrons (me*) according to their band structure calculations. Using the Spearman rank correlation coefficient Σ [zT than lattice thermal conductivity. At both room and high temperatures, the power factor depends most markedly on the band effective mass and band gap. Carrete et al. also provided simple rules to determine if nanograined HH compounds are likely to be good TE materials through machine learning techniques. In this work, they only considered a few elements’ properties, such as atomic numbers and masses, positions in the periodic table, atomic radii, Pauling electronegativities [Carrete et al. used the CMFP approximation to investigate 75 nanograined HH compounds, screened from 79,057 HH compounds included in the AFLOWLIB.org consortium repository . The selicient Σ , power ftivities , and Pettivities . Five prτ as energy-dependent, the small grain sizes  impede its widespread application. Therefore, CRT approximation becomes the most used approach to calculate the electronic transport properties of TE materials even with some uncertainties. In this approximation, α is independent of τ, whereas σ and κe are both directly proportional to τ. An actual value of τ is still needed to calculate the power factor and zT. The simplified zT (zTe = α2σT/κe) has been used to identify candidate TE materials [τ, but zTe is always greater than zT, since the lattice thermal conductivity κL is treated as zero. Alternatively, an approximate value τ from the experimental electrical conductivity can also be used to compute zT, assuming that τ is direction independent and a constant at a certain specific temperature and carrier concentration [Despite that CMFP approximation treats aterials . This mentration .τ of FeNbSb HH compounds [τ ~ ii/c(mb*3/2Ξ2) , in which mb* is very important to calculate τ. In their work, the mb* at all k points in the first Brillouin zone has been calculated, and then the average of the effective masses at all specific energies can be obtained. The calculated mb* near the VBM is ~1.87 me, a little higher than the experimental value of 1.6 me [σ are a little higher than the experimental values of FeNb1−xTixSb  at low temperatures  theory combined with the effective mass approximation is accurate to calculate ompounds . In thisf 1.6 me . The caleratures a. This deratures b. Howeve samples . Only thκL is the Debye-Callaway model [γ), which describes the strength of lattice anharmonicity, is set to be a constant. The predicted κL using this model showed fairly good agreement with experimental values at room temperature [Above the Debye temperature, the lattice thermal conductivity is mainly dominated by phonon-phonon Umklapp scattering. Actually, other phonon-scattering processes, including point defect scattering and grain boundary scattering, also contribute to the lattice thermal conductivity. The most widely used model for predicting ay model . In thisperature .τ. Using second- and third-order interatomic force constants as inputs, κL can be calculated via solving the phonon Boltzmann transport equation. Using this fully ab initio approach, Andrea et al. reported the κL of 15.4, 13.3, and 15.8 W m−1 K−1 at 300 K for TiNiSn, ZrNiSn and HfNiSn, respectively [κL were different from the experimental ones, which may be due to the different defects within the samples. Katre et al. revealed that Ni/vacancy antisites are the dominant defects affecting thermal transport in ZrNiSn [Considering the existence of lattice anharmonicity, third-order anharmonic force constants are computationally necessary to determine ectively . The caln ZrNiSn . The calEven though the fully ab initio approach is accurate, it cannot be implemented in high-throughput studies due to the computational requirements of third-order force constants. In this case, some semi-empirical models for high-throughput calculations are more simplistic and computationally tractable.κL of 75 thermodynamically-stable ordered HH alloys based on a combination of machine learning algorithms and automatic ab initio calculations [κL. The first method is based on the empirical observation that the force constants show a high degree of transferability between compounds sharing a crystal structure [κtransf with anharmonic force constants from Mg2Si, since it shares the HH lattice with sites A and B occupied by Mg atoms. For cross-validation, the anharmonic force constants and κω of 32 HH systems were also computed using the fully ab initio approach. The second proposed approach is calculating κforest via random-forest regression algorithm by leveraging the fully calculated κω of 32 HH compounds as a training set. The third method presents a new machine-learning descriptor of κω that integrates only the crucial pieces of the anharmonic properties of the solid. They calculated κanh with four exact anharmonic force constants and a linear model for the rest. The lattice thermal conductivities calculated with different methods for TiNiSn, ZrNiSn and HfNiSn are shown in κforest and κanh quantitatively agree well with κω and κL calculated using the fully ab initio approach, while κtransf shows an obvious discrepancy with κω and κL.Recently, Carrete et al. predicted the ulations . Three atructure . They caκLAGL of 75 thermodynamically-stable ordered HH alloys using a quasiharmonic Debye model, which includes anharmonic contributions to a certain extent [κLAGL and κLanh  and p-type FeRSb  HH compounds. Indeed, the first-principles calculations have helped with the understanding of experimental results and the rationalization of experimental approaches and speeding up the new investigation of TE materials. Basic band structure calculations are beneficial for the deep understanding of intrinsic defects in n-type MNiSb compounds and the rational design and development of p-type FeRSb HH alloys. By density functional theory, combined with Boltzmann transport theory, electronic transport properties of some types of HH compounds have been calculated to screen new promising TE materials with excellent electrical properties. Lattice thermal conductivities of HH compounds have also been investigated via fully ab initio or high-throughput calculations based on some semi-empirical models.HH compounds, containing hundreds of semiconductors, are a vital group of materials for high temperature thermoelectrics. Recent progress in TE performance optimization achieved high Although first-principles calculations have been widely used in the research of HH-based TE materials, the limitations of first-principles cannot be ignored. There are some approximations and semi-empirical models in the calculations. Therefore, the predicted transport properties of individual materials will have some intrinsic uncertainty. However, for a class of materials with the similar structures, the calculated results are expected to be comparable with each other and could provide a systematic evaluation about their transport properties. Certainly, assessing prediction accuracy from experimental work is also needed. It is a significant challenge to obtain relevant experimental results in a timely manner for each candidate identified in a first-principles calculation. Typically, the intrinsic defects may be present in many cases and the solubility limit of extrinsic dopants need to be identified to control the carrier concentration. Therefore, assessing the dopability of new TE materials is imperative ,82.0.84CoSb using synchrotron X-ray diffraction and DFT calculations [δ0.8+CoSb (0 ≤ δ < 0.05), with a remarkable enhancement on TE performance, have been successfully synthesized by levitation melting [0.75+xPtSb was successfully synthesized and confirmed using X-ray studies. The work on nominal 19-electron compounds opens a new avenue to search for potential HH-based TE materials theorically and experimentally. Also worth noting is that Tang et al. reported a narrow solubility range on the Ti-Ni-Sn phase diagram primarily in the range of TiNi1+xSn (0 ≤ x ≤ 0.06) at 1223 K using phase boundary mapping, which explains the large discrepancy of the literature data on the thermoelectric properties of TiNiSn within a unified phase diagram framework [Due to the very large influence of the valence electron count on the electronic structure and physical properties of HH compounds, the 18-electron rule is widely used in the exploration of new promising HH phases . Recentlulations . After t melting . Recentl melting . Using tramework . This wo


Subjects completed six 15 min blocks  of intermittent shuttle running, with a 15-min half-time. Blocks 3 and 6, allowed self-selection of running speeds and sprint times, were assessed throughout. Subjects consumed 250 mL of either a 12% carbohydrate solution (CHO) or a non-caloric taste matched placebo (PLA) before and at half-time of the LIST. Sprint times were not different between trials . Total distance covered in self-selected blocks  was not different between trials. There was no difference between trials for distance covered (p ≥ 0.297) or mean speed (p ≥ 0.172) for jogging or cruising. Blood glucose concentration was greater (p < 0.001) at the end of half-time during the CHO trial. In conclusion, consumption of 250 mL of 12% CHO solution before and at half-time of a simulated soccer match does not affect self-selected running or sprint performance in a fed state.This study assessed the effect of carbohydrate intake on self-selected soccer-specific running performance. Sixteen male soccer players (age 23 ± 4 years; body mass 76.9 ± 7.2 kg; predicted VO With sporting events being won and lost by the finest margins, athletes are constantly striving for ways to improve training and performance, and gain a competitive edge. One well-known method by which athletes can achieve this is through carbohydrate ingestion during prolonged >1 h) bouts of exercise  h bouts ,3.Fatigue during prolonged exercise is coupled with the depletion of glycogen stores , a decreA number of studies have reported a performance improvement of carbohydrate ingestion during prolonged continuous cycling ,3 and ruDespite a number of studies reporting improvements on simulated soccer performance, many have methodological limitations that restrict their application to real-world soccer match performance. Several studies have not used ecologically valid feeding strategies, for example testing subjects in a fasted state ,15,17, oTherefore, the purpose of this study was to investigate the effect of carbohydrate intake in a fed state, using an ecologically valid feeding strategy , on sprint and self-selected soccer-specific running performance in competitive soccer players.−2; predicted VO2max 54.2 ± 2.9 mL∙kg−1∙min−1; body fat 11.8% ± 3.0%) volunteered for this study, which was approved by the Loughborough University Ethics Approvals (Human Participants) Sub Committee (reference number: R15-P159). Before commencement of the study, subjects provided written informed consent and completed a medical screening questionnaire. Subjects were non-smokers, had a soccer playing history of 13 ± 4 years, and participated in soccer training and/or matches 3 ± 1 times per week. All subjects completed a preliminary trial, familiarisation trial and two experimental trials, separated by a minimum of 3 days.Sixteen male soccer players   2.5 h before arrival at the laboratory, and consumed 500 mL of water 1.5 h before arrival to the laboratory .To ensure similar metabolic conditions prior to each experimental trial, all subjects recorded their dietary intake and habitual physical activity for the day preceding and day of their first experimental trial. These diet and activity patterns were replicated prior to the second experimental trial and adherence to these requirements was verbally checked. Subjects also refrained from any strenuous exercise or alcohol intake during this period. The specific time of trials was standardised for each subject to prevent any diurnal effects. Subjects consumed a standardised pre-trial meal providing 2 g∙carbohydrate∙kg2max and velocity at VO2max were predicted using a progressive multistage shuttle run test [2max) and cruising (95% VO2max) during the experimental trials. All trials were completed on an indoor 20 m running track, with only one subject completing the test at a time.During the first visit, body mass and height  were recorded, and body fat percentage was estimated using skinfold caliper measurements at four sites . Each srun test , and the2O−1 was taken to indicate the absence of hypohydration [Timing of trials was standardised within subjects. Upon arrival at the laboratory, subjects voided their bladder into a plastic container, and nude body mass was recorded. This urine sample was analysed for osmolality  to assess hydration status, and a urine osmolality of <900 mOsm∙kgHydration . No subj−1), sprinting (15 m), rest (4 s), jogging (three shuttles at 55% predicted VO2max) and cruising (three shuttles at 95% predicted VO2max). Subjects completed six blocks of the LIST totalling 90 min of simulated soccer performance. A 15 min passive recovery period  separated the six blocks of the LIST into two 45 min halves. The exercise intensities throughout the first two blocks of both halves  were dictated by audio cues as per the LIST protocol [During the modified LIST, subjects were required to walk and run back and forth between two lines 20 m apart. Each block of the LIST was 15 min in duration and consisted of ~11 repeated cycles of walking  was recorded continuously throughout exercise and averaged for each 15 min block of the LIST. Finger-prick capillary blood samples (20 µL) were taken at rest, immediately before and after each self-selected block, and at the end of half-time, and were analysed for blood glucose and lactate . Arousal , GI dis−1) and potassium (4 mmol∙L−1).Subjects were given either a carbohydrate (CHO) or placebo (PLA) drink in a double-blind, randomised, counter-balanced design. The CHO drink was a 12% solution delivering 60 g carbohydrate per 500 mL bottle of a blend of sucrose, maltodextrin and isomaltulose, whilst the PLA drink was non-caloric and taste matched to the CHO drink using artificial sweeteners . Both drinks contained matched amounts of sodium  repeated measures ANOVA. Where the assumption of sphericity was violated, the degrees of freedom were corrected using the Greenhouse–Geisser estimate. Significant results were followed-up by post-hoc paired t-tests or Wilcoxon Signed Rank tests, as appropriate, and the familywise error rate was controlled using the Holm–Bonferroni adjustment. Data sets were accepted as being significantly different when p ≤ 0.05. All data are presented as mean ± SD, unless stated otherwise.Data were analysed using SPSS  and were initially checked for normality of distribution using a Shapiro–Wilk test. Pre-trial measures were analysed using paired 2O−1, PLA 386 ± 257 mOsm∙kgH2O−1; p = 0.828) and body mass  were not different between trials.Pre-trial urine osmolality (CHO 400 ± 240 mOsm∙kgHp = 0.305) and block 6  and mean running speeds for block 3  and block 6  during the first and second experimental trials.There was no trial order effect, with similar distances completed for block 3  in 15 m sprint times between CHO and PLA trials during any of the six blocks of the LIST (p = 0.013), with faster 15 m sprint times (p < 0.001) during the first three blocks (2.68 ± 0.13 s) compared to the final three blocks of the LIST (2.73 ± 0.16 s). There was no time by trial interaction effect (p = 0.337) for 15 m sprint times.There was no difference (the LIST . There wp = 0.122) or mean speed (p = 0.070) between CHO or PLA trials. There was a main effect of time for total distance covered (p = 0.011) and mean speed (p = 0.005), with more distance covered and faster mean speeds in block 3  than block 6 . There were no differences in distance covered (p ≥ 0.297) or mean speed (p ≥ 0.172) for jogging and cruising between CHO and PLA trials. There was a main effect of trial for both distance covered (p = 0.030) and mean speed (p = 0.045) for walking, however, post-hoc tests revealed no differences during block 3  or block 6 . There were no interaction effects (p ≥ 0.343) for total distance covered or mean speed, or distance covered and mean speed for walking, jogging or cruising. There were also no time (p ≥ 0.497), trial (p ≥ 0.131) or interaction (p ≥ 0.905) effects for total recovery time or mean recovery time per lap of the LIST.The self-selected distance covered and mean speed for blocks 3 and 6 of the LIST during the CHO and PLA trials are displayed in p < 0.001) and GI discomfort (p = 0.026), but not for arousal (p = 0.198), stomach fullness (p = 0.409) or bloating feeling (p = 0.248). There was a main effect of trial for stomach fullness (p = 0.001); with subjects reporting higher levels of stomach fullness during the CHO trial (3.2 ± 1.9) compared to the PLA trial (2.6 ± 1.7), but no interaction effect (p = 0.759). There were no main effects of trial  or interaction effects  for any of the other subjective feelings questionnaires.Data from the subjective feelings questionnaires are displayed in p < 0.001; p < 0.001), with greater blood glucose concentration at the end of half-time during the CHO trial . There were no main effects of trial for blood glucose (p = 0.265) or lactate (p = 0.637) concentrations and no interaction effect for blood lactate concentration (p = 0.399).Due to problems with blood collection during two experimental trials, the blood glucose and lactate analysis only includes 14 subjects. There were main effects of time for both blood glucose and lactate concentration (p = 0.087), or total sweat loss between trials .Ad-libitum fluid intake during half-time of the familiarisation trial was 238 ± 162 mL and all subjects replicated this volume of fluid intake in the experimental trials. There was no difference in the percentage of body mass lost between trials  or interaction  effects for heart rate or RPE (p < 0.001) for heart rate and RPE. Heart rate increased from rest to block 1 of the LIST and remained elevated throughout exercise, while RPE increased gradually throughout exercise.There were no trial  before and at half-time of a simulated soccer match did not improve self-selected running performance or sprint speed. Despite the lack of effect of carbohydrate intake on running performance, the current study provides clarity in an area of the literature where the majority of studies are limited by ecological validity [The purpose of the present study was to assess the effect of carbohydrate intake using an ecologically valid feeding strategy  on sprint and self-selected soccer-specific running performance in a fed state. The main finding was that consumption of 250 mL of a 12% carbohydrate solution  and every 15 min throughout exercise (2 mL∙kg−1 BM). Likewise, Davis et al. [−1 BM) and every 15 min throughout the LIST (2 mL∙kg−1 BM). Both of these studies, like several others that have found beneficial effects of carbohydrate ingestion on intermittent running performance [The main finding is in contrast to a number of similar studies that have examined the effect of carbohydrate intake on simulated soccer performance ,13,15,17formance ,11,26, iformance , and did−1 BM in the 4 h before exercise [−1 was used by Goedecke et al. [−1 for prolonged exercise [−1 BM) and high- (2.2 g∙kg−1 BM) carbohydrate pre-trial beverage compared to a non-caloric placebo following an overnight fast. The pre-trial meal implemented in the present study may have negated the beneficial effects of carbohydrate ingestion during exercise, potentially explaining the absence of an effect of carbohydrate ingestion on self-paced running or sprint performance. It could also explain the presence of a beneficial effect of carbohydrate intake in other studies that required subjects to exercise under fasted conditions [Moreover, in the present study, subjects consumed a pre-trial meal consistent with pre-exercise guidelines; i.e., 1–4 g·carbohydrate∙kgexercise . The majexercise ,13,17. Cexercise  asked sue et al. , which iexercise . In otheexercise  found ~4−1. Although this rate of carbohydrate ingestion is in alignment with the recommended amount for prolonged (1–2 h) exercise of 30–60 g∙h−1 [Another possible reason for the different outcome in the present study compared to other studies that have investigated carbohydrate intake on intermittent running performance could be the regularity of carbohydrate ingestion throughout exercise. Typically, players would not be able to consume fluids or food during each 45 min half of soccer unless extenuating circumstances  permitted. In this study, subjects consumed 250 mL of carbohydrate solution before and at half-time, whereas in other similar studies ,13,17,1860 g∙h−1 , no diff−1, compared to a placebo, during 90 min of the LIST. Interestingly, Foskett et al. [Evidence is inconsistent with regards to the effect of carbohydrate ingestion on sprint performance during intermittent running exercise ,30. Nicht et al. ,14,16.−1 BM of a 6% carbohydrate solution), in between quarters (3 mL∙kg−1 BM of a 6% carbohydrate solution) and at half-time (5 mL∙kg−1 BM of a 18% carbohydrate solution) on 20 m sprint times during an intermittent high-intensity shuttle running protocol consisting of 15-min quarters. Sprint times were ~14% faster in the fourth quarter when subjects consumed carbohydrate. Ali et al. [Conversely, there are a few studies that have reported an improvement in sprint performance ,15. Welsi et al. , it couli et al. .2max. While muscle glycogen content was not measured in the present study, if the ingestion of carbohydrate before and at half-time did reduce the utilisation of muscle glycogen, the absence of an effect on self-selected running or sprint performance between trials suggests the duration and/or nature of the exercise did not deplete glycogen stores significantly enough to impact on performance. However, both Nicholas et al. [−1 BM) has been shown to increase muscle glycogen concentrations by 11% three hours post ingestion [−1 BM, consumed ~3 h before exercise in the present study may have replenished liver glycogen and elevated muscle glycogen concentrations, potentially negating a beneficial effect of carbohydrate ingestion during exercise.Nicholas et al.  found ins et al.  and Tsins et al. , performs et al. . Consumpngestion . The preIt is well known that carbohydrate ingestion during exercise alters blood glucose concentration either intermittently or throughout exercise ,9,13,15.The carbohydrate concentration (12%) of the solution administered in the present study was considerably greater than the 6%–7% carbohydrate concentration adopted by many other similar studies ,17,18. DIn conclusion, consumption of 250 mL of a 12% carbohydrate solution before and at half-time of a simulated soccer match does not affect self-selected running performance or sprint times in a fed state.


Working memory (WM) is a buffer that temporarily maintains information, be it visual or auditory, in an active state, caching its contents for online rehearsal or manipulation. How the brain enables long-term semantic knowledge to affect the WM buffer is a theoretically significant issue awaiting further investigation. In the present study, we capitalise on the knowledge about famous individuals as a ‘test-case’ to study how it impinges upon WM capacity for human faces and its neural substrate. Using continuous theta-burst transcranial stimulation combined with a psychophysical task probing WM storage for varying contents, we provide compelling evidence that (1) faces (regardless of familiarity) continued to accrue in the WM buffer with longer encoding time, whereas for meaningless stimuli (colour shades) there was little increment; (2) the rate of WM accrual was significantly more efficient for famous faces, compared to unknown faces; (3) the right anterior-ventrolateral temporal lobe (ATL) causally mediated this superior WM storage for famous faces. Specifically, disrupting the ATL (a region tuned to semantic knowledge including person identity) selectively hinders WM accrual for celebrity faces while leaving the accrual for unfamiliar faces intact. Further, this ‘semantically-accelerated’ storage is impervious to disruption of the right middle frontal gyrus and vertex, supporting the specific and causative contribution of the right ATL. Our finding advances the understanding of the neural architecture of WM, demonstrating that it depends on interaction with long-term semantic knowledge underpinned by the ATL, which causally expands the WM buffer when visual content carries semantic information. They looked specifically at the contralateral delay activity (CDA), a neural signature that diminishes in amplitude when information transits from WM to episodic memory. Results showed that WM capacity for objects increased as a function of longer encoding time, which was reflected in significantly greater CDA. By contrast, WM capacity for colours remains constant despite more encoding time, which was mirrored in a smaller magnitude of CDA. These indicate that, compared to meaningless abstract stimuli, entities that hold ecological relevance  are tackled differently by the WM system, presumably aided by semantic knowledge or familiarity with objects' configuration.Working memory (WM) is a vital cognitive faculty that holds information in a temporary cache. Information kept in WM is used to guide cognition  and action . In the domain of visual WM, most researchers use abstract stimuli, such as colour patches, in an attempt to gauge the bare capacity while insulating it from the ‘contamination’ of existing knowledge . Colour patches were included as control stimuli. We selected faces as the target stimuli based on the following considerations: First, faces are of paramount ecological importance, crucial for survival, which would be endowed with expanded WM storage to fulfil the need of social interaction. Second, by comparing celebrity and unfamiliar faces, we are able to glean insight into how person-related semantic knowledge affects WM capacity. Third, face processing is associated with a well-defined neural network, which enables us to target a specific neural locus, transiently unsettle its functioning using non-invasive neurostimulation, and test the interactive impacts of brain stimulation and experimental factors.Advancing from the electrophysiological correlates discovered by Brady et al., in the present study we investigated the causative neural regions and mechanisms that mediate this boosting impact of ecologically relevant stimuli on WM capacity. We focused on the obvious yet untested hypothesis that the effect hinges on semantic knowledge . We utilised the ecologically salient test-case of human faces and compared faces that are highly recognisable and carry semantic information (celebrity faces) It is well-established that face processing is supported by a neural network distributed along the ventral occipitotemporal cortex, starting from the occipital face areas (OFA) sensitive to componential face features, through the fusiform face areas (FFA) sensitive to holistic configuration of face-like stimuli, and culminating in the anterior temporal lobe (ATL). At the apex of this hierarchy, the ATL codes face identity and person-related attributes , as wellDue to its adjacency to facial nerves, stimulating the ATL evokes twitches of facial muscles. To ascertain that effects of ATL stimulation cannot be driven by non-specific factors , in addition to the conventional control site of the vertex we included the lateral prefrontal cortex (PFC) as a control site. The lateral PFC serves as a suitable control region because it is also near facial nerves (hence eliciting similar twitches during stimulation). Besides serving as a control site, the inclusion of PFC allowed evaluating a region that underpins executive processes but does not represent the content of WM and semantic knowledge . SpecifiWe report two experiments in this study. Experiment 1 was a psychophysical investigation in which we independently manipulated different types of stimuli and encoding duration. We established a robust effects that faces were endowed with an advantage of WM storage over abstract stimuli, and this advantage is further enhanced for faces associated with person-related knowledge. Experiment 2 was a neurostimulation investigation in which we exploited theta-burst stimulation to impede the processing of the ATL, while the PFC and the vertex were included as control sites to ensure the specificity of ATL stimulation.Twenty-seven volunteers , gave informed consent. All participants are right-handed, had normal vision, completed safety screening for TMS and MRI before the experiments, and reported no history of neurological or psychiatric issues. This study was reviewed and approved by the local research ethics committee.2 system equipped with a figure-of-eight coil (70 mm). Stimulation was guided using Brainsight 2 (Rogue Research Inc.), a frameless stereotaxic neuronavigation system that allows precise targeting and flexible calibration (see below for detailed protocols).For the transcranial magnetic stimulation (TMS) experiments, we first acquired a high-resolution T1-weighted anatomical image for each volunteer using a 3T Philips Achieva scanner equipped with an 8-element head-array coil; in-plane resolution was 0.94 mm; slice thickness was 0.9 mm. In the subsequent sessions, we conducted behavioural testing combined with TMS. Visual stimuli were shown using MATLAB with Psychtoolbox  on a comi) whether WM capacity would be boosted for human faces, compared to abstract stimuli and (ii) whether WM would be further augmented for famous faces, compared to unknown ones. We used a 3 × 3 within-participant factorial design, with Stimuli  and Encoding Duration  as repeated-measure variables. Built upon a similar design of Experiment 1 was a psychophysical investigation with twofold aims to test  were used for the ‘famous’ condition. These images contained 60 male faces and 60 female faces. The faces included politicians, athletes, and celebrities widely known in the United Kingdom. These 120 faces were selected from a much larger set of faces, unanimously judged by five UK residents as highly familiar. Another 120 faces  were used in the ‘unknown’ condition; these faces were also selected from a larger set of materials, all judged as unfamiliar. Faces and locations were randomly permutated to ensure each array contained a novel combination of constituents. To prevent strategic grouping within an array, male and female faces were presented in separate trials.It is noteworthy that pair-wise visual distance by comparing their GIST descriptors, iterated the computation for the exhaustive combination of 1770 pairs, and performed separately for famous/unknown faces of males/females . The resultant measure of visual similarity (1 minus GIST distance) ranged from zero to one, with a higher value indicating greater visual similarity. Comparisons of image similarity between conditions showed that the extent of similarity between famous male/female faces has been matched to that of unknown male/female faces, supported by statistics . In addition to controlling for GIST, we also ensured that luminance is matched between the conditions – we averaged the pixel-wise values of luminance for each image and compared between famous and unknown faces. Results revealed no significant difference between the two conditions (t(238) < 1, p = .65, n.s.). Together, these careful procedures ensured that the famous and unknown faces have been well-matched on low-level visual characteristics. Thus, any difference of WM performance between the face conditions cannot be attributed to one set of stimuli being more distinguishable than the other set.Of particular concern is whether the famous and unknown faces are matched for low-level visual statistics. It has been demonstrated that WM performance tends to improve when the items are visually distinct from each other, relative to them being less distinguishable . Thus, iExperiment 2 was a TMS experiment to investigate the neural structures that causatively underlie the functional impact of face identity on WM capacity. We selected the ATL as the target, while the PFC and vertex served as control sites. Their neuroanatomical definition was based on relevant fMRI studies about the neural correlates of face perception and visual working memory. For the ATL, stimulation was guided using the peak locus of a face-sensitive cluster situated in the right anterior fusiform gyrus, based on the We used a 3 × 3 × 2 within-participant factorial design, with TMS target , Stimuli  and Encoding Duration  as repeated-measure variables. The psychophysical procedure and stimuli were identical to Experiment 1, except the following modifications: instead of presenting trials of different encoding duration in separate blocks like our Experiment 1 and immediately following stimulation. This offline cTBS approach avoids non-specific interferences such as discomfort, noise, muscle twitches and so on, that online TMS  usually produces and is suggested to be effective for probing high-level cognitive functions . Stimulation was delivered onto the targeted site in repeated trains of 300 bursts  with an inter-train-interval of 200 ms (5 Hz); the stimulation lasted for 60 s, with a total number of 900 magnetic pulses . Particiunctions . The stilateral ATL contains information that allow cross-classification between faces and person-related attributes, which also overlap with our right-ATL target. Intriguingly, our ATL target falls in close proximity to the centre-point of hypo-metabolism , and converted the coordinates of the literature-defined ATL and MFG sites to derive the corresponding coordinates in each participant's anatomical native space. As the location of the ATL site is slightly too ventral and medial to be accessed by stimulation on the scalp, we adjusted the location of this stimulation target based on individual anatomy, making it more lateral and dorsal to the original site and hence accessible to TMS. Meticulous care was taken to strike a balance between adjacency to the original converted site and accessibility to the more lateral scalp stimulation point. The MNI coordinates of the ATL and MFG sites averaged across participants were  and , respectively see . Note th2 neuronavigation system, which tracked the position of the coil during stimulation and allowed online adjustment to achieve accurate positioning. For all three stimulation sites, the coil was placed tangentially to the scalp with the handle pointing posteriorly . For each individual, the TMS sessions were separated by at least 48 h.Before the WM experiments, we performed a co-registration procedure mapping the cerebral site of TMS target of each session onto the corresponding point on the scalpal surface using the Brainsight K proposed by K = SetSize × [(Hit Rate) – ], indicating the number of accurately remembered items maintained in WM. The capacity estimates of all experimental conditions are displayed in β = 0.176, t(14) = 0.87, p = .39, n.s.; the upper inset box of β = 0.809, t(14) = 4.33, p = .001; the middle box) and celebrity faces  = 5.56, p = .00007; the lower box). As evident in the bar graph of F = 8.47, p = .001, ηp2 = 0.38) and Encoding Duration  = 33.89, p < .001, ηp2 = 0.71). Crucially, the Stimuli × Duration interaction was statistically significant  = 2.73, p = .03, ηp2 = 0.16). Based on the significant interaction, we examined simple main effects by different durations and conducted a posteriori comparisons where appropriate. At the briefest 0.25-sec duration, the simple effect of Stimuli was not significant  < 1, p = .51, ηp2 = 0.04, n.s.), indicating that WM capacity for the three types of contents did not differ from one another. At the intermediate 1-sec duration, however, there was a significant effect of Stimuli  = 3.37, p = .04, ηp2 = 0.19). Post-hoc tests revealed that WM capacity for famous faces significantly surpassed that for colours (p = .008) and showed a trend greater than unknown faces (p = .08). At the longest 2-sec duration, the simple effect of Stimuli also reached significance  = 9.56, p = .001, ηp2 = 0.4). Post-hoc tests indicated that, under this lengthy duration, the advantage for famous faces persisted, making its storage significantly exceeded both colours (p = .001) and unknown faces (p = .02); moreover, the superiority of unknown faces started to emerge, making it marginally greater than colour patches (p = .059).Participants performed well on the digit task, achieving overall accuracy of 89% (SD: 3%). For each condition, we computed its estimate of WM capacity using Cowan's K is a measure that taps into the number of WM items, which might not be suitable for the colour condition where there was no conspicuous variation between hues. Thus, we calculated performance accuracy (proportion of correct responses), which might better characterise WM when participants were limited by precision . The accuracy results are entirely consistent with the K measures: For colour squares, the slope as a function of Encoding Duration was not different from zero  = 0.67, p = .52), indicating little or no improvement. By contrast, for unknown and famous faces, accuracy significantly increased with longer viewing time  = 3.18, p = .007; famous: β = 0.081, t(14) = 4.38, p = .001). Taken together, these results suggest that (i) the WM system has greater capacity for retaining human faces relative to meaningless stimuli and (ii) faces that carry abundant identity-level information are kept better in WM than unfamiliar faces devoid of semantic information.It has been suggested that the number of items held in WM and the precision/fidelity of WM content quantify distinct dimensions of memory ability e.g., . This clK) of every condition are displayed in F = 3.72, p = .08, ηp2 = 0.25), despite a slight trend consistent with Experiment 1 and previous literature. In addition, TMS did not modulate WM for colours  = 1.18, p = .33, ηp2 = 0.1), nor did the interaction of TMS × Encoding Duration  < 1, p = .43). In the condition of unknown faces  = 77.34, p < .001, ηp2 = 0.87), replicating the significant facilitatory effect we had observed in Experiment 1. Brain stimulation, however, did not affect WM for unknown faces, nor did the interaction of TMS × Encoding Duration  < 1, ps > 0.91).Participants performed well on the digit task, achieving mean accuracy of 90% (SD: 3%). The capacity estimates  = 129.67, p < .001, ηp2 = 0.92). Critical to our aim to examine the modulatory impact of cTBS, we found a significant interaction of TMS × Encoding Duration  = 6.62, p = .006, ηp2 = 0.38). Based on the significant interaction, we carried out further post-hoc comparisons: While the effect of Encoding Duration was significant in all of the three TMS conditions , the magnitude of this effect was modulated by applying cTBS to different sites. Right-ATL stimulation significantly attenuated the facilitation of longer encoding time, compared to right-MFG stimulation (t(11) = 3.15, p = .009, Cohen's d = 0.909) and vertex stimulation (t(11) = 2.61, p = .024, Cohen's d = 0.753). There was no difference between the MFG and vertex condition (p > .5). As illustrated in the rightmost part of K2.0 – K0.25) significantly declined by a margin of 39% after ATL stimulation relative to MFG stimulation (tested against zero/no reduction: t(11) = 3.20, p = .008, Cohen's d = 0.925) and by 34% relative to vertex stimulation (tested against zero: t(11) = 2.24, p = .04, Cohen's d = 0.648).Strikingly different patterns were seen in the results of famous-face condition: Longer encoding time led to significantly greater WM capacity (vs. the absence of MFG stimulation effect), we performed power calculations. The comparisons against the control site vertex provides a critical baseline to assess this possibility. Relative to vertex stimulation, ATL stimulation significantly mitigated the semantic facilitation impact (t(11) = 2.61, p = .024); by contrast, MFG stimulation had no influence (t(11) = −0.695, p = .501). To gauge the size of power, we calculated for the ‘vertex vs. ATL’ contrast that revealed a significant TMS effect – under its effect size (D=0.753), Type-I error probability (α = 0.05), sample size (n = 12) – the power (1–β) is 0.79. According to a comprehensive meta-analysis that surveyed 26,481 t-test records from 3801 recent papers from the neuroscience and experimental psychology literature, the median effect size and power are D = 0.65 and 1–β = 0.7, respectively (D = 0.201) was considerably weaker than the D of ATL stimulation and would be deemed as a small effect by traditional criterion  and tested whether its slope (accuracy as a function of Encoding Duration) was modulated by TMS. The results are entirely consistent with K: For both coloured squares and unknown faces, the slopes (accuracy by time) of the three TMS conditions did not differ  = 0.94, p = .41, ηp2 = 0.08; unknown: F = 0.09, p = .91, ηp2 = 0.01), suggesting that both were immune to TMS modulation. Critically, for famous faces, TMS significantly modulated the slope of accuracy by Encoding Duration  = 6.22, p = .007, ηp2 = 0.36); post-hoc tests revealed that ATL stimulation attenuated the steepness of slope , relative to vertex and MFG stimulation (both ps < 0.05), while no difference was found between vertex and MFG stimulation (p = .49). Together, multiple analyses coherently suggest that ATL stimulation genuinely produced a selective and causative influence to hinder the rate of increment for famous faces in the WM buffer.In addition to not affecting unknown faces and colours, showing that this brain area is specifically engaged when WM content carries semantic information about individuals. Moreover, neither right-MFG nor vertex stimulation affected WM capacity for any type of materials, ruling out non-specific impacts of cortical stimulation that might alter arousal level or cause distraction. Our data replicated the WM advantage for faces reported previously  that affix each face to a unique individual identity and other person-related attributes. Such semantic representations might help individuate each stimulus in working memory, making their neural coding more separable, rather than partially overlapped, in an abstract representational space. Thus, while the ATL might not directly underpin WM, it supports semantic knowledge that boosts WM. Our view is consistent with the multi-dimensional hypothesis by vs. wolves. Whilst naming items they resort to generic, superordinate-level terms  to refer to a broad collection of related concepts, due to blurred division between specific entities (or a drastic reduction in the dimensions available to represent different concepts). As a part of their semantic deficits, SD patients lose the ability to differentiate between the faces of famous individuals while preserving normal ability to perceive faces, suggesting a loss of person knowledge driven by ATL atrophy , and the PFC involvement has been interpreted as evidence of executive control during WM  are more likely to elicit PFC activity, compared to a task that does not require updating, such as the paradigm we used in the present study (The results of PFC stimulation ensure the selectivity of ATL stimulation in perturbing WM advantage for famous faces. Applying cTBS to this control site resembles ATL stimulation in tactile sensation but this region does not represent WM content and semantics nt study . Patientnt study . Thus, wnt study . Taken tThere is a parallel, established literature on the impact of semantic knowledge on verbal WM . For exaBy disturbing neural processing of targeted cortical regions using TMS, we showed that virtually lesion the right ATL causally reduces the benefits to WM brought about by famous faces whiling leaving the effect of unknown faces intact. The specificity of the ATL in mediating these effects was supported by the fact that MFG and vertex stimulation did not modulate WM performance. These data suggest that the ATL, a neural structure that has been neglected as a possible node of the WM network by the field of vision sciences, contributes to buttressing WM storage for meaningful information, via the mediation of semantic knowledge. Together, our findings point at a fruitful future direction to investigate the neural basis that underpins the WM processing of socially meaningful information.The authors declare no competing financial interests.


Previously, a “purchase” pattern  was identified among adults in urban Ghana and was inversely associated with T2D, while a “traditional” pattern  increased the odds of T2D. To investigate, if specific fatty acids (FAs), partly reflecting the intakes of certain food groups and cooking methods, might explain the observed diet-disease relationships, serum phospholipid fatty acid profiles were characterized and their relationships with blood lipids that are common risk factors for T2D were analyzed.The relative proportions of 28 FAs (%) in 653 Ghanaians without T2D were measured by gas chromatography. In a cross-sectional analysis, the associations of FAs with dietary patterns and with serum lipids that are likely involved in T2D development were investigated. The FAs distributions across dietary pattern scores were examined. Standardized beta coefficients (β) were calculated for the associations of dietary pattern scores (per 1 standard deviation (SD) increase) with FAs. Across the tertiles of selected diet-related FAs, adjusted means of serum triglycerides, cholesterol, HDL-cholesterol and LDL-cholesterol were calculated.2), saturated FAs (SFAs) contributed 52% to total serum FAs, n-6 polyunsaturated FAs (PUFAs) 27%, monounsaturated FAs 12%, n-3 PUFAs 9% and trans FAs (TFAs) <1%. The “purchase” pattern was related to lower proportions of n-3 PUFAs , but higher proportions of linoleic acid (LA) . The “traditional” pattern was characterized by lower proportions of arachidic acid . LA was inversely associated with triglycerides, but positively with HDL-cholesterol and LDL-cholesterol.In this mainly female (76%), middle-aged  and predominately overweight study population  and deep-fried meals (TFAs) did not contribute to the observed associations between dietary patterns and T2D. Still, LA might partly explain the health-beneficial effect of the “purchase” pattern.The online version of this article (10.1186/s12937-017-0286-x) contains supplementary material, which is available to authorized users. Diabetes mellitus is a global health challenge, affecting 415 million people worldwide . PopulatTherefore, we previously evaluated the importance of dietary patterns for T2D among adults living in urban Ghana . By meanr = 0.13–0.71) with blood lipid fractions were seen . The. The4]. Regarding the characteristics across the dietary patterns Table , particiThe distributions of serum phospholipid FAs across the tertiles of the “purchase” and the “traditional” pattern scores are shown in Table p = 0.16). For MUFAs, lower proportions were observed for palmitoleic (16:1n-7), oleic and vaccenic acid across the “purchase” pattern tertiles. The n-3 PUFAs EPA and DHA, were significantly lower; this was still discernible after multiple adjustment . Within n-6 PUFAs, significantly higher proportions were observed for LA, which remained after adjustments . While dihomo-γ-linolenic and arachidonic acid were lower across tertiles of the “purchase” pattern, no further n-6 PUFAs were significantly associated. In a sensitivity analysis, the positive association of the “purchase” pattern with LA was confirmed for the characteristic fat-containing foods margarine , vegetable oil  and groundnut .For the “purchase” pattern, there was no significant association with SFAs, except for lower proportions of heptadecanoic acid in higher tertiles, but this was not statistically significant after multiple adjustment for potential confounders . EPA, docosapentaenoic acid (DPA), and DHA proportions were nominally higher across the tertiles of the “traditional” pattern. In the group of n-6 PUFAs, significantly higher proportions were observed for eicosadienoic acid, whereas proportions tended to be higher for arachidonic acid and lower for LA (Table p < 0.0001) and plantain . After adjustment for respective confounders, no significant association remained for n-3 and n-6 PUFAs with the “traditional” pattern. Proportions of TFAs neither differed across tertiles of the “purchase” nor of the “traditional” pattern  are likely . Still, In conclusion, in this urban Ghanaian population, neither serum SFAs nor TFAs seemed to be responsible for the direct association of the “traditional” pattern with T2D. Alternative explanations for this relationship need to be explored. With regard to the “purchase” pattern, the association of LA with blood lipids was health-beneficial, possibly contributing to the inverse association of this pattern with T2D.Additional file 1:Fatty acid (FA) analysis in serum phospholipids (PL) by gas chromatography (GC). (DOCX 16 kb)Additional file 2:Overview of the 33 food groups and respective food items, that were collapsed into the food groups. (DOCX 19 kb)Additional file 3:Construction of the socio-economic status (SES) sum score. (PNG 101 kb)


Moreover, curvature-strain data indicates that Stoney’s simplified curvature-stress relation is not valid for thin substrates with regard to the expected strains, but can be addressed using more sophisticated plate bending theories.Rapid progress in the reduction of substrate thickness for silicon-based microelectronics leads to a significant reduction of the device bending stiffness and the need to address its implication for the thermo-mechanical fatigue behavior of metallization layers. Results on 5 µm thick Cu films reveal a strong substrate thickness-dependent microstructural evolution. Substrates with  Since biaxial film stresses develop as a consequence of the thermal mismatch strain, mε, then:sα and fα, determination of stresses is only connected to the variation of the film/substrate curvature. Thermo-mechanical fatigue of metallic thin films has been one of the key concerns in microelectronics during a product’s lifecycle. The material damage and subsequent failure regarding functionality is often associated with film cracking, severe surface roughening, and void formation in the film interior. The driving force behind such microstructural changes is always connected to the evolving stresses in the film material. Stresses arise as a consequence of the substrate constraint and the different coefficients of thermal expansion (CTE) between the film and substrate. The cornerstone of experimental evaluation of film stresses is performed with the well-known Stoney Equation . Althougfσ the corresponding curvature is proportional to 1/sh2 and fh, and scales with the elastic properties of the substrate. To guarantee validity, Equation (1) is based on the main assumption that fh is much less than sh [h* = fh/sh is not strictly defined, but rather arbitrarily chosen  of the substrate curvature can occur due to deposited films [In other words, for the same  than hs . Thereby.01, see ). In mod.01, see ,9. In li.01, see ,11,12, bed films ,14. Thisfh = 5 µm were electrodeposited using a Cu electrolyte on 725 µm thick, (100)-oriented silicon wafers. Afterwards, samples were annealed for 30 min in an inert/reducing atmosphere at 400 °C. For detailed information regarding the used copper film and its microstructure, see references [sh down to ~200 µm. Below that thickness, sample integrity  becomes a major concern. For thermal cycling and subsequent microstructural analysis, samples with sh of 725, 541, 323, and 220 µm resulting in h* of 0.007, 0.009, 0.015, and 0.023, respectively, were used. Those samples were thermo-mechanically cycled in an infrared furnace between 170 °C and 400 °C in a formic gas atmosphere. To study the effect of varying substrate thickness on the thermo-mechanical behavior of Cu films, a site-specific microstructural tracking technique was applied throughout the thermal cycling process [Copper films with ferences ,16, wher process . Experim process ,20.sh with respect to the cyclic thermo-mechanical behavior of the 5 µm thick Cu film, sh = 725 and 541 µm, an almost identical grain size evolution is present, where marginal grain growth during thermo-mechanical loading occurs. Below the 541 µm substrate thickness, significant grain growth could be observed. For sh = 323 µm, the grain size increased up to 4.3 ± 1.3 µm after 500 cycles, while for sh = 220 µm, the average grain size increased by a factor of two after 500 cycles. sh = 541, 323, and 220 µm. The inverse pole figure (IPF) images with overlaid image quality (IQ) in normal direction (ND) document the grain growth with respect to cycle number, where white lines indicate high angle grain boundaries (HAGB ≥ 15°) and thin black lines indicate primary twins (misorientation = 60°). For the Cu film on the thick substrate, sh = 541 µm, marginal microstructural changes could be observed during the cycling with respect to the initial stage. For instance, the ~ {100}//{212}-oriented parent/twin grain highlighted by a circle showed no essential plasticity during cycling, and in particular no twin boundary migration, as this controls grain growth in these films on standard 725 µm thick substrates [sh = 323 and 220 µm) revealed grain growth during the thermo-mechanical loading in combination with noticeable twin boundary migration as a plastic deformation mechanism. This was highlighted for sh = 220 µm in the squared section. The approximately {110}-oriented twinned grains showed distinct grain growth via HAGB migration as well as detwinning during cycling. To quantitatively assess the effect of decreasing bstrates . On the sh. An almost identical roughness evolution for sh = 725 and 541 µm was observed, in accordance with the grain size evolution in sh = 323 and 220 µm, a significant increase was observed. After 750 cycles, the RMS roughness of the Cu films on sh = 323 and 220 µm was increased by a factor of 3 and 5 compared to that on sh = 541 µm. The significant increase of surface roughening for thinner substrates was due to the formation of hillock-like features and voids on the surface , thermal film stresses were supposedly the same in every cycled sample and, hence, cannot cause the different thermal fatigue behavior. The experimental findings show a significant substrate thickness dependency with regard to the thermo-mechanical fatigue behavior. The substrates with n growth  and restn growth a, thus cb, where b = 2sh/3 [h* smaller than 0.1, Stoney’s formula would underestimate the corresponding bending curvature by a factor of ~2.  due to thermal stress will always result in a net bending moment as long as there is an elastic bending curvature . In othe = 2hs/3 , but leaigure 6, ). Therebsh = 725 and 400 µm using substrates that were processed using semiconductor industry tools to exclude preparation artefacts. Both wafers had the same 5 µm thick Cu film on the top, and specimens of 10 × 10 mm in lateral dimension were used. In sh down to 400 µm increased the substrate curvature by a factor of ~5. For both configurations, the resulting thermal elastic strain in the copper film at any given temperature was nearly the same and followed Equation (2). We assume a constant CTE mismatch between Cu and Si of Δα = 14 ppm/K. Using the temperature data from the curvature measurements, the respective strain evolution is plotted as a thick black line in −4 and −65 MPa respectively  at 50 °C is obtained. Rearranging Equations (1) and (3), we can calculate the strain from the curvature data using sM = 180.5 GPa. For a common wafer thickness, sh = 725 µm, final strains of −4.9 × 10−4 and −2.5 × 10−4 are obtained, which would result in −82 MPa and −42 MPa for Stoney and Chu, respectively. One could argue that this discrepancy regarding an overestimation for Stoney (and an underestimation for Chu’s relation) could simply be a sensitivity problem due to the small curvature evolution [sh = 400 µm, where Stoney’s relationship would result in −7.0 × 10−4 and −118 MPa. This would overestimate the strain/stress by almost a factor of ~2, whereas the analysis of Chu et al. perfectly correlates with the developed stress by the predicted CTE mismatch of −65 MPa in the Cu film. To validate the predictions of the actual bending curvature using Stoney and Chu curvature-(film) strain relations, the curvature evolution due to thermal mismatch was measured for substrate thicknesses of volution . Howeverκstoney, correlates well with our experimental observations. In fact, this emphasizes that the simplified model of having a net-zero bending moment with regard to the composite curvature is not correct. If we consider the stress fields proposed in reference [κ, scaling with the resulting bending curvature and the applied thermal strain mε. This is similar to the bending strain relationship for flexible electronics, where the strain in the outer fiber  is proportional to its bending curvature [sh and the understanding that the curvature is underestimated by a factor of ~2, significant strain gradients could locally lead to higher stresses in the surface region and cause an accelerated microstructure evolution, as evidenced in Gρ is proportional to |κ|, which would give rise to a strain gradient in the bent lattice curvature [These observations confirm that, in general, Stoney’s equation is only an approximation of the stress development for thin films on thick rigid substrates. For thin substrates, it leads to the wrong curvature-strain relationship, while the Chu et al. derivation, where the curvature is ~2·eference , Equatiourvature . With thurvature . sh = 400 µm and 210 µm, an abrupt “snap over” of the substrate curvature occurred, seen as a bifurcation of the sample curvature. Besides the impracticable measurement of the curvature evolution for sh = 210 µm, this observation points to the presence of large non-linear deformation. Focusing on the ellipsoidal shape of the detected laser spots suggests that the curvature is a function of position and that twist moments are present. Such effects rise inevitably in modern microelectronics, and are not considered in common analysis but can have a pronounced effect on the thermo-mechanical material behavior.Furthermore, the CCD (charge couple device) detector images of the deflected laser beams in sh = 323 and 220 µm. The examination of Stoney’s curvature-strain relation using wafer curvature measurements showed distinct deviations between the expected and measured curvature. The significantly larger sample curvature in combination with expected plastic strain gradients in the film material can serve as an explanation for the accelerated material degradation. The observations with respect to non-uniform sample curvature and bifurcation for thinner substrates  further highlight the need for more detailed investigations of the actual limits of Stoney’s assumptions on small substrate deformation and its implications for microstructural effects on semiconductor thin film materials.The detailed results regarding the microstructural evolution of 5 µm thick Cu films upon thermo-mechanical fatigue revealed a strong substrate thickness dependency. The findings showed that distinct grain growth coupled with twin migration and accelerated surface roughening was present for Cu films cycled on thin substrates with


Seven randomized controlled trials including 4261 patients were analyzed among this systematic review and meta-analysis. We found preventive antibiotics treatment at the time of stroke onset did reduce the incidence of infections in adults with acute stroke , including reducing the number of urinary tract infections , but did not significantly decrease the rate of post-stroke pneumonia . Importantly, antibiotics treatment also showed no significant effect on the number of fatalities among stroke patients  and functional outcome scores on the modified Rankin Scale . Our study indicated that preventive antibiotics treatment not reduced the rate of post-stroke pneumonia or mortality, even though decreased the risk of infections, especially urinary tract infections. Thus, preventive antibiotics treatment may not be recommended for acute stroke patients.Post-stroke infections are common complications in acute stroke patients and are associated with an unfavorable functional outcome. However, reports on the effects of prophylactic antibiotics treatment on post-stroke infections are conflicting, especially those on post-stroke pneumonia and outcomes. We searched the PubMed, Embase, and Web of Knowledge databases up through March 11 Stroke is a leading cause of death worldwide. It is often followed by complications, especially infections, which occur in 30% of stroke patients and are strongly associated with unfavorable outcomes and high mortality124Previous studies on the preventive use of antimicrobials in patients with acute stroke found conflicting results. Recently, a meta-analysis including 506 patients concluded that prophylactic antibiotics treatment after the onset of stroke significantly reduced the infection rate without major adverse effects, but had no effect on the mortality rate. Moreover, its effectiveness in reducing post-stroke pneumonia was ambiguousThere were 808 records identified using different search strategies in three databases  and 1 record identified by ref. 91011121314The characteristics of the studies included in analysis are listed in 911121014P = 0.005)  , Table 3P = 0.385) (P = 0.996) (P < 0.001)  were included. In this meta-analysis, we found that prophylactic antibiotics did not reduce the incidence of pneumonia in adult patients with acute stroke  , Table 3= 0.996) , but dec< 0.001) , Table 3P = 0.743) (p = 0.124)  , Table 3I2 = 63.4%, P = 0.018)  (Obvious between-study heterogeneity was found while estimating the effects of preventive antibiotics treatment on post-stroke infections (= 0.018) , Table 3= 0.018) , which w< 0.001) . TherefoI2 = 31.0%, P = 0.225; I2 = 0.0%, P = 0.826; I2 = 26.2%, P = 0.238, respectively)  .P = 0.348, P = 0.734, P = 0.497, P = 1.000 respectively). The funnel plots are shown in Each study was removed sequentially to verify the effect of each individual study on our on our results. No obvious changes were found after excluding any study. Therefore, our results were reliable (data not shown). Both Egger’s and Begg’s methods were applied to explore the publication bias in our meta-analysis. There was no significant publication bias among the occurrence rate of post-stroke infections, post-stroke pneumonia, urinary tract infections, mortality analysis in our study  statement.th, 2016. Key words were identified as follows: “stroke”, “cerebral infarction”, “brain infarction”, “cerebrovascular disease”, “cerebral hemorrhage”, “intracranial hemorrhage” or “cerebrovascular disorder”; and “infection”, “inflammation”, “fever”, “bacteraemia”, “sepsis”, or “pneumonia”; and “antimicrobial agents”, “antibiotics” or “prophylactic antibiotics”; and “prophylaxis” or “prevention”. The updated literature search, data extraction, and quality assessments were conducted independently by two authors . All articles were retrieved and their references were checked to avoid missing other relevant articles. If data were not included in the original articles, we contacted the authors to obtain them.All published articles were searched in the PubMed, Embase, and Web of Knowledge databases up through March 11The inclusion criteria were as follows: (1) studies evaluating the effects of preventive antibiotics treatment in adult acute stroke patients (predefined as age 16 years or older); (2) randomized controlled trials were eligible for inclusion; and (3) The effect estimates of studies could be extracted or calculated from the available data. The exclusion criteria were as follows: (1) studies with insufficient data to calculate or extract effect estimates and (2) case reports, reviews, comments, abstracts or animal studies.Two independent researchers  conducted data extraction to ensure the reliability of the results. Disagreement was resolved by discussion. The information of studies meeting the inclusion criteria were extracted using a standardized extraction form. Relevant information included the first author’s name, publication year, inclusion criteria, exclusion criteria, intervention, outcomes, the numbers of cases and controls, the infection rate, urinary tract infections and pneumonia rate, other infections rate, the rate of mortality, mRS score, antibiotic related side effects and the Jadad Score.The quality of the studies was evaluated by two independent reviewers  according to the Jadad Scale, which contains three dimensions: randomization, blinding and withdrawals for case-control studies. The Jadad Scale is a validated 5-point scale assessing the following criteria: (1) whether randomized ; (2) whether randomization was described appropriately ; (3) whether double-blind ; (4) whether the double-blinding was described appropriately ; and (5) whether the dropouts and withdrawals were described . The quality score ranges from 0 to 5 points, where 0–2 points is defined as a low-quality report study and a high quality study score is at least 3 points.For all included studies, we (L.L and X.Y.X.) independently assessed the risk of bias for the following items: adequacy of sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; Incomplete outcome data; selective reporting; and other sources of bias. We have categorized these judgments as ’low’, ’high’, or ’unclear’ risk of bias2) statistic and Chi-square-based Q-tests were used to investigate the heterogeneity across studiesP > 0.10 for the Q test and I2 values less than 50% suggested no obvious heterogeneity across studies and a fixed (Mantel-Haenszel) effects model was applied; otherwise, a random (DerSimonian-Laird) effects model was usedFor each study, unadjusted odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were derived from patient numbers with each outcome categorized by antibiotics treatment. A Z test was conducted to assess the statistical significance of pooled ORs and 95% Cis. I-squared .Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Copper transporter 1 (CTR1), copper transporter 2 (CTR2), copper-transporting p-type adenosine triphosphatase 1 and 2 (ATP7A and ATP7B) are key mediators of cellular cisplatin, carboplatin and oxaliplatin accumulation. In this meta-analysis, we aimed to evaluate the relation of CTR1, CTR2, ATP7A and ATP7B to overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) and treatment response (TR) of cancer patients who received chemotherapy based on published literatures, the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) datasets. Hazard ratios (HRs) and odds ratios (ORs) were pooled using random-effect models. Subgroup analysis and sensitivity analysis were conducted; heterogeneity and publication bias were assessed. Twelve literatures and eight datasets with 2149 patients were included. Our results suggested that high CTR1 expression was associated with favorable OS, PFS, DFS and TR in cancer patients who underwent chemotherapy with acceptable heterogeneity. The relationship of CTR1 to cancer prognosis remained significant in the subgroup of patients who underwent platinum-based chemotherapy, the patients with ovarian cancer and those with lung cancer. The significance of these relationships was not influenced by geological region of publication, data origin or detection method. However, there was no evidence for relation of CTR2, ATP7A or ATP7B to OS, PFS, DFS or TR. Test of publication bias and sensitivity analysis suggested a robustness of all the summary effect estimates. In conclusion, high CTR1 level predicts prolonged survival and enhanced response to chemotherapy in cancer patients who underwent chemotherapy and CTR1 might be a potential target to circumvent chemotherapy resistance. Platinum-based chemotherapy remains a first-line treatment of various epithelial malignancies including lung, bladder, head and neck and gynecological cancers for over 30 years. Although over half of the patients respond well to platinum-based chemotherapy, relapse and drug-resistance are major limitations for successful treatment of cancers. The platinum drugs exert cytotoxicity mainly through binding DNA to form crosslinks, which interfere normal DNA activities and induce cellular apoptosis . HoweverPrecedent evidence suggested that platinum drugs entered cancer cells through passive diffusion because the time-linear influx of platinum did not reach saturation at relevant drug concentration, was not inhibited by any structural analogous nor was it dependent on an optimal pH . AccordiTherefore, we conducted a meta-analysis of published literatures as well as datasets to assess the association between the expression of copper transporters and the prognosis in cancer patients who underwent chemotherapy. To obtain more detailed information, subgroup analyses stratified by cancer type, chemotherapy regimen, geological region, data origin and detection method were conducted.A total of 1793 literatures were identified from electronic search. Full texts of thirty publications were retrieved after reviewing titles and abstracts. After exclusion of 18 literatures , finallyP = 0.000; for PFS, HR = 0.65, 95% CI: 0.57-0.75, P = 0.000) . However, there was no significant relation of the expression of CTR2, ATP7A and ATP7B to OS or PFS/DFS , lung cancer” , “platinum-based” , “America” , “Asia” , “dataset” , “literature” , “gene array”  and “IHC” . Similarly, high CTR1 expression was associated with an improved PFS/DFS in the subgroups of “ovarian cancer” , “platinum-based” , “America” , “Asia” , “Europe” , “dataset” , “literature” , “gene array” , “IHC”  and “PCR”   and acceptable. High CTR2 was associated with an unfavorable PFS in the “America” subgroup , while in the “Europe” subgroup high CTR2 was associated with a favorable OS  and PFS/DFS . No evidence of a significant heterogeneity was found (Table P = 0.016) with a significant heterogeneity (I2 = 69.0) , especially in the subgroups of “ovarian cancer” , “lung cancer” , “Asia” , “dataset” , “literature” , “gene array”  and “IHC”  subgroups. The heterogeneities were moderate and acceptable. No evidence for a correlation between CTR2, ATP7A or ATP7B expression and TR was found .According to sensitivity analyses, the summary HRs for OS of CTR1 and PFS of CTR2 were influenced by one study in the “Europe” subgroup . All theIn this meta-analysis, we systematically evaluated the relationship between four copper transporters  that influence cellular platinum accumulation and prognosis of cancer patients who received chemotherapy. Our results showed that high CTR1 expression was significantly associated with a favorable OS, PFS, DFS and TR, suggesting that CTR1 is a potential prognostic factor for survival in cancer patients underwent chemotherapy and a treatment target for overcoming platinum resistance.Ever since the introduction of chemotherapy, drug response becomes a major determiner of cancer prognosis, which parallels with FIGO stage and residual debulked tumor volume. The cure rate of testicular cancer zoomed from 15% to 90% attributing to a great response to platinum-based chemotherapy. In ovarIn our study, we focused on evaluating the initial copper transporter expression in blood and tissue specimens obtained before or during primary surgery. We found that a high initial hCTR1 expression predicted improved prognosis in ovarian and lung cancer patients. However, pre-clinical evidence indicates that the expression of CTR1 is dynamic. Prompt reaction of CTR1 to acute copper concentration alteration is a well-recognized mechanism that regulates hCTR1 expression. Excessive copper triggers rapid hCTR1 internalization by endocytosis, which reduces the transportation activity of CTR1 , 40. CopIn relation to chemotherapy response and cancer prognosis, according to our results, CTR1 is of particular attractiveness to serve as a promising target to circumvent platinum resistance. Since correlation between reduced hCTR1 expression and platinum resistance was exhibited in precedent and the present studies, combination of copper lowering agents and platinum based chemotherapy, which stimulates hCTR1 expression and improve platinum uptake, is a promising strategy to treat hCTR1 deficiency mediated platinum resistance. Ishida S et al. successfully enhanced the cytotoxic effect of cisplatin on human cervical and ovarian cancer cells by up-regulating hCTR1 expression through administration of a copper chelating agent tetrathiomolybdate in vitro . Fu et aWe initially expected diverse prognostic values of CTR2 in distinct cancer types, in patients with different genetic background and in studies applied inconsistent CTR2 detection methods based on existing studies. Though CTR2 shares a substantial similar structure with CTR1, it plays drastically different role in platinum uptake. Unlike CTR1, preclinical studies revealed that high CTR2 level was associated with decreased cellular platinum uptake and poor drug response in ovarian cancer , 47. AddThe present study is the first meta-analysis regarding the impact of copper transporters on the outcomes of cancer patients who received chemotherapy to our knowledge. We used multiple data sources and performed subgroup analyses stratified by geological regions of publication, data origins and detection methods to accommodate possible biases and provide detailed results that help accelerate the relevant clinical translation. However, all the enrolled studies are retrospective, which provide evidence of Level II-1 or II-2  and limiTo sum up, high CTR1 level is associated with improved survival and TR in cancer patients, especially in patients with ovarian or lung cancer undergoing platinum-based chemotherapy, Prospective randomized studies are needed to verify the clinical value of CTR1in tumor patients.http://www.ncbi.nlm.nih.gov/gds) and the Cancer Genome Atlas (TCGA) datasets (http://cancergenome.nih.gov) for relevant information. The key words used were “CTR1”, “CTR2”, “ATP7A”, “ATP7B”, “platinum” and “Homo sapiens”.An independent systematic literature search of studies in all languages to May 2016 across PubMed, EMBASE, and Chinese Wanfang databases was conducted. The search terms used were “copper transporter 1”, “human copper transporter 1”, “copper transporter 2”, “ATP7A”, “ATP7B” and “platinum-based chemotherapy”. The electronic search of literature was supplemented by reviewing the reference lists of retrieved studies. Additionally we searched the Gene Expression Omnibus (GEO)  clinical studies measured CTR1, CTR2, ATP7A or ATP7B in solid tumors regardless of detection methods; 2) published prospective and retrospective cohort studies; 3) studies provided information of survival and chemotherapy response. Exclusion criteria included: 1) the patients enrolled did not receive chemotherapy; 2) studies focused on gene polymorphisms or DNA methylation; 3) studies investigated different end-points; 4) studies did not provide sufficient data. Eligible datasets should meet the following criteria: 1) cancer patients received chemotherapy; 2) the sample size should be more than 40; 3) gene array was performed using Affymetrix platform. If multiple studies shared overlapped populations, the study with the largest sample size was included. If multiple studies with overlapped populations used different detection methods, all were included.The quality of the included literatures was assessed according to the Newcastle-Ottawa Scale (NOS) for cohort studies. We extrhttp://kmplot.com/analysis/) with the selection of optimal cut-off point and microarray probe set was used to calculate the HRs and 95% CIs using data from GEO and TCGA datasets [I2 statistic with the method of Higgins et al. [I2 ≥ 50%. Subgroup analyses stratified by tumor type, geographic region, data origin and detection method were performed. Sensitivity analyses were performed by excluding one study at a time to evaluate the influence of single studies on summary HRs. Publication bias was assessed by funnel plot and Egger's test [P values less than 0.05 were considered statistically significant.The aim of our study was to investigate the relationship between the expression of copper transporters and the prognosis of cancer patients who received chemotherapy. The primary outcome measure was overall survival (OS), and secondary measures were progression-free survival (PFS)/disease-free survival (DFS) and treatment response (TR). The impact of platinum-transporter expression on OS, PFS and DFS was assessed by hazard ratio (HR), odds ratio (OR) in case of TR, and its 95% confidence interval (CI). The HRs and 95% CIs were extracted from eligible studies directly or calculated using the survival data extracted from the reported Kaplan-Meier curves with the software GetDATA Graph Digitizer 2.25 according to the method described by Tierney et al. . An on-ldatasets –54. Randdatasets . The hets et al. . A heterr's test . All ana