Purpose: In this study, we explored whether improved hand function is possible in poststroke chronic hemiparetic individuals with severe upper limb motor impairments when they participate in device-aided task-specific practice.Subjects: Eight participants suffering from chronic stroke  with severely impaired upper extremity movement  score between 10 and 24) participated in this study.Methods: Subjects were recruited to participate in a 20-session intervention (3 sessions/7 weeks). During each session, participants performed 20–30 trials of reaching, grasping, retrieving, and releasing a jar with the assistance of a novel electromyography-driven functional electrical stimulation (EMG-FES) system.This EMG-FES system allows for Reliable and Intuitive use of the Hand  during multi-joint arm movements. Pre-, post-, and 3-month follow-up outcome assessments included the UEFMA, Cherokee McMaster Stroke Assessment, grip dynamometry, Box and Blocks Test (BBT), goniometric assessment of active and passive ranges of motion (ROMs) of the wrist and the metacarpophalangeal flexion and extension , Nottingham Sensory Assessment–Stereognosis portion (NSA), and Cutaneous Sensory Touch Threshold Assessment.Results: A nonparametric Friedman test of differences found significant changes in the BBT scores , the passive and active ROMs , and the NSA scores  following a multi-session intervention using the ReIn-Hand device.Conclusions: These results suggest that using the ReIn-Hand device during reaching and grasping activities may contribute to improvements in gross motor function and sensation (stereognosis) in individuals with chronic severe UE motor impairment following stroke. Stroke is the second most common cause of mortality and the third most common cause of disability worldwide , 2. MoreSeveral studies have suggested that repetitive task-specific training can improve upper extremity (UE) function –14 in miThere is limited research targeting chronic stroke individuals with severely impaired UE. These individuals are less able to participate in task-specific training because of minimal volitional activation of the impaired arm . FurtherThe purpose of this study is to determine the effect of device-assisted task-specific training on hand motor function and sensation (stereognosis and cutaneous sensory touch threshold) in individuals with chronic stroke and severe UE impairment. An electromyography-driven functional electrical stimulation (EMG-FES) with an intelligent detection software that detects the hand opening intention even with the presence of flexion synergies was used to assist the hand opening while subjects were performing required reaching and grasping tasks. We expected that by training a functional activity that involves arm-lifting, reaching and grasping, retrieving and releasing, poststroke participants with severely impaired UE would improve their arm/hand motor function and sensation.Some parts of the results from various assessments  have been briefly reported in a previous publication  that focEight adults  with chronic (mean time since stroke 11.2 years) UE hemiparesis resulting from a unilateral stroke participated in this study. All subjects completed the intervention protocol and before intervention (pre-), after intervention (post-), and 3-month follow-up assessments.Inclusion criteria for this study included the following: 1) severe UE impairments with Upper Extremity Subscale of the Fugl-Meyer Motor Assessment (UEFMA) scores between 10 and 24 ; (2) mod severe UThe study took place in a university research laboratory. All participants were recruited from the Clinical Neuroscience Research Registry hosted by the Shirley Ryan AbilityLab (former RIC) and Northwestern University. The Institutional Review Board at the Northwestern University approved the protocol for this study. Written informed consent was obtained from all subjects prior to testing.“ReIn-Hand” is a recently developed EMG-FES device that uses the combination of an EMG collection unit , an intelligent detection software “the ReIn-HAND platform,” and an electrical stimulator  . The ReISubjects participated in a 1.5–2.5-h session, 3 times per week, for 7 weeks. At the beginning of each session, muscles in the paretic arm/hand were stretched for about 10 min. The recording and stimulating electrodes were placed and the stimulation intensity was adjusted to allow for a maximal hand opening without discomfort. Each participant was seated in front of a height-adjustable table with a plastic jar  placed in front of their trunk, in line with the middle of their body . Training consisted of 20–30 trials (approximately 1.0 h) of the following activities: (1). reaching forward toward the jar placed on a tabletop, (2). attempting to open the hand and activating finger/wrist extensor muscles to trigger the ReIn-Hand device in assisting the opening of the paretic hand, (3). grasping the jar, (4). bringing the jar toward their body and placing it on a table, and (5). releasing the jar. Hand opening and releasing were aided by the ReIn-Hand device. All the subjects were instructed not to fight the stimulation once the FES was successfully triggered; instead, they were asked to adjust their strategies to maximize the FES-assisted hand opening . The diameter and weight of the jar and the distance/height to reach it were increased to make the task progressively more challenging, yet the task was set to allow each participant to complete the task and trials , after intervention (post-assessment), and at 3-month follow-up assessment. The BBT –37 was uThe PROM measurements were averaged across three joints and reported as a single measure of the hand combining wrist and fingers. The AROM measurements were also averaged across joints and reported as a single measure of the fingers.p < 0.05) values, post-hoc Wilcoxon signed-rank tests with Dunn-Sidak corrections for multiple comparisons were performed to further evaluate the impact of the intervention. Results are reported as significant (p < 0.05).Statistics were performed using Matlab (2016a). The effects of the intervention were assessed with a nonparametric Friedman test. To obtain conditional to statistically significant . However, there was no retention of these gains but with a significant BBT decrease at 3-month follow up compared to post-assessment (p < 0.05). Only one subject surpassed the minimal detectable change (MDC = 5.5 blocks) and reached the smallest real difference (SRD) (6 blocks) for BBT  for the fingers . Additionally, no significant changes were found in either UEFMA or CMSA-H.Similarly, the intervention had a significant effect on the active and passive ROMs, χ fingers . There w2 = 6.42, p < 0.05). Five out of eight participants showed an improvement of at least 10% from pre- to post-assessment in the NSA scores . At 3-month follow-up, improvements were not retained.This study aimed to examine the impact of the reaching and grasping training aided by the ReIn-Hand device on UE function of chronic, severely impaired poststroke individuals. The ReIn-Hand device is unique in its ability to enable even severely impaired individuals with stroke to open the hand reliably regardless of proximal arm position and activation level of the shoulder abductor muscles . In thisOur results show that in severely impaired individuals with poststroke hemiparesis, device-assisted reaching and grasping training may produce gains by reducing impairment and increasing activity levels. To determine the changes in activity level, specifically at manual dexterity and in UE function, participants were evaluated using the BBT. As the main outcome of the study, we found a significant increase from pre- to post-intervention assessment, but the gains were not maintained at 3-month follow-up. Specifically, six out of eight subjects showed an increase of at least one block. The increase in post-BBT scores may have been aided by the post-intervention gains in the AROM, since improvements in the ROMs, especially active, may contribute to improved upper extremity function , 49. In Active and passive ROM of the hand and wrist showed a significant increase from pre- to post- assessment. This improvement might possibly be due to the effect of FES on motor control , 52, joip = 0.09). The lack of significant increase in grip strength may be due to the fact that the stimulation exclusively facilitated hand opening (wrist/finger extensors) and was never aimed at finger/wrist flexors.Grip strength has been shown to influence ADLs , 58. TheNo significant changes were found in either UEFMA or CMSA-H between pretesting, posttesting, and follow-up testing. We think that these two assessments might not have enough resolution , 60 to dSensory deficits (tactile and stereognosis) are a common problem following stroke. Stereognosis requires the combination of many integrated primary sensory inputs . There iThe underlying mechanisms for the improved hand/arm function from the observations are not fully understood. We did assess changes in grip strength and found no significant change. However, it is possible that that other strength changes might have occurred, such as an increase in shoulder abduction or an elbow extension. Therefore, we cannot fully assess if the adaptation was a result of increased muscle strength or true recovery. Instead, we measured intervention-induced cortical changes and reported an increased reliance on the ipsilesional hemisphere during hand opening following the intervention . Since mSeveral limitations of this study should be noted. First, there was a small sample size that included a homogenous population. Second, the intervention study was limited to 7 weeks and 20–30 trials/session, whereas other studies have looked at interventions in this population for up to 12 weeks . Third, In addition, the ReIn-hand device uses a triggered mode. Once triggered, an individual can choose to relax instead of continuing to try to open, since attempting to open can actually result in closing and diminishes the FES-generated opening in individuals with severe motor impairments . This caThese results suggest that using the ReIn-Hand device during functional reaching and grasping activities may contribute to improvements in gross motor function and stereognosis sensation of the paretic arm in individuals with moderate to severe impairment following chronic stroke.Task-specific training aided by the ReIn-Hand device might improve motor and sensory function in severely impaired chronic stroke.Further research is needed to assess the effectiveness of this intervention for improving clinical outcomes in randomized controlled trials.This study was carried out in accordance with the recommendations of Northwestern University, institutional review board with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the name of committee.CC helped with the intervention design, participated in running the intervention, performed the clinical assessments, and was the primary author of the manuscript. KW participated in running the intervention, processed the data, and helped with manuscript writing. JD participated in running the intervention and helped with manuscript preparation. JS helped in designing the intervention and manuscript writing. JPAD helped with manuscript writing. JY was the primary designer of the intervention, participated in running the intervention, and helped with manuscript writing and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Incorporating reinforcement into the practice of digital concrete construction, often called 3D-concrete-printing, is a prerequisite for wide-ranging, structural applications of this new technology. Strain-Hardening Cement-based Composites (SHCC) offer one possible solution to this challenge. In this work, printable SHCC were developed and tested. The composites could be extruded through a nozzle of a 3D-printer so that continuous filaments could be deposited, one upon the other, to build lab-scaled wall specimens without noticeable deformation of the bottom layers. The specimens extracted from the printed walls exhibited multiple fine cracks and pronounced strain-hardening characteristics under uniaxial tensile loading, even for fiber volume fractions as low as 1.0%. In fact, the strain-hardening characteristics of printed specimens were superior to those of mold-cast SHCC specimens. Digital concrete construction (DC) is usually carried out by means of an automated, selective, layer-by-layer deposition of fine-grained cementitious materials. Numerous research and commercial projects have been reported, including Contour Crafting , ConcretMost of the 3D-printing technologies developed as yet are focused on the placement of concrete, while the suggested solutions for incorporating reinforcement are still rudimentary. However, the understanding of the necessity of reinforcement for most structural applications is evident and various approaches have been suggested to deal with this issue. In the context of the selective material deposition techniques, extrusion-like methods, the following approaches have been proposed: 1) the placing of conventional steel reinforcement ,9 or met the placThe research at hand takes the approach of using dispersed, short-fiber reinforcement. This approach seems capable of being relatively easily integrated into the 3D-printing process by using fiber-reinforced concrete (FRC) instead of plain concrete. This straightforward approach is surely worth being pursued, especially taking into account the tremendous advances in the field of high-performance fiber-reinforced cement-based composites; see, e.g., ,22. ShorHambach et al. ,18 used With respect to structural performances, the use of strain-hardening cement-based composites (SHCC) is particularly promising . Under uIn the framework of the research project presented in the article at hand, the authors have developed 3D-printable, strain-hardening, cement-based composites (PSHCC) by using various contents of high-density polyethylene (HDPE) microfibers. The choice of this fiber type instead of less expensive PVA fiber (as used in ) was madIt is noteworthy that at this stage 3D-printed SHCC was tested by applying tensile loading parallel to the longitudinal axis of the deposited filaments. While the proven strain hardening likely benefitted from preferential fiber orientation due to extrusion process, the authors are aware that the mechanical performance of PSHCC may be more modest for tensile loading acting lateral to the printed wall or even more so for the loading perpendicular to layer-to-layer interface. The authors intend to address the anisotropy of PSHCC elements in a follow-up paper, which should also present strategies to counteract pronounced anisotropy by material design and processing technique on one hand, and to wisely consider it in architectural and structural design on the other hand.Four SHCC mixtures were investigated, designated as Mixtures A to D; see As aggregate, a fine sand with a maximum particle size of 1.0 mm was used for all the mixtures. Such particle size is uncommonly large for SHCC; usually, the maximum aggregate size does not exceed 0.3 mm. The purpose of using larger particles in this investigation was that they should be helpful in achieving a higher yield stress of fresh mixture and consequently higher shape stability of the deposited material . AdditiPumpability—The ease and reliability with which material is moved through the delivery system;Printability—The ease and reliability of depositing material through a deposition device;Buildability—The resistance of deposited fresh material to deformation under load;Open time—The period where the above properties are consistent within acceptable tolerances.The rheological behavior of cementitious materials in the fresh state is crucial for DC applications. Rheological properties must be fine-tuned since they affect not only the pumping behavior  ,32, extrLater, Nerella et al.  reassessThere are few methods to evaluate the criteria named above. For example, Mechtcherine et al.  showed tEarlier researchers suggested that the existing flow tests on cement-based materials yield values which can be associated with their printability and buildability ,40. ThusExtrudability is a critical aspect when it comes to applying fiber-reinforced concrete. Moreover, the addition of fibers pronouncedly modifies the rheological properties of fresh mixes. After a critical dosage limit is reached ;Extruding at a constant displacement rate of 15 mm/s by control with an electric motor (linear actuator).Specific steps in the ram-extrusion test procedure are as follows:The 3D-concrete-printing test device used in this study is shown in The buildability of the SHCC mixtures developed was verified with the help of direct printing tests using 3DPTD. SHCC walls of length 1000 mm, width 30 mm and height up to 120 mm were fabricated in one round. The wall height was the result of seven SHCC layers deposited one upon the other. The mixture tested was considered buildable if such a down-scaled wall retained its geometry and shape without observable deformations. Note that no accelerating agents were used in this study.Mechanical properties were investigated on printed specimens made of the compositions Mixture B and Mixture C, both of which were proven extrudable and buildable; see The seven layer-walls printed in the framework of buildability testing were eventually used for testing the mechanical properties of hardened SHCC. The minor unevenness and deformations (±3 mm) of the printed wall, resulting in some deviation from the rectangular form of cross-section, were therefore removed during the cutting process and have no influence on quantified strength values; see Both printable compositions, Mixtures B and C, were used as well to produce mold-cast specimens for the uniaxial tensile tests; see All specimens (both mold-cast and printed) were cured in water for seven days starting with SHCC age of 24 h. After that, they were stored in a climatic chamber at a constant temperature of 20 °C and a relative humidity of 65%. At an age of 22 days, the samples were cut from the printed walls using wet-grinding and subsequently strengthened by casting SHCC at both the ends. After the casting, printed specimens were stored again in the climatic chamber. Both the printed and casted specimens were under the self-same curing conditions up to 22 days. Since CEM II/A-M (S-LL) 52.5 R cement was used, most of the hydration should have already completed at this age. The slight variation of surrounding conditions after 22 days is unavoidable, as the printed specimens “must” be cut and prepared for the mechanical testing. All specimens were removed from the climatic chamber at an age of 26 days. Both tension and compression tests were conducted at an age of 28 days.The uniaxial tension tests were performed in a manner similar to those presented in earlier works at the TU Dresden  in an InAs detailed in previous sections, mold-cast, dumbbell-shaped samples of cross-sectional dimensions of 24 mm by 40 mm were used as reference see b. The prThe results of the flow table tests are summarized in After shocks both Mixtures A and Mixture D have higher flow spread diameters and higher uildable . Based oTo estimate risk of blockages, a ram-extruder device was used. Interestingly, the extrusion force appears to decrease with increasing fiber content. This observation directly contradicts the common understanding that increasing fiber dosage affects the flowability of FRC negatively, and thus potentially decreases extrudability as well. On closer examination, however, it is evident that the extrusion force, measured with the ram-extruder results presented in this paper, is governed more by the sand-to-binder ratio than by the fiber content. The S/B of Mixtures A, Mixture B and Mixture C were 1.20, 0.50 and 0.20, respectively; see The results of ram-extruder tests suggest that all tested mixtures may be suitable for the 3D-printing from the extrudability perspective. However, this conclusion does not consider differences in extrusion devices, i.e., ram-extruder vs. screw-extruder. The results obtained by means of screw-extruder as employed in the 3DPTD are presented in the following subsection.3D-printing tests were conducted using Mixtures B and C only, since these two compositions seemed to be most promising as based on the interpretation of flow table test results with respect to buildability; see As indicated above and as estimated based on flow table test results, i.e., flow spread of 153 mm after strokes and , MixtureValues of first-crack stress, tensile strength and strain capacity as obtained from uniaxial tension tests are given in The difference in behavior was much more pronounced at higher strain levels. research .Additionally, the fracture surfaces of the specimens were examined. The fiber distribution was found to be uniform in all specimens. However, mold-cast specimens (B-cast and C-cast) had more relatively large voids when compared to the printed specimens, B- and C-print; see Another object of examination on fracture surfaces was fiber orientation. (1)The PSHCC mixtures developed could be printed by depositing consistent filaments with a time interval of one minute between subsequent layers; wall elements with a height of 120 mm could be built without any noticeable deformation of the bottom layers.(2)The shape stability of the printed wall elements could be roughly estimated from the results of flow table tests.(3)Extrudability, as quantified by means of a ram extruder, depends on the sand content of the mixture in the first place. The ease of extrusion increases with decreasing sand content.(4)The specimens extracted from the printed walls exhibited pronounced strain-hardening behavior under uniaxial tensile loading for fiber concentrations as low as 1%. For a fiber content of 1.5%, strain capacity was considerably higher, and very uniformly distributed fine multiple cracks were observed.(5)Printed specimens exhibited superior strain-hardening behavior and more pronounced multiple cracking in comparison to mold-cast specimens made of the selfsame SHCC mixtures. This can be likely traced back to (1) the absence of large air voids in printed specimens due to compaction in the printhead; and (2) the favorable orientation of fibers as a result of the extrusion process.Printable, Strain-Hardening, Cement-based Composites (PSHCC) with HDPE fiber contents of 1% and 1.5% suitable for digital construction were developed and characterized. The results of the research at hand can be summarized as follows:The ongoing work of the researchers is to focus on (1) detailed characterization of the time-dependent rheological properties of PSHCC in the fresh state and their relation to the process parameters of 3D-printing; (2) quantifying mechanical properties of layer-to-layer interfaces and their effect on the anisotropy of printed SHCC; and (3) comprehensive investigation of the microstructure of printed SHCC.


The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts . 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years , 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories . Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes . The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies.EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research. Evidence before this studyThe blood concentrations of non-HDL and LDL cholesterol are accepted as causal cardiovascular risk factors and constitute a cornerstone of cardiovascular disease risk prediction in the general population. The benefit of lipid-lowering interventions for cardiovascular disease risk reduction is proven by mendelian randomisation studies, prospective epidemiological cohort studies, and randomised trials. For the present study, we assessed recommendations made by the European and US guidelines and their underlying references for lipid-lowering strategies in primary prevention. Furthermore, we reviewed the cardiovascular risk calculators as recommended by these guidelines . We found very little data describing the effect of baseline non-HDL and LDL cholesterol on long-term or even lifetime outcomes. Cardiovascular risk assessment was mainly based on 10-year medium-term follow-up. All identified randomised trials for lipid-lowering intervention in cardiovascular primary prevention did not exceed a follow-up of 7 years and, moreover, especially young individuals were underrepresented in those studies.Added value of this studyTo our knowledge, our study provides the most comprehensive analysis of long-term risk for cardiovascular disease related to non-HDL cholesterol and offers an easily applicable tool to assess the long-term probabilities for cardiovascular disease events associated with non-HDL cholesterol. On the basis of a derivation and validation approach to risk prediction, our data provide robust multinational information. By using an up-to-date multinational population-based pooled cohort dataset, we provide a model that calculates the potential benefit of an early lipid-lowering strategy in individuals without prevalent cardiovascular disease across a range of non-HDL cholesterol categories.Implications of all the available evidenceThere is evidence for the positive outcomes in lipid-lowering interventions in individuals with cardiovascular disease or those with very high cholesterol concentrations. Our data extend current knowledge and highlight the impact of non-HDL cholesterol on very long-term cardiovascular disease outcomes. A simulation of early reduction of non-HDL cholesterol across a range of lipid concentration categories estimates the risk reduction in the general population. Meeting targets for global reduction of cardiovascular disease morbidity and mortality will require increased awareness of the value of early cholesterol determination and careful evaluation of potential strategies for reduction of lipid concentrations across the lifespan.Numerous studies have provided consistent evidence for a causal relationship between blood cholesterol concentrations and cardiovascular disease.In this risk-evaluation and risk-modelling study, we used individual-level data from the Multinational Cardiovascular Risk Consortium . CurrentOur outcome measure was the first occurrence of a major cardiovascular event . This waWe based our cholesterol threshold concentrations on the treatment-determining cholesterol categories of the 2016 European guidelines on cardiovascular disease prevention.The following study variables were considered for analysis (but were not endpoints): age, sex, year of examination, body-mass index (BMI), systolic blood pressure, smoking status, use of cholesterol-lowering medication, total cholesterol, HDL cholesterol, and non-HDL cholesterol. History of arterial hypertension, diabetes, stroke, and myocardial infarction were defined as they had been documented or self-reported. Antihypertensive medication, lipid-lowering medication, and smoking status were self-reported. For individuals receiving lipid-lowering therapy, baseline concentrations of non-HDL cholesterol and LDL cholesterol were inflated by 30% for the analyses, assuming that treatment with statins had a moderate effect on lipid reduction and was initiated late during lifetime.For each analysis, only individuals with all data available on the relevant variables were used. To investigate the association of non-HDL cholesterol concentrations and time to cardiovascular disease, sex-specific cumulative incidence curves were produced according to the defined baseline non-HDL cholesterol threshold concentrations, with death of non-cardiovascular-disease causes as competing risk, using the Aalen-Johansen estimator. Multivariable Cox proportional hazards models were then computed, stratified for cohort and sex. Non-HDL cholesterol was coded as a categorical variable, with the help of dummy variables, using our predefined thresholds and included an interaction term with sex, to obtain sex-specific associations. To examine the association of non-HDL cholesterol across different ages, the models were expanded by adding an interaction between age category  and non-HDL cholesterol. Additional Cox regression analyses were done to model the concentrations of non-HDL cholesterol as a continuous variable via cubic splines. All Cox models were adjusted for age , sex (strata), cohort (strata), and classical cardiovascular risk factors . In a sensitivity analysis, sex-specific hazard ratios (HRs) for non-HDL cholesterol as a categorical variable were estimated in each country using models similar to the primary analysis, and the results were pooled using a random-effects multivariate meta-analysis. Further sensitivity analyses include the computation of time-dependent HRs for non-HDL cholesterol to examine deviations from the proportional hazards assumption .To establish a tool to assess the probability of cardiovascular disease by the age of 75 years, we split the whole data randomly into two parts of approximately equal size into derivation and validation datasets. In particular, each single cohort was part of both datasets. Using those observations where the required endpoint and covariate information was available, we developed a model that was calculated on the basis of cause-specific Cox models for cardiovascular disease stratified for sex and cohort. Death from non-cardiovascular-disease causes was added as a competing risk, to account for the fact that an individual dying from such a cause before developing cardiovascular disease will not be able to develop cardiovascular disease. These models used age as the timescale and the same variables as our previous Cox models. Non-HDL cholesterol, BMI, and systolic blood pressure were modelled using cubic splines. The models included an interaction between non-HDL cholesterol and sex. The model computation used the full available follow-up periods but was applied only to individuals aged between 35 and 70 years at baseline to estimate their probability of cardiovascular disease by the age of 75 years. These predicted probabilities were averaged within each combination of sex, non-HDL cholesterol category, age category, and according to whether the number of risk factors present  was greater than or equal to two, or less than two. We then assumed a reduction of the probabilities and their averages through a 50% or 30% reduction of non-HDL cholesterol, on the basis of the equation 1 – exp(−0·249 + [number of years of treatment–5] × [–0·0152]) for the expected proportional risk reduction per mmol/L in LDL cholesterol for a given treatment duration.To obtain predicted probabilities from the cause-specific Cox models for each combination of sex and cohort, the respective cause-specific baseline hazard function was estimated by fitting a Weibull curve to age and adjusting for the linear predictor of the Cox model. By using age as the timescale, it is possible to estimate the probability of an event within each combination of sex and cohort for the whole range of ages available in that part of the data. C-indices and smooth calibration curves were calculated for different timeframes separately in the derivation and validation datasets. The calibration curves were based on smoothing pseudo-values calculated with the Aalen-Johansen estimate of cumulative incidence.Sensitivity analyses used time-dependent coefficients that were allowed to change with attained age in the predefined groups . To calculate the effect of non-HDL cholesterol reduction on cardiovascular risk, we assumed a reduction of baseline non-HDL cholesterol by 30% or 50% (adapted from the 2018 American College of Cardiology/American Heart Association Guideline on the Management of Blood Cholesterol).To compare the discrimination of a model using non-HDL cholesterol with that of a model using LDL cholesterol, additional cause-specific Cox models were computed using age as the timescale, sex and cohort as strata, adjusting for cardiovascular risk factors , and including a sex–lipid variable interaction. All continuous variables, except age, were modelled using cubic splines. Tenfold cross-validation was used when computing the C-indices. The main analyses for non-HDL cholesterol were repeated for LDL cholesterol. All statistical methods were implemented in R statistical software, version 3.6.1.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (SB) and the lead statistician (FO) had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication.We identified 38 cohorts reporting on 398 846 individuals with 5 604 735 person-years of follow-up data available for analysis, of whom 184 055 (48·7%) were women . Examinavs 262 [7·7%] in women and 7689 [43·6%] vs 375 [12·8%] in men). Multivariable analyses confirmed a strong continuous association of concentrations of non-HDL cholesterol with the sex-specific cardiovascular disease risk. The lowest hazard for cardiovascular disease was found in women and men with the lowest non-HDL cholesterol concentrations, whereas there was a continuous and linear increase for higher non-HDL cholesterol concentrations  occurred throughout the follow-up period. The predefined thresholds of non-HDL cholesterol concentrations strongly differentiated cardiovascular disease risk, particularly beyond 10 years, even in the lowest cholesterol categories . The cumtrations . This astrations . The stetrations . Similartrations  and thostrations  at baseltrations .Figure 1We found similar results for the association of blood concentrations of LDL cholesterol and incident cardiovascular disease to non-HDL cholesterol . Cardiovvs ≥2) of classical modifiable cardiovascular risk factors  were incorporated into this model (To estimate the long-term probability of a cardiovascular disease event associated with non-HDL cholesterol, we established a model for cardiovascular disease risk up to the age of 75 years on the basis of a derivation–validation approach. Besides the non-HDL cholesterol category, sex, age, and the baseline number (≤1 is model . For exais model . Countryis model .Figure 4We calculated the optimally achievable risk reduction for cardiovascular disease by the age of 75 years assuming a 50% reduction of non-HDL cholesterol . In the Using individual-level data from the Multinational Cardiovascular Risk Consortium of individuals without prevalent cardiovascular disease, we characterised the age-specific and sex-specific long-term association of non-HDL cholesterol with cardiovascular disease. On the basis of this association, we derived and validated a tool specific for age, sex, and cardiovascular risk factors to assess the individual long-term probability of cardiovascular disease by the age of 75 years associated with non-HDL cholesterol. Further, we modelled the potentially achievable long-term cardiovascular disease risk, assuming a 50% reduction of non-HDL cholesterol.The proatherogenic effects of apoB-containing lipoproteins are largely based on the development and progression of atherosclerotic plaques and by accumulation of these lipoproteins within the arterial intima.9Considerable uncertainty exists about the extent to which slightly increased or apparently normal cholesterol concentrations affect lifetime cardiovascular risk and about which thresholds should be used to merit a treatment recommendation, particularly in young people. Our study extends current knowledge because it suggests that increasing concentrations of non-HDL cholesterol predict long-term cardiovascular risk, particularly in cases of modest increase at a young age. Only a few studies have reported the age-dependent association of lipids and cardiovascular disease with focus on young individuals.The risk circle tool displays the individual lifetime risk of non-fatal and fatal cardiovascular disease by the age of 75 years that is associated with non-HDL cholesterol and is specific for the burden of age, sex, and risk factor. It also estimates the corresponding risk reduction from lipid-lowering therapies. The risk scores currently used for decision making about lipid-lowering intervention assess only the 10-year cardiovascular riskThe following limitations merit consideration. First, due to the population-based longitudinal study design, the endpoint information is mainly based on medical reports or local registers and we cannot exclude misclassification of endpoints for some of the observed effects. However, endpoint information was harmonised on the basis of individual data according to the specification of the MORGAM study, and multivariable analyses were adjusted for potential confounders. Therefore, the best achievable data quality can be assumed for the current analyses. Second, only baseline data of blood lipids were available for current analyses. No information about dynamic changes during follow-up or about the initiation of lipid-lowering therapy, particularly in those individuals with very high blood concentrations, could be considered.This online publication has been corrected. The corrected version first appeared at thelancet.com on December 6, 2019


The progression of liver fibrosis in chronic hepatitis B (CHB) patients is currently insufficiently controlled worldwide. The Yi Guan Jian decoction (YGJD) has been widely used in the treatment of liver fibrosis in CHB cases. Although animal studies have reported the antifibrotic effects of the decoction, the active ingredients of the YGJD remain unknown. This study aimed at identifying the potential active ingredients and exploring the mechanisms of action (MOA) of the decoction when treating CHB patients with fibrosis. In vitro validation, including a cell proliferation assay and Western blot analysis, was conducted to evaluate the prediction results.  Using data mining techniques and a structural clustering analysis, the potential active ingredients were determined. A network analysis of the differentially expressed genes was conducted to identify the potential targets. Selected compounds were docked to the potential targets for the compound-target interaction simulation.  In the microarray data, 224 differentially expressed genes related to liver fibrosis were considered to be potential targets. Thirty active ingredients of the YGJD and 15 main targets and relevant pathways were identified. Among them, two active ingredients, methylophiopogonone A and 8-geranyloxypsoralen, were validated as exhibiting antifibrotic effects on hepatic stellate cells.  We identified the potential active ingredients of the YGJD and proposed the possible explanation for the MOA in the treatment of CHB patients with liver fibrosis. Moreover, this study provides a methodological reference for the systematic investigation of the bioactive compounds and related MOA of a traditional Chinese medicine formula in a clinical context. Indeed, the World Health Organization has estimated that some 257 million people are infected with the HBV globally, with the virus having been associated with nearly one million deaths in 2015 alone, mainly due to complications such as cirrhosis and liver cancer [Due to the issues associated with mainstream treatments, the use of herbal products as a form of complementary medicine has long been widely practiced in Asian countries. In China, over 90% of chronic hepatitis B (CHB) patients received the traditional Chinese medicine (TCM) therapy . StudiesRehmannia glutinosa), Glehniae Radix , Ophiopogonis Radix (Ophiopogon japonicus), Angelica Sinensis Radix (Angelica sinensis), Lycii Fructus (Lycium barbarum), and Toosendan Fructus (Melia toosendan). Three possible mechanisms of action (MOA) have been suggested for the antifibrotic effects of the YGJD: first, the inhibition of hepatic stellate cell (HSC) activation and hepatocytes apoptosis [α/VEGF signaling pathway [As a TCM formula listed in the “Catalogue of Classical TCM Prescriptions” issued by the State Administration of TCM of the People's Republic of China, the Yi Guan Jian decoction (YGJD) is known to have hepatoprotective effects . The YGJpoptosis ; second, pathway ; and fin pathway . HoweverIn clinical practice involving TCM, the YGJD has been widely used as a basic formula in the treatment of liver-kidney Yin deficiency syndrome (LKYDS) in patients with CHB . LKYDS iin vitro experiments, to analyze the collected data. The research roadmap is shown in To achieve the abovementioned research aims, this study gathered relevant bioinformatic data concerning both the YGJD and CHB patients with LKYDS. Further, the study comprehensively employed various methods of analysis, including network pharmacology , microarThe relevant chemical information concerning the YGJD was retrieved from four TCM databases in December 2017, including the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) , the Her2 [We used the two parameters proposed by Veber for the preliminary screening of the collected compounds. Veber's filter was used for the oral bioavailability prediction , which m2 . FurtherThe ChemmineR package run in Rstudio was used to compute the fingerprints and the Tanimoto coefficients among the compounds. The obtained cross-similarity matrix was subsequently applied to build the structural similarity network of the compounds with Tanimoto coefficients ≥0.6 . The MCOp value <0.05. The collected genes were then submitted to the STRING database to establish the protein-protein interaction (PPI) network, while the edges with confidence scores greater than 0.7 were retained for further analysis.The microarray data concerning the leukocyte samples obtained from three CHB patients with LKYDS and three healthy donors were provided by the Research Center for TCM Complexity System, Shanghai University of TCM . The difThe liver fibrosis-related genes were collected from DisGeNET. Using the search term of “Fibrosis, Liver” (UMLS CUI: C0239946), a total of 354 genes were selected from among the results. The CHB with LKYDS genes that exhibited high correlations (a confidence score greater than 0.9 in the STRING database) with the liver fibrosis-related genes were considered to be potential targets for the YGJD. PPI network analysis via pathway enrichment and topological parameter calculation was performed to verify the importance of the potential targets [3. To eliminate any bias caused by the properties of the protein pockets, all the docking scores for each protein were normalized by the median number, as shown in equation  network and the compound-target-pathway (C-T-P) network for the YGJD in the treatment of fibrosis caused by CHB. Two main parameters, namely, the degree centrality (DC) and the betweenness centrality (BC), were used to determine the key nodes in the network . The pat2.The LX-2 immortalized human hepatic stellate cell line was purchased from the Type Culture Collection of the Chinese Academy of Sciences  . The celT and C refer to the absorbance of the treatment group and the control group, respectively.After being seeded overnight in 96-well plates with DMEM containing 2% FBS, the LX-2 cells were treated with serially diluted compounds for 24 h, 48 h, and 72 h. The cell number was measured by means of a Cell Counting Kit-8  assay. The absorbance was monitored at 450 nm using a microplate reader (PE Envision). Further, the viability percentage was calculated using the following equation:α-smooth muscle actin (α-SMA) in the LX-2 cells was determined by means of Western blot analysis. The LX-2 cells were treated under different conditions with the active ingredients in 5 ng/mL of TGF-β1 for 24 h. The lysates of the denatured cells were separated on NuPAGE 4–12% Bis-Tris gel (Thermo Fisher Scientific), and the proteins were transferred to Hybond ECL membranes . The membranes were incubated overnight at 4°C with the primary antibodies against collagen type I (Abcam), α-SMA (Abcam), and β-actin (Sigma) as the endogenous controls, followed by the corresponding secondary peroxidase-coupled antibodies (Sigma). After the chemiluminescence had been enhanced , the digital detection was evaluated using Image Lab Software .The cellular content of the collagen I and the A total of 836 compounds contained within the YGJD were acquired from the databases, with 526 being predicted to exhibit better oral bioavailability. A structural similarity network was constructed to identify the representative compounds among the 526 ingredients . The netAccording to the theory of structure-activity relationship, structurally similar compounds tend to perform similar biological activities . The repThe CHB with LKYDS genes were mapped by means of analyzing the microarray data concerning the CHB with LKYDS patients who had been diagnosed by senior TCM doctors at the Shanghai Longhua Hospital. A PPI network for the differently expressed genes was constructed . In ordeTo verify the importance of the selected targets, the different gene sets were subjected to a pathway enrichment analysis  and a toThe selected compounds from The ROC curve presented in The C-T network consisted of selected compounds and their respective targets, as visualized in The C-T-P network was constructed  to furthThe BC was used to measure the importance of the targets within the C-T-P network. Those targets with high BC scores were the intermediaries that controlled the flow of interactions within the network. Based on the BC score, the top 15 targets, which are listed in Next, based on the C-T-P network, we calculated the shortest paths from the active ingredients to each pathway. By ranking the scores for this indicator, the key biological pathways influenced by the YGJD were identified. The top ten pathways included MAPK signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, hepatitis C, endocytosis, PI3K-Akt signaling pathway, hepatitis B, metabolic pathways, chemokine signaling pathway, and osteoclast differentiation. Details concerning these key pathways are provided in In the 30 active ingredients in α-SMA, were determined by means of Western blot analysis after the cells were treated with the compounds for 24 h. As shown in β1-induced collagen I and α-SMA expression.Additionally, two of the main markers of HSC activation, namely, collagen I and The YGJD is an herbal formula that is widely used in clinical practice involving TCM for the treatment of CHB patients with LKYDS, a syndrome known to be related to liver fibrosis. Modern pharmacological studies have confirmed the antifibrotic and anti-inflammatory effects of YGJD . In thisN-p-coumaroyltyramine from Ophiopogonis Radix, 8-geranyloxypsoralen from Glehniae Radix, and sitogluside from Rehmanniae Radix were all reported to be involved in anti-inflammatory activities [β1 and collagen levels [For the 30 active ingredients predicted by our method, some have been reported to exhibit effects against liver fibrosis. Diosgenin from Ophiopogonis Radix and levistolide A from Angelica Sinensis Radix were observed to inhibit the HSC activation and proliferation , 33. Luptivities –39. In an levels , 41. ThuInterestingly, 17 of the 30 active ingredients were found to belong to 57 representative compounds in κB p65), which has previously been reported to be downregulated in YGJD treatment [α1(I) collagen, a key part of the ECM in fibrosis, via the p38 MAPK signaling pathway [To reveal the MOA of the YGJD in relation to the effective treatment of CHB patients with liver fibrosis, the main targets and the relevant pathways were obtained using the C-T-P network analysis. The findings reported in the literature regarding these principal targets support the suggestion that the YGJD attenuated or even reversed the progression of liver fibrosis among CHB patients using three main approaches. The first approach was the inhibition of the fibrosis-related HSC activation and proliferation. RELA (also known as nuclear factor-reatment , was foureatment . Additioreatment . Furtherreatment . HGS migreatment . The secreatment . Moreove pathway . The thi pathway . Further pathway . All of The key pathways were also confirmed to be involved in the above-mentioned three approaches accordingly. The MAPK signaling pathway and the PI3K-Akt signaling pathway both played an important role in the entire pathological process of liver fibrosis. Moreover, it was found that the active substances targeting the two pathways could hinder the HSC activation and exert an antifibrotic effect , 51. CytHowever, a research limitation should be noted. In this study, only two active ingredients were verified to exhibit antifibrotic effects on the HSC by significantly inhibiting the cell proliferation. Further animal experiments and clinical trials on the two ingredients and more potential active ingredients may be performed to explore the scientific nature of YGJD.in vitro. And almost half of the active ingredients have been reported to have antifibrotic or anti-inflammatory effects.This study predicted 224 potential targets for treating CHB-caused liver fibrosis using microarray data analysis and PPI network analysis and also identified 278 candidates of active ingredients of YGJD through network cluster analysis. The interaction between the compounds and potential targets was revealed by molecular docking analysis and led to a total of 30 active ingredients. Among these active ingredients, methylophiopogonone A and 8-geranyloxypsoralen were found to inhibit HSC proliferation in LX-2 cells As for the MOA, fifteen genes related to the liver fibrosis caused by the CHB were predicted to be the main targets of YGJD. Literature findings regarding these main targets support YGJD attenuated or even reversed the progression of liver fibrosis among CHB patients by inhibiting fibrosis-related HSC activation and proliferation via RELA, EGFR, OCRL, INPP5B, and HGS, preventing excessive ECM deposition via FN1, JUN, FOS, and MAPK12, and regulating inflammatory response to HBV by regulating both IL-1B and IFNA1. Furthermore, the network analysis revealed the pathways involved in the YGJD treatment, including MAPK signaling, PI3K-Akt signaling, cytokine-cytokine receptor interaction, Toll-like receptor signaling, endocytosis, and metabolism pathway.In summary, we identified the active ingredients in the YGJD and proposed the possible MOA for the YGJD in the treatment of liver fibrosis among CHB patients. Our study not only provided a direction for the development of new drugs to treat liver fibrosis in CHB patients, but also offered an alternative approach for the systematic investigation of the MOA of a TCM formula by using the YGJD as an example.


The benefits of six months exclusive breastfeeding are well established for both mother and infant. One of the 10 steps of the Baby Friendly Hospital Initiative is rooming-in . A Cochrane review found only one randomised controlled trial (RCT) examining the effects of continuous rooming-in versus nursery care on breastfeeding duration, and concluded there was insufficient evidence to support or refute either practice. We aimed to examine the effect of continuous or intermittent rooming-in on breastfeeding duration.We included all prospective controlled studies (randomised and non-randomised) comparing rooming-in to nursery care that reported full or partial breastfeeding up to six months. We used the 2016 search results of the Cochrane review and updated the search to August 2018 using OVID MEDLINE. Duplicate data extraction and assessment of risk of bias were performed. Meta-analyses were performed using REVMAN 5. The GRADE approach was used to assess quality of evidence.Seven studies were included, five had 24-hour-per-day, one daytime only and one 8-hours-per-day rooming-in. Four studies had at least one additional co-intervention: Differences in delivery room management, and educational packages.All studies contributing to meta-analyses had 24-hour rooming-in. There was no difference in the proportion of infants on full breastfeeding at 3 months , 4 months  and 6 months . The proportion of infants on partial breastfeeding at 3–4 months was higher with rooming-in .The addition of non-randomised prospective controlled studies to existing evidence did not add further information on the effects of rooming-in on breastfeeding duration but resulted in lower quality of evidence. Uncertainty about the effects of rooming-in on breastfeeding duration remains. Breastfeeding is well known for its numerous benefits to both mothers and babies . The WorThe recent update of the Cochrane Review, “Rooming-in for new mother and infant versus separate care for increasing the duration of breastfeeding”, (August 2016) , found nThe Cochrane authors chose to include only studies with 24-hours-per-day rooming-in thus making assumption that any rooming-in less than 24 hours per day would not provide breastfeeding protection. However, this notion has been queried and has been described as a rigid, oppressive and compulsory hospital routine . For exaWe postulated that by including non-randomised prospective controlled studies and studies with intermittent rooming-in as well as continuous rooming-in might provide additional information and contribute to the body of knowledge on the effect of rooming-in on breastfeeding outcomes. Therefore, the objective of this systematic review is to examine the effect of rooming-in of any duration (continuous or intermittent) compared with nursery care on breastfeeding outcomes on both primiparas and multiparas by including prospective controlled studies of any design.Apart from the change in the inclusion criteria and breastfeeding definition, we followed the protocol of the Cochrane review .We included all prospective controlled studies examining the effect of any duration of rooming-in (continuous or intermittent) during hospital stay compared with nursery care that reported breastfeeding outcomes.We excluded studies that only examined rooming-in practices in the delivery room or after hospital discharge, and studies that did not report any breastfeeding outcomes.We defined continuous rooming-in as placing mother and baby in the same room next to each other for 24 hours per day, soon after leaving the delivery room until hospital discharge. Intermittent rooming-in means mothers practiced rooming-in with intermittent separation such as separation at night time. We defined nursery care as placing mother in a postnatal ward while baby was placed in a separate nursery. For nursery care, a mother may have had access to the nursery to feed her baby or alternatively, her baby could be brought to her for feeding.We followed the breastfeeding definition of Labbok et al. . Our priExclusive breastfeeding means that breastmilk and nothing else is given to the baby . Almost We also reported the following breastfeeding related outcomes if they were reported in the included studies: breastfeeding frequency, maternal confidence in breastfeeding, satisfaction in breastfeeding, bonding between mothers and babies, as well as maternal and infant adverse events such as infection in infants, infant crying episodes and maternal wound breakdown, puerperal sepsis, fainting episodes, postpartum haemorrhage.The original search was done on the 30th May 2016 by the Cochrane Pregnancy and Childbirth Group. The results of the search are published in the Cochrane review. We obtained the results of the search from the authors of the Cochrane Review. We updated the search by searching only OVID MEDLINE using the search strategy from the Cochrane Pregnancy and Childbirth Group . We limiWe used the standard Cochrane methods for selection of studies, and data extraction . DecisioWe assessed risk of bias using the following domains: selection bias , blinding (study personnel and outcome assessors), attrition bias, reporting bias and other biases. We classified each of the domains as low, high, or unclear risk of bias as described in the Cochrane handbook .Finally, for the primary outcome, we assessed the overall quality of evidence by using GRADE approach developed by GRADE working group .We entered the data into REVMAN 5 software. Dichotomous breastfeeding outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). Meta-analysis was performed using Mantel-Haenszel fixed effect model.2 and Chi2 statistics. We regarded heterogeneity as substantial if I2 was greater than 30% or if there was a low P value (less than 0.10) in the Chi2 test for heterogeneity. If heterogeneity was found, we attempted to explore the reasons.We tested for statistical heterogeneity in each meta-analysis using the IIn an attempt to explain any heterogeneity we intended to perform a limited number of subgroup analyses and we chose the subgroup analyses stated in the Cochrane Review , which wWherever possible we analysed outcomes on an intention-to-treat basis.We planned a sensitivity analysis for the primary outcomes by trial quality (RCT versus NRSs) but we did not do this because there was only one RCT  in the mOf the seven prospective controlled studies included in this systematic review, two were RCTs , 44, fivFour studies had more than two arms , 33, 35.Details of the assessment of risk of bias of the included studies is shown in We combined the outcomes of exclusive and almost exclusive breastfeeding and analysed the proportion of infants on full breastfeeding. Four studies , 33, 42 2 0%; very-low-quality evidence)  breastfeeding at three months of age  . We down2 0%; very-low-quality evidence)  breastfeeding at four months of age  . We downWe found no difference in proportion of infants on full breastfeeding at six months of age  . We downFor subgroup analysis by parity (primiparous and multiparous), we found no difference between the groups for full breastfeeding at all 3 time points.2 22%; very-low-quality evidence). We downgraded the quality two levels for very serious study limitations (3 studies were non-randomised prospective controlled studies) and one level for concerns about indirectness .Three studies , 33, 35,2 = 0%. One study did not report the parity. On subgroup analysis of primiparous and multiparous (excluding the study with parity not stated), we found no difference between the primiparous group and multiparous group as well, chi-square = 0.39, I2 = 0%.On subgroup analysis we found no difference between the subgroups by parity , RR for primiparous group 1.29,  and RR for multiparous group 0.98 , chi-square test for subgroup differences was 1.75, IThree studies reported frequency of breastfeeds during hospitalisation , 32, 35.There was no difference between the groups in self-reported breastfeeding problems in Greenberg et al.  Click here for additional data file.


Tuberculosis treatment failure results in increased risk of morbidity, drug resistance, transmission and mortality. There are few data about tuberculosis treatment outcomes in Burkina Faso. The current study investigated the factors associated with tuberculosis treatment failure in the central east health region of Burkina Faso.We conducted a case-control study. All cases of pulmonary tuberculosis failing first-line treatment matched to those who were cured (controls) in the Central Eastern Region were sampled from January 2010 to December 2014. Predictors of treatment failure were determined using multiple conditional logistic regression.A total of 381 patients with positive microscopic pulmonary tuberculosis were included. Of these 76 cases failed first-line treatment while 305 controls were cured. Weight loss between diagnosis and first sputum-smear examination was significantly associated with the tuberculosis treatment failure . In addition, the delay from between treatment initiation to first sputum-smear examination, and high bacillary load at the first sputum-smear examination were significantly associated with treatment failure (p<0.001).Strengthening the relationship between health care services and local communities to improve the follow-up of tuberculosis patients, and improving adherence to tuberculosis treatment among tuberculosis patients with weight loss between treatment initiation and 2-month sputum-smear examination could be useful to reduce the risk of unsuccessful outcome. Worldwide, Tuberculosis (TB) remains a major public health problem. In 2014, the World Health Organization (WHO) estimated that 28% of all TB cases were recorded from Africa although unevenly distributed throughout the region . DespiteSetting: Our study was conducted in the central-eastern health region of Burkina Faso. In 2014, the Central-Eastern health region composed of seven health districts , including 159 primary health-care and 6 secondary health care centres. Its population was estimated at 1,384,663. In that same year, the incidence of tuberculosis and relapse cases were 24 per 100,000 population ) [ZE/4RH]) .Study design and population: We conducted a case-control study among bacteriologically confirmed pulmonary TB patients treated in the eastern-central health region of Burkina Faso from January 2010 to December 2014. Cases and controls were matched individually by age and sex. A case was defined as a patient with a new bacteriologically confirmed pulmonary TB aged more than 15 years with TB treatment failure. Treatment failure has been defined as a TB patient whose sputum smear examination is positive at month 5 or later during TB treatment. A control was a patient with a new bacteriologically confirmed pulmonary TB who successfully completed treatment (sputum-smear examination negative at 5-month and 6-month of treatment). To increase the power of our study, we matched each case to 4 controls. The controls were selected randomly in the same sex group and in age group-interval of 5 years.Data collection: The data were extracted from three registries at the regional tuberculosis diagnostic and treatment centres . The demographics and parameters collected sampled from the registry for each patient included: age when the individual was diagnosed with TB, sex, occupation, distance from patient's home to the closest primary health facility, distance from patient's home to the closest TB diagnosis and treatment care facility, type of directly observed treatment (DOT) centre, weight at diagnosis, weight at 2-month sputum-smear examination, results of 2-month and 5-months sputum-smear examination, bacillary load at diagnosis and at 2-month sputum-smear examination, HIV status.Statistical analysis: We described the characteristics of our study population. Categorical variables were compared by Mac-Nemar χ² tests or the Cochran Mantel-Haenzel χ² test. Quantitative variables were compared by the student t test for paired variables. Conditional logistic regression was used to identify factors associated with TB treatment failure. The outcome variable was “TB treatment failure” (case/control). Independent variables associated with TB treatment failure at 30% threshold in the univariate analysis were included in the multivariate analysis model. The final model was obtained by a manual stepwise descending approach. A P-value < 0.05 was considered as significant. Multivariate analysis was adjusted on HIV status to account for its potential confounding effect. All analysis were done with R .Ethical approval: This study was authorized by the Central Eastern Regional Health Director who sent an information letter to all Medical District Officers and to the Director of the Regional referral hospital. The questionnaires did not mention patient's name to assure the anonymity of the patient.Characteristics of the study population: A total of 381 cases with bacteriologically confirmed pulmonary TB were included. Of these, 76 were cases of TB treatment failure and 305 were controls (cured) ( (cured) . The med (cured) . This pr (cured) . HIV co-Univariate analysis: Four variables were associated with TB treatment failure at the threshold of 30%. These variables were weight at diagnosis, change in patient weight between diagnosis and first sputum-smear examination, time from treatment initiation to first sputum-smear examination and bacillary load at first sputum-smear examination  and on the other hand the poor application of the directly observed treatment. These findings underlined the need to strengthen laboratory capacity and to improve collaboration with community health workers to monitor treatment. Unlike findings reported in some studies , 21, ourStrengths and limitations of the study: Our study has some limitations. Data for treatment outcomes were available only for patients who underwent smear tests. Therefore, cases and controls are probably not representative of all cases of TB patients treated in the entire Central Eastern health region over the study period. Moreover, the retrospective nature of data collection was accompanied with large number of missing data. In addition, confounder variables such as discontinuation of treatment, antiretroviral therapy for TB/HIV co-infected patients, comorbidities  could not be collected. These factors may influence adherence and therefore the effect of the TB treatment. Height was not reported and therefore it was impossible to study the association between the Body Mass Index (BMI) and TB treatment failure. Despite these limitations, our study is the first to use programmatic tuberculosis data from an overall health region in Burkina Faso to identify factors associated with TB treatment failure.Weight loss from the initiation of TB treatment to the first sputum-smear examination, delay in 2-month sputum-smear examination and the high bacillary load at 2-months smear examination were determinants of first line anti-tuberculosis treatment failure. The Improvement of tuberculosis patient's outcomes in East Health Region of Burkina Faso requires strengthening collaborative strategies with community health workers in TB treatment monitoring. A strategy of systematic research for drugs resistant tuberculosis and non-mycobacterium tuberculosis in any new case of tuberculosis with a decrease in weight between the treatment initiation and the 2-month sputum-smear examination could improve treatment outcomes. For effective monitoring in co-infected patients, integration of tuberculosis and HIV care services is necessary. There is an urgent need to actively monitor cases of TB treatment failure in Burkina Faso in order to achieve the goals of the End-TB strategy by 2035.Lack or poor adherence to TB drugs predisposes patients to treatment failure.In the context of Burkina Faso, a weight loss after TB treatment initiation, delay in the 2-mont sputum-smear examination, and a high bacillary load at the 2-month sputum-smear examination were predictors of TB treatment failure. These factors could be identified early and reinforcement of treatment adherence could be implemented to improve TB treatment outcomes. There is an urgent need for the national tuberculosis control program to make available bacilloscopy examination tests according to the requirement of the scheduled protocol.The authors declare no competing interests.


Single-photon lidar has emerged as a prime candidate technology for depth imaging through challenging environments. Until now, a major limitation has been the significant amount of time required for the analysis of the recorded data. Here we show a new computational framework for real-time three-dimensional (3D) scene reconstruction from single-photon data. By combining statistical models with highly scalable computational tools from the computer graphics community, we demonstrate 3D reconstruction of complex outdoor scenes with processing times of the order of 20 ms, where the lidar data was acquired in broad daylight from distances up to 320 metres. The proposed method can handle an unknown number of surfaces in each pixel, allowing for target detection and imaging through cluttered scenes. This enables robust, real-time target reconstruction of complex moving scenes, paving the way for single-photon lidar at video rates for practical 3D imaging applications. The use of single-photon data has been limited by time-consuming reconstruction algorithms. Here, the authors combine statistical models and computational tools known from computer graphics and show real-time reconstruction of moving scenes. While geometric and reflectivity information can be acquired using many scanning modalities , single-photon systems have emerged in recent years as an excellent candidate technology. The time-correlated single-photon counting (TCSPC) lidar approach offers several advantages: the high sensitivity of single-photon detectors allows for the use of low-power, eye-safe laser sources; and the picosecond timing resolution enables excellent surface-to-surface resolution at long range (hundreds of metres to kilometres)6. Recently, the TCSPC technique has proved successful at reconstructing high resolution three-dimensional images in extreme environments such as through fog7, with cluttered targets8, in highly scattering underwater media9, and in free-space at ranges greater than 10 km6. These applications have demonstrated the potential of the approach with relatively slowly scanned optical systems in the most challenging optical scenarios, and image reconstruction provided by post-processing of the data. However, recent advances in arrayed SPAD technology now allow rapid acquisition of data11, meaning that full-field 3D image acquisition can be achieved at video rates, or higher, placing a severe bottleneck on the processing of data.Reconstruction of three-dimensional (3D) scenes has many important applications, such as autonomous navigation13 propose a hierarchical Bayesian model and compute estimates using samples generated by appropriate Markov chain Monte Carlo (MCMC) methods. Despite providing robust 3D reconstructions with limited user supervision , these intrinsically iterative methods suffer from a high computational cost . Faster alternatives based on convex optimisation tools and spatial regularisation, have been proposed for 3D reconstruction16 but they often require supervised parameter tuning and still need to run several seconds to minutes to converge for a single image. A recent parallel optimization algorithm17 still reported reconstruction times of the order of seconds. Even the recent algorithm18 based on a convolutional neural network (CNN) to estimate the scene depth does not meet real-time requirements after training.Even in the presence of a single surface per transverse pixel, robust 3D reconstruction of outdoor scenes is challenging due to the high ambient (solar) illumination and the low signal return from the scene. In these scenarios, existing approaches are either too slow or not robust enough and thus do not allow rapid analysis of dynamic scenes and subsequent automated decision-making processes. Existing computational imaging approaches can generally be divided into two families of methods. The first family assumes the presence of a single surface per observed pixel, which greatly simplifies the reconstruction problem as classical image reconstruction tools can be used to recover the range and reflectivity profiles. These algorithms address the 3D reconstruction by using some prior knowledge about these images. For instance, some approaches21. In this context, 3D reconstruction is significantly more difficult as the number of surfaces per pixel is not a priori known. The earliest methods21 were based on Bayesian models and so-called reversible-jump MCMC methods (RJ-MCMC) and were mostly designed for single-pixel analysis. Faster optimisation-based methods have also been proposed19, but the recent ManiPoP algorithm20 combining RJ-MCMC updates with spatial point processes has been shown to provide more accurate results with a similar computational cost. This improvement is mostly due to ManiPoP’s ability to model 2D surfaces in a 3D volume using structured point clouds.Although the single-surface per pixel assumption greatly simplifies the reconstruction problem, it does not hold for complex scenes, for example with cluttered targets, and long-range scenes with larger target footprints. Hence, a second family of methods has been proposed to handle multiple surfaces per pixel22. We extend and adapt the ideas of plug-and-play priors25 and regularisation by denoising27, which have recently appeared in the image processing community, to point cloud restoration. The resulting algorithm can incorporate information about the observation model, e.g., Poisson noise28, the presence of hot/dead pixels30, or compressive sensing strategies32, while leveraging powerful manifold modelling tools from the computer graphics literature. By choosing a massively parallel denoiser, the proposed method can process dozens of frames per second, while obtaining state-of-the-art reconstructions in the general multiple-surface per pixel setting.Here we propose a new algorithmic structure, differing significantly from existing approaches, to meet speed, robustness and scalability requirements. As in ManiPoP, the method efficiently models the target surfaces as two-dimensional manifolds embedded in a 3D space. However, instead of designing explicit prior distributions, this is achieved using point cloud denoising tools from the computer graphics community28 that the incoming light flux incident on the TCSPC detector is very low, the observed photon-counts can be accurately modelled by a linear mixture of signal and background photons corrupted by Poisson noise. More precisely, the data likelihood which models how the observations A lidar data cube of mentclass2pt{minimAssuming mutual independence between the noise realizations in different time bins and pixels, the negative log-likelihood function associated with the observations 33, computing proximal gradient steps on the blocks of variables 34. While the gradient step takes into account the single-photon lidar observation model , the denoising step profits from off-the-shelf point cloud denoisers. A summary of each block update is presented below, whereas an in-detail explanation of the full algorithm can be found in  , the execution time of the proposed method only incurs a small overhead cost while significantly improving the reconstruction quality of single-photon data. The performance of the algorithm was also validated in other raster-scanned scenes . Minimal operating conditions  are discussed in  to exploit the parallel structure of the update rules. Both the initialisation  as the source for the flood illumination of the scene of interest. This had a central wavelength of 1550 nm and a spectral full width half maximum (FWHM) of ~9 nm. The output fibre from the laser module was connected to a reflective collimation package and the exiting beam then passed through a beam expander arrangement consisting of a pair of lenses. The lenses were housed in a zoom mechanism that enabled the diameter of the illuminating beam at the scene of interest to be adjusted to match the field of view of the camera  was attached to the camera to collect the scattered return photons from the scene. This resulted in a field of view of ~0.5 arc degrees. As these measurements were carried out in broad daylight, a set of high performance passive spectral filters was mounted between the rear element of the lens and the sensor of the camera in order to minimise the amount of background light detected.Our optical setup was a bistatic arrangement—the illuminating transmit channel and the collecting receive channel had separate apertures, i.e., the two channels were not co-axial. This configuration was used in order to avoid potential issues that could arise in a co-axial (monostatic) system due to back reflections from the optical components causing damage to the sensitive focal plane array. The parallax inherent in the bistatic optical configuration meant that a slight re-alignment of the illumination channel, relative to the receive (camera) channel, was required for scenes at different distances from the system.Supplementary InformationPeer Review FileDescription of Supplementary InformationSupplementary Movie 1Supplementary Information


There are racial/ethnic disparities in breast cancer mortality may be attributed to differences in receipt of adjuvant cancer treatment. Our purpose was to determine whether the mortality disparities could be explained by racial/ethnic differences in long-term adherence to adjuvant endocrine therapy (AET).We conducted a retrospective cohort study with the Texas Cancer Registry and Medicaid claims-linked dataset of women (20-64 years) diagnosed with local and regional breast cancer who filled a prescription for AET from 2000-2008. Adherence to AET was measured at three time points  using a value for the percentage of medication filled for each period divided by the total number of possible prescriptions prescribed . We created a binary variable of adherence (MPR≥80%). We performed multivariable logistic regressions to assess racial differences for the odds of AET adherence and Cox proportional hazard models to determine the risk of mortality adjusting for potential confounding variables of SES, comorbidities, tumor prognostic factors, and other cancer treatment.Of the 1,497 women with breast cancer who initiated AET, 56.9%, 42.3%, and 33.3% were adherent for 1, 3, and 5-years, respectively. Hispanics compared to non-Hispanic whites did differ in the proportion that were adherent to 5-years of AET. In the adjusted analysis for long-term adherence to AET, Hispanics did not have a significantly increased risk of death compared to non-Hispanic white patients . However, black compared to non-Hispanic white patients had significantly lower odds of three-year adherence . After controlling for 5-year adherence to AET, the risk of death for black compared to non-Hispanic white patients was 12% lower  and in the fully adjusted model, the disparity was reduced and no longer significant .Long-term adherence in the Medicaid population is suboptimal and racial/ethnic differences in AET adherence may partially explain disparities in mortality. This study underscores the critical need to ensure long-term adherence to AET for all racial/ethnic groups to decrease disparities in mortality. Minorities with breast cancer have an increased risk of breast cancer death than non-Hispanic whites –4. TheseThe National Comprehensive Cancer Network (NCCN) recommends women with hormone receptor-positive breast cancer receive five-years of treatment with either tamoxifen if women are premenopausal or an aromatase inhibitor  or tamoxifen if they are postmenopausal , 15. WhiOther factors associated with poor adherence include the presence of chronic conditions , age at Moreover, poor adherence to AET is associated low socioeconomic status , 27. In Women with breast cancer aged 20-64 who initiated AET within 1.5 years after the date of cancer diagnosis were identified from Texas Cancer Registry-Medicaid linked database (TCR-Medicaid database) from 2000-2007. Medicaid claims data were available through December 31, 2008  over each of the three time periods  –35. PatiAll-cause mortality was defined as dead (of any causes). Patients who were alive at the last follow-up of vital statistics  were censored. The mean and median follow-up time from breast cancer diagnosis until the end of the study period or death of the one-year adherence cohort in this study were 2,229 days and 580 days ; of the three-year adherence cohort in this study were 2,678 days and 2,650 days ; of the five-year adherence cohort in this study were 3,188 days and 3,167 days .We created a single measure for race/ethnicity as identified in Texas Medicaid enrollment file as Non-Hispanic White, Non-Hispanic Black, Hispanic, and other (including Asian or missing race/ethnicity). We included categorical county-level variables for the proportion of the population living below the federal poverty level, median income, and the number of direct primary care (DPC) physicians per 100K population. These variables were categorized into tertiles and based on the 2000 US Census linked to the dataset. Geographic region variables were included and based on the location where patient lived at the time of diagnosis along the Texas-Mexico Border (Yes/No) based on 3-digit county Federal Information Processing Standard (FIPS) codes. These codes were also used to determine whether patients resided in counties that were metropolitan regions or non-metropolitan regions including urban and rural areas based on the US Census Rural-Urban Continuum Codes.Categorical tertiles for age groups and the number of chronic conditions were included as patient characteristics. We measured the number of comorbid conditions between 6 months before and 3 months after breast cancer diagnosis with a modified version of the Charlson comorbidity index (CCI) based on diagnostic and procedures codes described elsewhere –38. ClinDescriptive statistics were used to illustrate patient sociodemographic and clinical treatment and prognostic factors across the racial/ethnic groups. We examined the proportion of adherent patients (MPR≥80%) in the three adherence periods  across all variables. We ran three separate multiple logistic regression models to assess the association between race/ethnicity, geographic region, and AET adherence –35. Cox In the first cohort, there were 1,497 breast cancer patients with 1-year of continuous enrollment in the Texas Medicaid after the month of initiating AET. For patients with continuous enrollment for 3 and 5-years there were 718 and 300 patients, respectively. Table One-, three-, and five-year adherence to AET (MPR≥80%) were calculated in this study Table . A greatTable We found a significant impact of both short- and long-term adherence on survival Table . In the We also found racial/ethnic disparities in survival among breast cancer patients receiving AET Table . In the In the unadjusted model (model 1), Hispanic patients had a lower risk of mortality, for the cohort with complete adherence data available for 1-year, compared with Non-Hispanic White patients . However, Hispanics did not have significantly decreased risk of death compared to non-Hispanic white patients in the long-term cohorts .In this study of the Texas Cancer Registry and Medicaid-linked data set, we found that black patients compared to non-Hispanic white patients had significantly lower odds of 1- and 3-year adherence to AET. After adjusting for long-term adherence (5-years), the disparity in mortality between black and non-Hispanic white patients was 12% lower. This is an important finding since in this cohort of patients with comprehensive health coverage and no out-of-pocket costs for medication, adherence for the recommended 5-year period was suboptimal, where nearly two-third of patients did not complete recommended AET treatment.Prior studies that examined racial/ethnic differences in AET adherence are mixed and vary by insurance status, household income, and out-of-pocket costs for the medication. Studies among privately insured populations did not find significant differences in adherence by race/ethnicity , 43, 44,In our study, merely 33.3% of women were adherent to AET for the five-year recommended duration. Further, we found that 42.3% of patients were adherent to AET for three years. This is lower than previously reported. Partridge and colleagues measured long-term adherence at three years using similar claims-based methodology among non-elderly patients and reported 62–79% were adherent at three years  and New In this study, we found that black patients were not statistically more likely to die compared to non-Hispanic white patients after controlling for long-term adherence to AET and age. This is similar to our other finding using the SEER-Medicare dataset among an older publicly insured population . In thisWhile previous studies of AET patterns and outcomes used only medical claims or pharmacy data without details on tumor characteristics , 47, 48,Our study has some limitation. First, our study included women <64 years, continuously enrolled in Texas Medicaid that may have different enrollment eligibility criteria compared to other state-Medicaid programs, and with minority women who may have different life experiences than others throughout the United States. These factors may limit the generalizability of the study findings. Second, unmeasured confounding such as psychosocial factors or factors related to the quality of care women receive  could affect their use of AET but were not measured in this study . Third, About two-thirds of patients with who initiated AET were non-adherent to AET over the recommended five-year study period. AET adherence was independently associated with a significantly lower risk of all-cause mortality even after adjusting for all other treatment, clinical prognostic, and sociodemographic characteristics. After adjusting to 5-year adherence to AET, we did not observe racial/ethnic differences in all-cause mortality. The findings are novel because they emphasize the importance of improving the low rates of adherence among racial/ethnic minorities as a way to decrease racial/ethnic disparities in cancer mortality.