Falls impose significant health and economic burdens on older people. The volume of falls prevention economic evaluations has increased, the findings from which have been synthesised by systematic reviews (SRs). Such SRs can inform commissioning and design of future evaluations; however, their findings can be misleading and incomplete, dependent on their pre-specified criteria. This study aims to conduct a systematic overview (SO) to: (1) systematically identify SRs of community-based falls prevention economic evaluations; (2) describe the methodology and findings of SRs; (3) critically appraise the methodology of SRs; and (4) suggest commissioning recommendations based on SO findings.The SO followed the PRISMA guideline and the Cochrane guideline on SO, covering 12 databases and grey literature for the period 2003–2020. Eligible studies were SRs with 50% or more included studies that were economic evaluations of community-based falls prevention (against any comparator) for older persons (aged 60 +) or high-risk individuals aged 50–59. Identified SRs’ aims, search strategies and results, extracted data fields, quality assessment methods/results, and commissioning and research recommendations were synthesised. The comprehensiveness of previous SRs’ data synthesis was judged against criteria drawn from literature on falls prevention/public health economic evaluation. Outcomes of general population, lifetime decision models were re-analysed to inform commissioning recommendations. The SO protocol is registered in the Prospective Register of Systematic Reviews (CRD42021234379).Seven SRs were identified, which extracted 8 to 33 data fields from 44 economic evaluations. Four economic evaluation methodological/reporting quality checklists were used; three SRs narratively synthesised methodological features to varying extent and focus. SRs generally did not appraise decision modelling features, including methods for characterising dynamic complexity of falls risk and intervention need. Their commissioning recommendations were based mainly on cost-per-unit ratios  and neglected aggregate impact. There is model-based evidence of multifactorial and environmental interventions, home assessment and modification and Tai Chi being cost-effective but also the risk that they exacerbate social inequities of health.Current SRs of falls prevention economic evaluations do not holistically inform commissioning and evaluation. Accounting for broader decisional factors and methodological nuances of economic evaluations, particularly decision models, is needed.The online version contains supplementary material available at 10.1186/s12913-022-07764-2. An ageing population with increased prevalence of falls in older age  has made falls prevention a global public health priority . Falls cFalls prevention interventions have been found to be effective in reducing the number of falls and fallers in community settings –12. AccoThe rising volume of economic evaluations has been accompanied by systematic reviews of available evidence. For a well-formulated research question, a systematic review uses systematic and explicit methods to identify relevant studies, synthesise relevant extracted data, and critically appraise their quality , 14.Two central functions of systematic reviews of economic evaluations can be: (A) to inform commissioning decisions; and (B) to summarise and evaluate the methodological features of economic evaluation in a topic area. Related to (A), the reviews can aid commissioning decisions by summarising the evaluation results most applicable to the decision-making context and/or identifying existing decision models that can be adapted and re-used . In EnglRelated to (B), systematic reviews can detail and critically appraise methodological features that significantly affect the evaluation results such as the identification, measurement and valuation of all relevant costs and consequences and structural assumptions made by decision models , 18. TheA systematic overview uses explicit and systematic methods to identify previous systematic reviews in a topic area . It thusSystematically search for and identify previous systematic reviews of community-based falls prevention economic evaluations;Describe the methods and findings of previous systematic reviews, including their aim, search strategy and results, data extracted, quality assessment and commissioning and research recommendations;Critically appraise the methodology of previous systematic reviews and highlight areas of improvement for future systematic reviews;Suggest commissioning recommendations for falls prevention interventions based on syntheses of results and methodological quality of economic evaluations identified by systematic overview.The aim is to conduct a systematic overview of previous systematic reviews of community-based falls prevention interventions. The objectives are to:The systematic overview followed the Cochrane guideline on overview of reviews  and the The search covered the period between January 2003 and December 2020 and 12 academic databases: Medline, Embase, PubMed, CDSR, CENTRAL, EconLit, CINAHL, PsycInfo, ASSIA, CRD, CEA Registry and PEDro. Grey literature studies were searched from online sites of Department of Health, Chartered Society of Physiotherapy, College of Occupational Therapy, Royal College of Nursing and Age UK. The start date was chosen based on a background knowledge that the number of economic evaluations before 2003 is low . The seaTwo researchers independently reviewed the titles and abstracts of identified articles at the first stage and the full texts of approved article at the second stage. Those that received two second-stage approvals were included for data extraction. Another researcher arbitrated in case of disagreement.Included studies must have conducted a systematic review – i.e., involving the use of explicit, reproducible methodology, comprehensive search strategy and acceptable methods for data extraction and validity assessment of included studies by two or more researchers . AdditioFollowing the Cochrane guideline , the folAs recommended by the Cochrane guideline , the 16-The methodological quality of reviews was further critically appraised narratively. Specifically, the following guidelines and academic papers were used to establish what methodological features and outcomes of falls prevention economic evaluations should be extracted and analysed by the systematic reviews: (a) the expert guideline and checklist on conducting and reporting falls prevention economic evaluation ; (b) theThe results and methodological features were extracted from a subset of primary economic evaluations and re-analysed to inform the commissioning recommendations made by the systematic overview. Specifically, data were extracted from general population models (as opposed to models targeting specific patient groups) analysed over lifetime horizons since these are most informative for jurisdiction-level commissioning decisions on falls prevention , 29. SucFigure Aim, search strategy and search result.Table Overall, the reviews identified 44 economic evaluations of community-based falls prevention interventions, of which 21 were decision models. All SVEs except one  were evaData fields extracted by systematic reviews.Table Quality assessment of economic evaluations by systematic reviews.All reviews except RCN ; and problems with generalizability. The PHE review noted the main limitations of evaluations as perceived by the evaluation authors or reviewers but did not group them by themes. The Huter review narratively synthesised how evaluations handled the challenges of societal analysis, namely the incorporation of: (1) informal caregiving cost; (2) productivity cost; (3) unrelated cost in added life years; and (4) wider non-health effects. It was found that these challenges were handled in few evaluations; and when handled, were done using very heterogenous methods.Commissioning and research recommendations in systematic reviews.Table Scarce cost-effectiveness evidence from the UK setting prevented the RCN review from making commissioning recommendations. The Davis review recommended single-component Otago home exercise based on the most favourable cost-per-unit ratio. The DJ review reported three exercise interventions and a citywide multifactorial intervention that produced the lowest cost-per-unit ratios from ‘Good’ quality evaluations (those that received 90–100% Drummond checklist score). The PHE review based recommendations by intervention type on cost-per-unit ratios. The Olij review recommended HAM over exercise and multifactorial interventions for community-dwelling older persons based on incremental cost per QALY ratios under CUA. The Winser review listed the characteristics of an ideal exercise intervention based on those of interventions that yielded favourable cost-per-unit ratios. It also found that single-component exercises produced more favourable ratios than exercises within multifactorial interventions but called for further direct comparisons.For research implications, the RCN and PHE reviews determined that a de novo model is required to assist commissioning due to lack of current evidence. The Davis and Olij reviews recommended that future evaluations follow a validated guideline or checklist for economic evaluations. The Davis review later informed the development of the expert guideline/checklist for falls prevention economic evaluations . The HutTable Limitations acknowledged by the review authors included: limited search coverage –34; lackThe limited range of methodological features extracted from studies, particularly models; andThe limited range of evaluation outcomes extracted to inform commissioning.Two further limitations of systematic reviews can be noted by this systematic overview:The first limitation is made clear by comparing Tables The second limitation concerns the way in which reviews’ commissioning recommendations were based chiefly on cost-per-unit ratios without considering aggregate outcomes. For example, the Davis review recommended the Otago home exercise for population aged 80 + based on a single SVE result that the intervention produced a net cost saving . Yet anoAssuming that decision-makers overseeing a health jurisdiction  would prefer general population, lifetime evidence to capture the full health and economic impacts of falls for the whole jurisdiction rather than specific patient groups , 29, Tab1Concerning principle (I), two salient features emerge from Table Combined multifactorial and environmental intervention in Johansson (2008) with QALY gain and lower cost relative to usual care ;HAM in Pega (2016) with ICER of £5,123 per QALY if implemented for the whole population and £1,139 if targeted at those with history of falls requiring medical attention  ;A non-specific intervention in Farag (2015) of £420 per-participant cost and 25% reduction in falls risk with ICER of £17,320 per QALY [Tai Chi in Church (2012) with ICER of £27,734 per QALY .Four models that conducted CUA produced cost-per-unit ratios for at least one intervention relative to usual care that can be deemed cost-effective under the cost-effectiveness threshold of £30,000 per QALY gain . In theGiven the favourable ratios, a key decisional factor under principle (II) is the population reach of each intervention that determines its aggregate impact, as well as any budget and capacity constraints of the decision-maker. For example, it may be the case that Tai Chi enjoys a substantially greater uptake rate than HAM in the decision-making setting . In thiThe combined multifactorial and environmental intervention in Johansson (2008) potentially has the greatest reach since it addresses community-wide environmental risk factors (independently of demand by older people) as well as individually tailored treatments including Tai Chi and HAM. However, the model is based on evidence from a quasi-experimental study in a small community of 5,500 older people, and there is no supplementary evidence that it can be successfully implemented in other communities. Hence, the decision-maker should first consult local stakeholders to determine whether the intervention in Johansson (2008) can be scaled up within the budget and capacity constraints. Whether older people’s productivity is considered in the evaluation is another decisional factor since the outcome changes from dominance to ICER of £16,890 per QALY if net consumption cost in added life-years is included.and had the greatest population reach (65.8%) and hence should be the preferred option. However, there were two main methodological caveats. First, no assessment of parameter uncertainty was conducted despite the paucity of evidence for several model parameters . Secondly, the population reaches of interventions were not based on the characteristics of the simulated model population but imposed exogenously. For example, gait stabilising device was eligible only for mobile seniors without disability, and according to an external survey, this group comprised 65.8% of the general geriatric population. The study then simply assumed that 65.8% of health gains and costs accrue to this intervention subgroup. But the simulated model population were defined by age, sex and MA falls history, not mobility or disability, and hence the true reach of gait stabilising device is unknown. These caveats reduced the credibility of the reported results.OMAS (2008) was the only model to conduct CEA for five single-component interventions relative to usual care: exercise, HAM, vitamin D & calcium, psychotropics withdrawal, and gait stabilising device . All intworsens the health inequity between Maori and non-Maori . Though the specific ethnic divide is unique to New Zealand, the decision-maker may choose to generalise this case to predict the distribution of HAM impact across locally relevant gradient in social marginalisation. Having done so, commissioning can consider HAM strategies that do not exacerbate the existing health inequity – e.g., targeting the socially marginalised group – even at the expense of reduced cost-effectiveness. It should also consider using an evaluation method that estimates the joint equity-efficiency impact given the decision-makers’ level of inequity aversion [Another key decisional factor under principle (II) is equity consideration beyond cost-effectiveness. Here, only Pega (2016) disaggregated the evaluation results into social subgroups: female vs. male; and non-Maori majority vs. Maori ethnic minority in New Zealand. Male and Maori subgroups had higher ICERs than their respective counterparts, and gained less QALYs per person . Hence, universal HAM provision aversion . Similarhigher than that of non-Maori (0.071 vs. 0.060) and the ICERs become similar. Hence, the inequitable impact can be attributed mainly to the life expectancy differential between ethnic subgroups – though other potential causes of inequitable impact  cannot be investigated due to homogenous parameter assumptions across ethnic subgroups. This suggests that falls prevention commissioning should be complemented by upstream interventions at earlier life stages to correct the life expectancy differential that emerges at age 65.Pega (2016) also provides an insight into the underlying cause of inequitable subgroup impacts. A scenario analysis was conducted wherein the Maori subgroup is assigned the longer life expectancy of the non-Maori subgroup, and it was found that Maori’s QALY gain becomes It should also be noted that life expectancy differential exists between age subgroups. Indeed, Pega (2016) estimated an ICER of £8,956 per QALY gained relative to UC for those aged 75 + which was higher than the ICER of £5,123 per QALY gained for those aged 65 + , despite the former’s higher falls burden . But the ICER difference should not motivate the targeting of the younger age groups, particularly since both ICERs were comfortably below the £30,000 per QALY gained threshold. Such targeting would also go against the principles of healthcare systems such as those of the NHS and NICE , 51. YouThere is some evidence that combined multifactorial and environmental intervention, HAM and Tai Chi are cost-effective over the lifetime for general geriatric populations aged 65 + .The decision-maker should investigate the feasible reaches of the above interventions in the local setting within the budget and capacity constraints. The reaches concern the intervention’s population coverage and its sustainability over time. Commissioning of additional implementation support  can also be considered.There is some evidence that national provision of HAM exacerbates the existing health inequity across social subgroups, and this may generalise to the other two interventions. The decision-maker could consider targeting the intervention at socially marginalised groups or a universal provision supplemented by additional implementation support for the marginalised groups. Upstream interventions at early life stages can also supplement falls prevention to reduce the life expectancy differential between subgroups.There are methodological caveats that may significantly influence the model outcomes. The decision-maker could consider commissioning the development of a de novo general population, lifetime model that addresses the main methodological challenges, such as the dynamic complexity in falls risk profile and the psychological and sociological factors that influence the intervention reach and hence its aggregate impact.Overall, the commissioning recommendations of this systematic overview are as follows:This systematic overview identified seven systematic reviews containing 44 falls prevention intervention economic evaluations for older people living in community. The number of data fields extracted from studies differed markedly across reviews, ranging from eight to 33. Four checklists were applied by reviews, while narrative quality assessment was conducted at varying levels of detail and topic range. Commissioning recommendations were based primarily on cost-per-unit ratios. Research recommendations ranged from a call for greater adherence to pre-established guidelines for economic evaluations to development of de novo decision models. The systematic overview made its own commissioning recommendations and critically appraised the methods of previous reviews, particularly regarding the extraction of methodological features and the synthesis of evaluation outcomes.volume of extracted detail in item 8 nevertheless does not capture the type of detail . Hence narrative synthesis should supplement the checklist application for the appraisal of systematic reviews.Application of the AMSTAR 2 checklist showed some evidence of an improvement in systematic review methods, from full adherence to only two checklist items in the RCN review in 2005 to nine or 10 items in the five reviews published in 2017 or later. The low performance of the RCN review is of particular concern given that it informed the development of NICE CG161. Certain aspects of AMSTAR 2 were mainly relevant to systematic reviews of intervention effectiveness studies rather than of economic evaluations. Thus, the checklist items 11, 12 and 15 concerning meta-analysis were less relevant to the reviews that did not pool outcomes due to the underlying methodological heterogeneity in economic evaluations. Moreover, items 2, 9 and 13 concerning risk of bias assessment had to be expanded to address the reviews’ broader methodological quality assessment of evaluations. The question in item 8 of whether the reviews described the evaluations in ‘adequate detail’ required background knowledge of the important features of falls prevention economic evaluations: i.e., the data fields in Table A noticeable finding of this overview was that the extraction and analysis of decision model features by previous systematic reviews was highly limited, although this was intentional in a couple of cases: Huter review focused on a pre-specified list of methodological challenges, while Winser review focused on RCT-based SVEs. The limited appraisal greatly compromises the ability of systematic reviews to inform decision-making at the population level over a time horizon long enough to capture all relevant costs and consequences of a preventive intervention , 49. AccA possible contributory factor to the neglect of decision model features is the nature of checklists used by previous systematic reviews to assess the reporting and methodological quality of their identified economic evaluations. All four checklists used by the reviews were designed for all disease areas and for all study designs. Though reviewers are not confined to extracting only the checklist items, the use of a generic, all-design checklist would likely reduce the effort spent in identifying how evaluations captured the disease- and modelling-specific features. Thus, using the fall-specific  checklist designed by falls prevention experts  may imprSole reliance on cost-per-unit ratios would generate incomplete and misleading commissioning recommendations. As noted above, single-component HAM or exercise may generate very favourable cost-per-unit ratios and yet perform poorly in terms of aggregate impact and/or coverage of priority groups relative to a multifactorial intervention. This observation contributes to an ongoing debate on whether less resource-intensive exercise should be preferred over (the widely recommended) multifactorial interventions , 59. TheThis systematic overview is the first of its kind in the falls prevention economic evaluation context. It covered 12 academic databases and grey literature between 2003 and 2020 and followed the Cochrane guideline [The overview nevertheless has limitations, including non-coverage of the period before 2003, non-inclusion of systematic reviews of falls prevention RCTs that contained a minority of studies that were economic evaluations (10–12), and non-inclusion of reviews that targeted specific patient groups such as those with neurological disorders . The sysThe systematic overview found significant limitations in the methodological quality of existing systematic reviews of falls prevention economic evaluations which could misinform commissioning decisions and hinder the design of future evaluations. Systematic reviews should: be as comprehensive as possible in the extraction and narrative synthesis of evaluation features associated with falls epidemiology, falls prevention intervention and decision modelling; they should also base the commissioning recommendations on the full range of reported outcomes and equity objectives to avoid incomplete information being provided to decision-makers.Additional file1: TableA1. Medline search strategyfor systematic overview and systematic review. Table A2. Embase search strategy for systematic overview ofsystematic reviews of falls prevention economic evaluation. Table A3. PubMed search strategy for systematic overview andsystematic review. Table A4. Cochrane Library (CSDR and CENTRAL) searchstrategy for systematic overview and systematic review. Table A5. EconLit search strategy for systematic overviewand systematic review. Table A6. CINAHL search strategy for systematic overview andsystematic review. Table A7. PsycInfo search strategy for systematic overviewand systematic review. Table A8. ASSIA search strategy for systematic overview andsystematic review. Table B. Studies excluded from systematic overview at fulltext screening and exclusion reason. Table C. Primary economic evaluations of community-basedfalls prevention interventions included in previous systematic reviews. Table D. Items contained in checklists used for qualityassessment of economic evaluations included in systematic reviews. Table E. Results of quality assessment by previoussystematic reviews of community-based falls prevention economic evaluations. Table F. AMSTAR 2 checklist for reporting andmethodological quality of systematic reviews (56).


Among the long-term consequences of sepsis  the increased risk of unexplained cardiovascular complications, such as myocardial infarction, acute heart failure or stroke, is one of the emerging specific health concerns. The vascular accelerated ageing also named premature senescence is a potential mechanism contributing to atherothrombosis, consequently leading to cardiovascular events. Indeed, vascular senescence-associated major adverse cardiovascular events (MACE) are a potential feature in sepsis survivors and of the elderly at cardiovascular risk. In these patients, accelerated vascular senescence could be one of the potential facilitating mechanisms. This review will focus on premature senescence in sepsis regardless of age. It will highlight and refine the potential relationships between sepsis and accelerated vascular senescence. In particular, key cellular mechanisms contributing to cardiovascular events in post-sepsis syndrome will be highlighted, and potential therapeutic strategies to reduce the cardiovascular risk will be further discussed. With improved management of patients, sepsis survivors are increasing each year.Early cardiovascular complications, of yet undeciphered mechanisms, are an emerging health issue in post-sepsis syndrome.Premature senescence of endothelium and vascular tissue is proven an accelerated process of atherogenesis in young septic rats.An increasing body of clinical evidence point at endothelial senescence in the initiation and development of atherosclerosis.Prevention of premature senescence by senotherapy and cardiological follow-up could improve long-term septic patients’ outcomes. Sepsis is considered as a life-threatening multiple organ dysfunction caused by a dysregulated host response to infection altering systemic arterial function , 2. AlthRecent data suggest that the increased risk of long-term mortality among sepsis survivors could be related to increased post-sepsis cardiovascular diseases . Hence, A potential mechanism that may link acute and chronic endothelial dysfunction is accelerated vascular aging associated with premature endothelial senescence ultimately promoting atherothrombosis Fig. .Fig. 1PoAs a proof of concept of the link between endothelial senescence and atherosclerosis, a pioneer work reported that senescent endothelial cells (ECs) overlay atherosclerotic plaques, in post-mortem aortic arch histological section from patients older than 70 years. These ECs were seen as a thin continuous layer of luminal senescence-associated β-galactosidase  activity, highly represented in vulnerable plaque . In miceIn an experimental model of atherosclerosis-prone mice, Kaynar and colleagues  corroborRecently, our team has provided new insights by characterizing a premature vascular senescence in rats after CLP surgery . Sepsis One of the other main contributors to the link between sepsis, senescence and atherosclerosis for cardiovascular disease is “inflammageing” . Inflamm“Senectus ipsa morbus est”, reflecting the disease paradigm while the Roman Galen asserted that, unlike diseases that are abnormal, ageing is universal and is, therefore, a natural process. Although the answer is not yet conclusive and this dichotomy still persists nowadays, recent progress in biology allows a better understanding of aging and senescence  and and80] atert-butylhydroperoxide with sublethal oxidative stress , 9897, 9In a major 2018 study, Kirkland and his colleagues at the Mayo Clinic provided a proof-of-concept evidence that transplanted senescent cells can cause physical disability and reduced lifespan in young and middle-aged mice. They also demonstrated that intermittent oral administration of a senolytic cocktail of dasatinib and quercetin significantly reversed the effect of senescent cells and increased median survival by 36% .−/− high-fat diet murine model [To date, one main senolytic strategy is to shift the senescent cells into apoptotic ones by triggering the member of the BCL-2 family , most ofne model . While tne model , senescene model .In 2019, first evidence that senolytics (dasatinib and quercetin) are safe and efficient in humans was published . Later tInhibiting SASP, via melanin for example , withoutInterestingly, SENEX is a TNFα-sensitive gene and in vitro treatment by low concentration of TNFα prompts the endothelial downregulation of this gene leading to apoptosis, confirming SENEX as a promising target in the early prevention of sepsis-induced endothelial senescence .−/− adult mice treated by metformin that inhibited endothelial cell senescence and thus contributed to partially decreased atherosclerotic plaque formation [Another vascular protective strategy would be to prevent the shift from endothelial quiescence to senescence by inhibiting the mTOR pathway. Confirmation was brought in atheroprone ApoEormation . This isormation .Post-septic cardiovascular disease, as a part of the morbidity and mortality observed in the post-sepsis syndrome, is one of the emerging health issues. Premature senescence of endothelium and vascular tissue appears to be one of the mechanisms involved in the accelerated atherogenesis in sepsis survivors. Targeting pro-senescent endothelial cells with senotherapy in sepsis seems promising to delay endothelial senescence and improve vascular health and long-term outcomes after sepsis.


Background and Objectives: Leg extension angle is important for increasing the propulsion force during gait and is a meaningful indicator for evaluating gait quality in stroke patients. Although leg extension angle during late stance might potentially also affect lower limb kinematics during the swing phase, the relationship between these two remains unclear. This study aimed to investigate the relationship between leg extension angle and knee flexion angle during pre-swing and swing phase in post-stroke gait. Materials and Methods: Twenty-nine stroke patients walked along a 16 m walkway at a self-selected speed. Tilt angles and acceleration of pelvis and paretic lower limb segments were measured using inertial measurement units. Leg extension angle, consisting of a line connecting the hip joint with the ankle joint, hip and knee angles, and increments of velocity during pre-swing and swing phase were calculated. Correlation analysis was conducted to examine the relationships between these parameters. Partial correlation analysis adjusted by the Fugl-Meyer assessment-lower limb (FMA-LL) was also performed. Results: On the paretic side, leg extension angle was positively correlated with knee flexion angle during the swing phase  and knee flexion angle and increments of velocity during the pre-swing phase . Partial correlation analysis adjusted by the FMA-LL showed significant correlation between leg extension angle and knee flexion angle during the swing phase  and knee flexion angle and increments of velocity during the pre-swing phase . Conclusions: Leg extension angle affected kinematics during the swing phase in post-stroke gait regardless of the severity of paralysis, and was similar during the pre-swing phase. These results would guide the development of effective gait training programs that enable a safe and efficient gait for stroke patients. In stroke patients, walking ability is a fundamental function for the activities of daily living and quality of life . TherefoPropulsion force, the anterior component of ground reaction force (AGRF) during late stance, has been identified as an important factor in post-stroke gait  and it iDuring Sw in post-stroke gait, knee flexion angle has been reduced ,16, whicAlthough leg extension angle during late stance and knee flexion during Sw are important factors in post-stroke gait, the relationship between these kinematic parameters remains unclear. The aim of this study was to investigate the relationship between leg extension angle and knee flexion during pre-swing and Sw in stroke patients. We hypothesized that leg extension angle could affect knee flexion during Sw even if the effect of the degree of the lower limb dysfunction is excluded. Elucidation of these interrelationships will help in designing gait training programs for improving knee flexion angle during Sw and walking speed in post-stroke gait.r = 0.50, α = 0.05, and power (1 − β) = 0.8, indicated that the required sample size was 26. Thus, we accepted that this study had a suitable sample size. Inclusion criteria were as follows: (1) first unilateral stroke, (2) at least three months elapsed since stroke occurring, and (3) the ability to walk independently with or without walking aids (cane and ankle-foot orthosis) for at least 16 m. Exclusion criteria were a history of neurological or orthopedic diseases that could interfere with gait such as cerebellar stroke, joint replacement, and fracture, or cognitive problems that could impair the ability to understand experimental tasks. All participants provided written informed consent prior to initiating the study. This study was approved by the Ethics Committee of Fujimoto General Hospital (Number 177).Twenty-nine stroke patients  participated in this cross-sectional study . Stroke Fugl-Meyer assessment-lower limb  and Brunnstrom recovery stage (BRS) were used to quantify lower limb motor impairment. Modified Ashworth scale (MAS) was used to quantify the lower limb muscle tone. Functional independence measurement (FIM) was used to evaluate performance during activities of daily living.Participants walked 16 m along a straight walkway at a comfortable velocity using the walking aids that they ordinarily used. Gait velocity was calculated from the time taken to walk the middle 10 m using a stopwatch. We measured gait kinematics using five inertial measurement units . The IMUs were attached by elastic belts to the sacrum, bilateral anterior thigh and shank. IMU consist of a 3D gyroscope, 3D accelerometer, and 3D magnetometer. The sampling frequency was 100 Hz. The three-axis acceleration and tilt angles in a global coordinate system were obtained from the magnetic and inertial data using the Kalman filter on the MT manager software . The reliability of the software-aided estimation of IMUs has previously been reported . WhereveThe middle ten gait cycles were analyzed. Low-pass filtering was performed on the angle and the acceleration data measured using IMUs with a 10 Hz and 20 Hz cutoff frequency, respectively. Leg extension angle, hip flexion and extension angle, and knee flexion angle during late stance were calculated from tilt angles and acceleration measured using IMUs during walking, on both the paretic and the non-paretic sides. The measured angles were adjusted by tilt angles of thigh and shank during relaxed standing.Leg extension angle was defined as the angle made by the laboratory’s vertical axis and a line connecting the lateral malleolus with the greater trochanter in the sagittal plane . Leg extHip and knee flexion angles were calculated from the tilt angles of sacrum, thigh, and shank sensors. The maximum hip and knee flexion angle during Sw and maximum hip extension angle during late stance were, respectively, calculated as the representative values. Knee flexion angle at the maximum leg extension angle during pre-swing was also determined.In addition, the time integral of anterior acceleration measured by the IMU affixed to the sacrum during late stance was calculated as an indicator of the propulsion force. A previous study showed that increments of velocity calculated from acceleration on the sacrum was strongly correlated with the impulse of AGRF during late stance . Data prp < 0.05.The Shapiro-Wilk test was used to determine whether the data were normally distributed for the following analysis. First, the differences in leg extension angle, hip flexion angle, knee flexion angle, and increments of velocity between the paretic and non-paretic sides were, respectively, compared using paired t-test or Wilcoxon signed-rank test. Next, the association between leg extension angle on the paretic side and hip flexion angle, knee flexion angle, and increments of velocity on the paretic side were investigated using the Pearson’s or Spearman’s rank correlation coefficient. In addition, the mutual association between these kinematic parameters on the paretic side was investigated using the partial correlation analysis after controlling by FMA-LL. SPSS software version 25.0 for Windows  was used for statistical analysis. Data are expressed as mean ± standard deviation, and the statistical significance was set at p = 0.006), hip flexion angle , hip extension angle , knee flexion angle , and increments of velocity  were significantly lower than those of the non-paretic side  and between hip extension angle during late stance and knee flexion angle during Sw   .r = 0.602, p = 0.001), knee flexion angle during pre-swing , and increments of velocity . No significant correlation was observed between hip extension angle during late stance and knee flexion angle during Sw   .This study investigated the relationships between leg extension angle during late stance and knee flexion angle during the pre-swing phase and Sw in post-stroke gait. Furthermore, the relationship was examined in consideration of the effects of paralysis. The results showed that leg extension angle was significantly associated with knee flexion angle during the pre-swing phase and Sw on the paretic side even after excluding the effects of lower limb motor impairment. This is the first study to demonstrate the association between leg extension angle and knee flexion during Sw in a post-stroke gait.In a correlation analysis, leg extension angle showed a significant positive association with the increment of velocity during late stance on the paretic side. The increment of velocity during late stance was calculated as the indicator of propulsion force in this study . Our finFurthermore, leg extension angle showed a significant positive association with knee flexion angle during the pre-swing phase and Sw on the paretic side. Knee flexion angle during pre-swing has been attributed to the reaction forces passing behind the knee joint. In healthy subjects and children with cerebral palsy, relationships between knee flexion angle during Sw and knee flexion velocity at toe-off has been reported ,27,28. SPartial correlation analysis adjusted by FMA-LL, leg extension angle was still significantly related to knee flexion angle during pre-swing and Sw on the paretic side. These results showed that leg extension angle could exert a significant effect on knee flexion angle during the pre-swing phase and Sw, regardless of the degree of paralysis. FMA-LL has been shown to be correlated with cadence and step length . AlthougIn addition, partial correlation analysis showed knee flexion angle during Sw was significantly associated with knee flexion angle during the pre-swing phase. Several studies have shown that knee flexion should begin in terminal stance  and that it can reach its normal swing peak only if knee flexion velocity during the pre-swing phase is adequate ,31. FurtThis study had several limitations. First, previous studies have reported the effect of ankle plantarflexor moment and muscle activity on leg extension angle and propulsion force in the paretic lower limb ,33,34. HOur results established a positive association between leg extension angle and knee flexion angle during Sw as well with the propulsive force during late stance, even when the effects of lower limb motor impairment were excluded. Similar results were shown during the pre-swing phase. Leg extension angle could reflect the kinematics and kinetics during the pre-swing phase and Sw in post-stroke gait, and it can be a meaningful indicator for estimating gait quality during gait training. These results could inform the design of effective gait training programs aimed at achieving a safe and efficient gait in stroke patients.


Sufficient sleep is relevant for both momentary cognitive functioning and long-term cognitive developments. However, which factors make people particularly vulnerable to the cognitive consequences of sleep loss remains an open question. Here, we obtained data from 122 young-old (66-69 years) and 35 very old (85-89 years) adults who provided six daily ambulatory assessments of working memory performance and daily sleep over one week, and long-term trajectories in processing speed and working memory performance. Our results add to current knowledge in three ways: First, results from multilevel structural equation models showed both too little and too much daily sleep was associated with poorer working memory in everyday life. Secondly, this association was independent of cognitive aging over the preceding four years. Thirdly, average sleep duration did not predict cognitive changes over the next year. Participants’ age and health as well as emotional functioning are discussed as further influences on the associations.


Astrocytes play key roles in CNS development as well as well as neuro-supportive roles in the mature brain including ionic, bioenergetic and redox homeostasis. Astrocytes undergo rapid changes following acute CNS insults such as stroke or traumatic brain injury, but are also profoundly altered in chronic neurodegenerative conditions such as Alzheimer's disease. While disease-altered astrocytes are often referred to as reactive, this does not represent a single cellular state or group of states, but a shift in astrocyte properties that is determined by the type of insult as well as spatio-temporal factors. Such changes can accelerate disease progression due to astrocytes neglecting their normal homeostatic neuro-supportive roles, as well as by gaining active neuro-toxic properties. However, other aspects of astrocytic responses to chronic disease can include the induction of adaptive-protective pathways. This is particularly the case when considering antioxidant defences, which can be up-regulated in many cell types, including astrocytes, in response to stresses, sometimes in concert with the activation of detoxification and proteostasis pathways. Protective responses, whilst potentially serving to mitigate neuronal dysfunction, may ultimately fail due to being insufficiently strong, or be offset by other deleterious changes to astrocytes occurring in parallel. Nevertheless, a greater understanding of early adaptive-protective responses of astrocytes to neurodegenerative disease pathology may point to ways in which these responses may be harnessed for therapeutic effect.  •Astrocytes play important homeostatic roles in the healthy brain.•They are widely known to change for the worse in neurodegenerative disease.•Changes include abandoning their homeostatic roles and becoming actively neurotoxic.•Some responses however are protective and may be relevant to early stage disease. Under nA role for astrocytes in providing redox support to neurons was established even before the discovery of Nrf2 as a major mediator . NeuronsOf note, recent studies have also demonstrated a role for astrocytes in protecting neurons from free-radical toxicity that may arise from detoxifying damaged mitochondrial membranes via mechanisms not directly linked to Nrf2 activation. This occurs both via transcellular transfer of mitochondria between neurons and astrocytes (transmitophagy)  a procesIn addition to Nrf2-independent anti-oxidant/redox homeostasis function of astrocytes, it is important to note that Nrf2 activation can trigger cytoprotective functions that are not directly related to detoxifying ROS. Nrf2 is capable of regulating proteostasis, evidenced by a number of gain- and loss-of-function studies. Pharmacological activation of Nrf2 has been shown in to repress cytotoxicity and unfolded protein response (UPR) over-activation in response to ER stress inducers, via maintenance of ER redox balance and disulphide chemistry . In addi3Astrocyte functions change significantly in response to disease, neurodegeneration and ageing. This phenomenon, called reactive astrogliosis (reviewed in detail recently ) was des42+ signaling, the Ca2+-dependent transcription factor NFAT, pro-inflammatory JAK/STAT signaling, and the stress/inflammation responsive transcription factor NF-kB [Changes to astrocytes in neurodegenerative disease can accelerate disease progression in two distinct ways. The first is through the decline of astrocytes’ ability to carry out the type of homeostatic functions described above in or NF-kB .in vitro studies (using both rodent and human cells) [in vivo as demonstrated by the ability of transplanted mutant SOD1 astrocytes to increase spinal MN death in wild-type animals. Finally, to support that the effects of astrocyte SOD1 mutations on neuronal pathology may not be due to simple loss of antioxidant function but rather a gain of toxic function, conditioned media from SOD1 mutant astrocytes is sufficient to drive neuronal death [Further evidence for the role of deleterious astrocytes in driving degenerative disease comes from models of amyotrophic lateral sclerosis (ALS), where the trigger is not the astrocyte's response to external brain pathology, but the cell-autonomous effect of mutation-containing astrocytes. Free radical damage and antioxidant stress are implicated as key mechanisms underlying ALS, with one of the first mutations identified associated with familial ALS being mutations in the SOD1 gene  with a rn cells) , and in al death ,75, via al death . Moreoveal death  which maal death .5In addition to neurodegeneration inducing changes to astrocytes that are associated with deleterious effects as detailed above, there is also emerging evidence that reactive astrocytes have the potential to mount adaptive-protective responses to pathology which may delay patho-progression . Many ceP301S respectively) and sequencing mRNAs associated with tagged ribosomes expressed specifically in astrocytes [In our recent study of astrocyte-specific translatome changes, we investigated the separate astrocyte response to both ß-amyloidopathy and tauopathy using relevant mouse models (APP/PS1 and MAPTtrocytes . We fountrocytes . Collecttrocytes . The ben6TFEA)) or the closely related RTA-408 (Omaveloxolone), which has recently been demonstrated to improve neurological function compared to placebo in Friedreich ataxia [Given the above body of evidence supporting that astrocytes exhibit a protective Nrf2 response in the degenerating brain there is interest in using pharmacological activation of Nrf2 in this context . Consideh ataxia . Finallyh ataxia . Therefo7A failure of antioxidant defence and CNS redox homeostasis is considered to be an important final common pathway driving neuronal death in many neurodegenerative diseases. Neurodegenerative processes induce profound reactive changes to astrocytes. Whilst it is clear that reactivity does ultimately lead to a detrimental failure in many key astrocyte functions such as glutamate homeostasis or metabolic function, we propose that the evidence supports that reactive astrocytes actually undergo adaptive-protective changes in the context of antioxidant support. However, whilst these changes have neuroprotective potential, they may be “too little, too late” to avert neuronal dysfunction and death in the context of disease. A fuller understanding of the changes that astrocytes undergo in chronic disease will point to therapies that prevent neuro-toxic changes, rescue deficits in homeostatic support, and facilitate (or boost) adaptive-protective pathways.


This paper presents an extended version of the Cox regression model to examine heterogeneous effects of risk factors on disease subtypes defined by a continuous biomarker. This approach can be easily applied to cancer studies and is accessible to researchers via user-friendly R scripts.Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods  allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts . We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure–disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method’s flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms. In clinical medicine, patients who share common symptoms and disease characteristics are grouped into a certain disease entity. However, molecular pathological diagnosis is a part of routine clinical practice, especially in oncology. Pathogenic mechanisms commonly vary between patients with the same disease entity. Therefore, when appropriate, patients with the disease are subclassified into groups (disease subtypes) based on their molecular pathological diagnosis to improve clinical management and treatment outcomes. Different disease subtypes are regarded as developing through distinct pathological mechanisms, on which risk factors may exert differential influence ,2,3,4. TDespite continuous measurement readouts of many biomarkers used for disease subtyping, such continuous biomarker measures are commonly reduced to a small number of categorical levels (sometimes only two or three) to define disease subtypes, which can simplify the statistical analysis and generate readily interpretable data. Therefore, most existing statistical methods for studying etiological heterogeneity have focused on categorical disease subtype settings . HoweverFor illustration, we applied the proposed method to assess how the association of alcohol intake with colorectal cancer incidence changes across DNA methylation level at long interspersed nucleotide element-1 (LINE-1), measured in tumors. We used data from two prospective cohort studies, the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS).i-th individual, the coefficient i-th individual, and To evaluate the association of an exposure with an incident disease in a cohort study, researchers typically use the Cox model , in whick-th element of the exposure, and Now, it is of interest to evaluate how the association of an exposure with the disease risk changes over the level of a disease marker. Extending Equation (1), we model the cause-specific hazards  of the dThe regression coefficients in the standard Cox model (1) are typically estimated by maximizing the partial likelihood . Under tZ; that is,j-th basis function of the restricted cubic spline, evaluated at Z. See We suggest using the restricted cubic spline approach  to charaon (BIC) , and typWe used the likelihood ratio test to test for zero elements of We conducted a simulation study to assess the finite sample performance of the method when actorily . When thWe used colorectal cancer (adenocarcinoma) and its subtyping biomarker, LINE-1 methylation  , as a diShown in p-values from testing the following null hypotheses for the same choices of knot numbers and cohort settings as in p < 0.001) and the combined cohort , but there was insufficient statistical evidence to establish such an association in the NHS cohort. There was insufficient statistical evidence to establish a difference in the comparison of ≤15 g/day intake versus 0 g/day in the NHS, HPFS, or the combined cohort (p < 0.001) under p = 0.54 for d cohort . FurtherIn this paper, we have presented a Cox proportional hazards regression model method to fully utilize a continuous biomarker measure for disease subtyping. This statistical method can examine subtype heterogeneity of diseases in the exposure–disease association with more comprehensive and versatile utilization of continuous marker measurements. The ability of this method to potentially reveal more complicated patterns in subtype heterogeneity can help us gain deeper insights into etiologies in molecular epidemiological research and provide further evidence in the development of personalized precision medicine.Statistical methods for investigating disease subtype heterogeneity for categorical and ordinal subtypes have been studied previously under several common study designs . HoweverMany biological phenomena and related biomarkers (including expressions of genes and proteins) are continuous in nature . LINE-1 The real-world application of this method in the two large prospective cohort studies has demonstrated its capability to depict the trend of the exposure effect across continuous molecular marker levels in contrast to use of solely categorical subtypes . Furtherhttps://www.hsph.harvard.edu/molin-wang/software/, accessed on 31 March 2022). This R function fits a Cox regression model for either incidence analysis or post-diagnosis survival analysis, where the model can include one or more exposure variables, a set of confounders , and one or more stratification variables . Left truncation and time-varying covariates, which are common in cohort data analyses, can be handled by putting the data in counting process form [A user-friendly R program that implements this method is publicly available  Gene Nomenclature Committee (HGNC) standards, recommended by the expert panel .To summarize, we have presented a Cox proportional hazards regression model for analyzing heterogeneous exposure–disease associations across disease subtypes defined by continuous biomarker measures. This method is helpful in decreasing bias caused by arbitrary subtype categorization and in increasing statistical power, as well as flexibility of assumptions about the pattern of pathologic heterogeneity. The utilization of continuous marker data without categorization for investigating subtype heterogeneity will advance our understanding of etiological heterogeneity and possibly contribute to precision medicine.


Lactococcus lactis subsp. cremoris (YRC3780), which is isolated from kefir, has been associated with anti-allergic effects in humans. However, it remains unknown whether daily intake of YRC3780 attenuates the response to psychological stress in humans in parallel with changes to the gut microbiome. We examined the fundamental role of YRC3780 in the gut microbiome, stress response, sleep, and mental health in humans.2) who were randomly assigned to placebo (n = 13) or YRC3780 (n = 14) groups. The HPA axis response to acute psychological stress, the diurnal rhythm of HPA axis activity, and gut microbiome were assessed and compared between the two groups.Effects of daily intake of YRC3780 on the hypothalamic-pituitary-adrenal (HPA) axis response to acute psychological stress were investigated in a double-blind, placebo-controlled clinical trial involving 27 healthy young men (mean age and body mass index: 23.5 years and 21.5 kg/mThe results showed that daily intake of YRC3780 significantly lowered morning salivary cortisol levels compared with placebo. In addition, salivary cortisol levels following a social stress test significantly decreased +40 min after beginning the TSST in the YRC3780-treated group compared to placebo. There were no significant differences between the two groups in terms of actigraphy-based sleep quality, but the subjective sleep quality and mental health were significantly improved in the YRC3780-treated group compared to placebo.Our study suggests that daily intake of YRC3780 improves the HPA axis response to acute psychological stress, which might be associated with a decrease in morning cortisol levels. The hypothalamic-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SAM) systems are major components of the stress response system . When inRecent research advancements have clarified the relationships between gut microbiota functions and metabolic syndrome, autism, autoimmunity, and cancer . SeveralLactococcus lactis subsp. cremoris YRC3780 (hereafter ‘YRC3780’), which is isolated from kefir, has been shown to exert anti-allergic effects in humans [Studies have confirmed that anti-inflammatory cytokines and regulatory T cells work effectively in animal models of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis , 25, whin humans  and immun humans . HoweverAll study protocols were approved by the ethical committee of Hokkaido University Graduate School of Education (no. 17–41) and conducted according to the Declaration of Helsinki.2) completed the study as paid volunteers. Table Twenty-seven healthy young male participants  and 12 cortisol non-responders . In the cortisol responders, the salivary cortisol concentration in the YRC3780 group was lower after the TSST than in the placebo group , while salivary cortisol concentrations in the non-responders did not show a significant increase after the TSST.To evaluate the effects of daily placebo/YRC3780 ingestion on the HPA axis stress response, participants were categorized as salivary cortisol responders and non-responders based on previously published classification criteria (1.5 nmol/L or 15.5% increase) . The claoup Fig. . SalivarAlthough the salivary cortisol concentrations after the TSST in the cortisol responders were significantly different between the placebo and YRC3780 groups, the HR after the TSST did not differ significantly between the two groups Fig. . Interesp = 0.031; GHQ-28 p = 0.038, Mann–Whitney U test). Table Table Alpha diversity  and fecal microbiota analysis was performed on all 81 fecal samples collected from the participants on the last day of baseline evaluations, and at 4 and 8 weeks after capsule ingestion. First, to assess the effects of the fecal microbiome on the HPA axis response to the TSST, the placebo and YRC3780 group participants were divided into cortisol responders and non-responders based on the published classification , and intWe demonstrated that daily intake of YRC3780 decreased morning salivary cortisol levels 6 and 8 weeks after beginning daily ingestion Fig.  and decrRegarding the HR stress reactivity to the TSST, both the cortisol responder and non-responder groups showed a similar tendency, for an increased HR just after starting the TSST. Nevertheless, the cortisol stress levels following the TSST were markedly different between cortisol responders and non-responders Fig. . Both thThe gut microbiota has been reported to undergo changes, with improvement in the intestinal environment even after ingestion of heat-killed lactic acid bacteria –37. In tThe immune system is also a factor in the stress response. Chronic stress, such as achieved via stress promotion tests, causes a decrease in natural killer (NK) cell activity, a tendency toward Th2 cell dominance –40, and L. brevis SBC8803 cells stimulates 5-HT production and release from intestinal chromaffin cells in vitro and result in increased sleep quality in vivo. The immunomodulatory effects of YRC3780 result from its interaction with immune cells in the small intestine, which might be involved in 5-HT production, as in the L. brevis SBC8803 strain, which stimulates excessive production of inflammatory cytokines. Taken together, these findings indicate that the daily intake of YRC3780 alleviates chronic stress and acute stress in daily living conditions by regulating the immune system. Further studies are needed to evaluate whether the daily intake of YRC3780 could stimulate intraluminal 5-HT release from intestinal cells.With respect to the neural pathways involved from the gut to the central nervous system, 5-HT produced by interaction with intestinal chromaffin cells localized in the small intestine acts on 5-HT receptors of the vagus nerve or the of the spinal cord nerve terminal and transmits information to the brain . YoshikaThere are some limitations to the present study. The present study only examined healthy young male subjects. Previous studies have reported that the stress reactivity of the HPA axis to the TSST differs between males and females . In addiThis study found that daily YRC3780 intake alters morning HPA axis basal activity, and improves subjective sleep quality, mental health, and HPA axis reactivity to acute psychological stress.Supplementary materialSupplemental material


The results demonstrated that the malaria RDTs currently commercially available might cause FN results in practice.Despite the widespread use of malaria rapid diagnostic test (RDT) in clinical practice, there are a lot of challenges. We conducted a secondary analysis of 129 malaria RDT data from rounds 5–8 of the World Health Organization (WHO) product testing summary and discuss the causes of false-negative (FN) results with a focus on low parasite density, improper RDT storage, operation and interpretation, and The online version contains supplementary material available at 10.1186/s40779-021-00345-0. Dear Editor,Malaria rapid diagnostic test (RDT) is becoming the most-used method to diagnose malaria worldwide, especially in sub-Saharan Africa because malaria RDTs are easier to utilize than microscopy and have been shown to have comparable detection capability in the field . DespitePlasmodium falciparum (Pf) with a pfhrp2/3 gene deletion.There were 129 RDT products enrolled into the product assessment on malaria RDT performance in this summary . The sumPlasmodium vivax  strip. The storage of RDTs for prolonged periods in hot or humid conditions may impair the diagnostic ability. This analysis showed that the positive rate of some products at low parasite density was impaired as the incubation temperature increased. Malaria is endemic in some geographic areas, such as sub-Saharan Africa and Southeast Asia, which are characterized by a hot, humid climate and poor storage infrastructures. As a result, RDTs were usually exposed to temperatures and humidity above the product recommended limits in these endemic areas, which may result in poor test performance.RDTs are considered to be an ideal way for parasite-based diagnosis, particularly in remote and resource-limited areas, mainly due to the simplicity of the test. The results of this analysis showed that approximately 20–27% of products need to be improved for blood safety and instruction quality, 30–35% of RDT test bands against Pf were minimally visible, and that the RDT test bands against Pv returned a higher proportion . Table S2. Percentage distribution of test band intensity score against wild-type Pv in 200 parasites/μl (%).


In the courseof evolution, nature has achieved remarkably lubricatedsurfaces, with healthy articular cartilage in the major joints being the prime example, that can last a lifetime as they slidepast each other with ultralow friction (friction coefficient μ= the force to slide surfaces past each other/load compressing thesurfaces < 0.01) under physiological pressures (up to 10 MPa ormore)). Such properties are unmatched by any man-made materials. Theprecise mechanism of low friction between such sliding cartilage tissues,which is closely related to osteoarthritis (OA), the most widespreadjoint disease, affecting hundreds of millions worldwide, has beenstudied for nearly a century, but is still not fully understood. Traditionally,the roles of load bearing by interstitial fluid within the cartilagebulk and that of thin exuded fluid films at the interface betweenthe sliding cartilage surfaces have been proposed as the main lubricationmechanism. More recent work, however, suggests that molecular boundarylayers at the surfaces of articular cartilage and other tissues playa major role in their lubrication. In particular, in recent yearshydration lubrication has emerged as a new paradigm for boundary lubricationin aqueous media based on subnanometer hydration shells which massivelyreduce frictional dissipation. The vectors of hydration lubricationinclude trapped hydrated ions, hydrated surfactants, biological macromolecules,biomimetic polymers, polyelectrolytes and polyzwitterionic brushes,and close-packed layers of phosphatidylcholine (PC) vesicles,all having in common the exposure of highly hydrated groups at theslip plane. Among them, vesicles (or bilayers) of PC lipids, whichare the most widespread lipid class in mammals, are exceptionallyefficient lubricating elements as a result of the high hydration ofthe phosphocholine headgroups they expose. Such lipids are ubiquitousin joints, leading to the proposal that macromolecular surface complexesexposing PC bilayers are responsible for the remarkable lubricationof cartilage. Cartilage, comprising ∼70% water, may be consideredto be a complex biological hydrogel, and studying the frictional propertiesof hydrogels may thus provide new insights into its lubrication mechanisms,leading in turn to novel, highly lubricious hydrogels that may beused in a variety of biomedical and other applications. A better understandingof cartilage lubrication could moreover lead to better treatmentsfor OA, for example, through intra-articular injections of appropriatelubricants or through the creation of low-friction hydrogels thatmay be used as tissue engineering scaffolds for diseased cartilage.In this Account, we begin by introducing the concept and originof hydration lubrication, extending from the seminal study of lubricationby hydrated simple ions to more complex systems. We then briefly reviewdifferent modes of lubrication in synovial joints, focusing primarilyon boundary lubrication. We consider modes of hydrogel lubricationand different kinds of such low-friction synthetic gels and then focuson cartilage-inspired, boundary-lubricated hydrogels. We concludeby discussing challenges and opportunities. In this context,the behavior of water under strong confinement, such as between twocontacting surfaces, is of particular interest. One of the uniquecharacteristics of water is its persistent fluidity, with a viscositythat remains comparable to that of bulk water when confined to thinfilms, down to a single molecular layer, an effect discovered onlysome two decades ago.2 In contrast, itis well established that the viscosity of nonassociative liquids (includingmost organic solvents and oils) diverges, and they become solidlikewhen they are confined by solid surfaces to films less than severalmolecular layers thick.3 This contrastunder confinement may be viewed in terms of the different phase behaviorof water and of nonassociating liquids: in both cases, the confiningsurfaces attract the confined liquids, which acts to densify them.4 In the case of water, however, densificationsuppresses its tendency to solidify5 , while formost nonaqueous liquids it is the solid phase which is denser, leadingto the confinement-induced solidification.3The central functions of water in biology arise from the dipolarnature of its molecules and their ability to associate, i.e., to formhydrogen bonds, giving liquid water its unique properties and itsrole in the biochemical and biophysical processes that enable life.+ ion in water have been estimated to beon the order of GPa.6) This mechanism,known as hydration lubrication, was first uncovered by Raviv et al.7 using a surface forces balance (SFB)  are sheared. The effective viscosity of the water in the hydrationlayers turns out to be ca. 200-fold larger than that of either bulkwater or similarly confined water which is not in hydration shells.This effective viscosity of the subnanometer hydration layers is sufficientlylow to account for the observed lubricating action of hydrated ionsor zwitterions in a wide range of studies, as considered below.Water molecules are electrically neutral overall but haverelativelylarge electric dipoles due to the difference between hydrogen atomsand oxygen atoms in their ability to attract electrons  liposomes,12 hydrated surfactants,14 biological macromolecules,15 and biomimeticpolymers16 (as illustrated in –4 orlower17 (as shown in 11 The robustnessof the surface arrays of liposomes even when sliding at contact pressuresof up to 100 atm or more (and for supported bilayers to slightly lowerpressures) arises from the strong attraction between the acyl tailson the PC lipids.12 Indeed, it is clearlyshown that longer tails 2 acyl tails) result in arraysthat lubricate to much higher pressures than shorter tails 2 aryl tails).19 Much of the research on hydration lubrication is carried out onmodel substrates  usingnanotribometric techniques such as SFB6 and colloidally tipped atomic force microscopy.20 However, since boundary lubrication depends much less onthe bulk substrate and much more on the contacting outer boundarylayers  stresses σs are feltby the cartilage surfaces as they slide past each other, decayingwith depth into the cartilage. They may be written as σs = μP, where P isthe local normal stress (which depends on body weight and activity).Such frictional stresses play an important dual role in cartilagedegradation through both the usual wear-and-tear processes and, moresubtly, through their effect on the chondrocyte cells (the only celltype in cartilage) embedded in its bulk. Chondrocytes are highly mechanosensitive:they require normal stresses to function optimally for cartilage homeostasis25 but upregulate catabolic genes (which producecartilage-degrading enzymes) in response to shear stresses σs.26 Thus, high friction, possiblyinitially induced by sports or accident traumas or by wear due toold age, and a consequently higher σs, will leadto more cartilage-degrading enzymes. These in turn increase the frictionas the cartilage surface degrades and so on in a self-reinforcingcycle,9 aggravated by the limited self-repaircapability of the articular cartilage , eventually leading to joint degenerationand osteoarthritis (OA). An in-depth understanding of the lubricationmechanism of articular cartilage thus has significance both for thedesign of efficient biolubricants to treat early OA (for example byintra-articular injections) and for the design of hydrogels that mightserve as synthetic cartilage for lesion repair or as scaffolds forcartilage tissue engineering.Synovial joints, such as hips and knees, are remarkable biotribologicalsystems, bearing most of the load of the human body while articulating,i.e., rotating, with very low friction when healthy; articular cartilageis the soft tissue coating the ends of joint bones where they arejoined and articulate /D] dx, takes place as the fluid film (trapped betweenthe two cartilage surfaces) is sheared .The thin-fluid-film models include hydrodynamic, elastohydrodynamic,squeeze-film, weeping, boosted lubrication, and other specific models.27 In a related mode, which does not require athin fluid film to separate the surfaces, the interstitial fluid pressurewithin the cartilage is proposed to support most of the load on thejoint (more than 90%).28 This is then proposedto reduce the effective contact pressure P betweenthe opposing cartilage surfaces, resulting in low shear stresses andlow sliding friction even at high loads.29 Experiments where cartilage explants slide across a glass countersurfaceand where the resulting sliding friction is shown to vary inverselywith the simultaneously measured interstitial pressure in the cartilagehave been carried out to provide direct evidence for this interstitial-fluid-pressurizationlubrication mode.30 The other major mechanismfor reducing frictional energy dissipation is boundary lubrication.In this mode, the opposing surfaces are in molecular contact, andthe friction is mainly mediated by the intermolecular interactionsand arises from irreversible processes  as the molecules slide past each other. The frictionin this case is relatively insensitive to sliding speed vs  techniques,33 as well asmacroscopic tribometry and torque-based approaches (rheometer).35 However, none of these biomolecules acting as a boundary layer can,by themselves, explain the low friction of the cartilage surface atthe high-pressure characteristic of the major joints. An elucidationof the lubricating boundary layer on healthy cartilage thus remainsa major challenge. Clues are provided by recent SFB work in our group,37 indicating that PC lipids can complex with surface-attached HA toprovide boundary structures that result in CoF values of as low asμ ≈ 0.001 at pressures P above 100 atm,as shown in P up to 100 atm or more). Sucha synergy directly demonstrates the role of hydration lubricationbecause slip occurs at the highly hydrated phosphocholine headgroupinterface exposed by the HA-PC surface complex: this suggests a wayforward to a better understanding of how cartilage boundary layerslubricate.In contrast to fluid film or interstitial-fluid-pressurizationmodels, understanding cartilage boundary friction clearly requiresa consideration of the detailed composition and structure of the biomoleculesin the boundary layer. The main molecules that have been implicatedin the lubricating cartilage boundary layers, either by themselvesor in combination, are hyaluronic acid , aggrecans (bottle-brush-like proteoglycanswith mainly chondroitin sulfate side chains), lubricin (a mucinousglycoprotein), and phospholipids (PLs), as well as others.38 measured friction between a cartilage explant sample slidingunder sustained compression across a glass surface. When they usedpure saline as the immersion medium, they observed that the CoF increasedfrom its initial low value (μ ≈ 0.01) with cartilagecompression time as the interstitial fluid pressure decreased, inline with earlier studies.30 However, whenHA, albumin, and DPPC were added to the saline, Murakami et al.38 found very little change with compression timeand the CoF retained its low value (μ ≈ 0.01), despitethe fact that the interstitial fluid pressure decreased. This impliesthat boundary lubrication, which is largely independent of any interstitialfluid pressure, may play a major role in reducing cartilage friction.In a more recent study, again using cartilage explants sliding undercompression across glass, Hilser et al.39 showed that the CoF becomes essentially independent of compressiontime when using a lubricant composed of HA and lipids in a salinemedium, while it increases with time, as previously seen,30 when using saline alone. Both of these studiesdemonstrate that lubricants comprising HA and lipids may account forthe low friction of cartilage without the need for the interstitial-fluid-pressurizationmechanism, in line with the SFB results for hydration boundary lubricationby these components.36 Such insight intothe lubrication of cartilage, which may be viewed as a complex biologicalhydrogel in view of its large (∼70%) water content, suggestthat synthetic hydrogels may also be lubricated by similar approaches.Efficient lubrication of hydrogels may thus in turn shed light oncartilage lubrication as well as having clear benefits when usinghydrogels for cartilage repair9 and fortheir better performance in biomedical applications such as the low-frictioncoating of catheters or in contact lenses.40Some recent macroscopic tribological studies also support the centralityof a boundary lubrication mechanism. Murakami et al.342 Approaches to repairing osteoarthritic cartilage lesions have includedusing hydrogel-based “artificial cartilage” to fillup (and thus “repair”) the lesions32 or for the tissue engineering of cartilage, where cell-incorporatinghydrogel scaffolds are glued into lesions.44 In both cases, it is important that the hydrogel surfaces be sufficientlywell lubricated in order that articulation at the high pressures ofthe joints does not shear them off (delamination) during repeatedcontact, deformation, and sliding.43 Similarto cartilage lubrication, the mechanisms of hydrogel lubrication canbe divided into two main categories: fluid film lubrication and boundarylubrication.45 Fluid flow dynamics withinthe hydrogels, where the flow results in viscous dissipation, andtheir elastic deformation, play important roles in this.49 The physicochemical attraction or repulsion between the hydrogelnetwork polymers and the substrate, or between the polymers on opposingdifferent hydrogels when sliding past each other, will likewise stronglyaffect the friction. Repulsion between the chains and the slidingcountersurface tends to draw fluid into the interface between them,while adsorption drives the fluid out, leading to more solidlike friction.On the other hand, polymers in the hydrogel network may also be highlyhydrated even when attracted to the countersurface, resulting in ahydrated boundary layer during sliding.Hydrogelsare water-permeated 3D polymer networks with a high-watercontent and a low modulus resembling those of biological tissues,rendering them the material of choice for many applications in thefield of biomedical devices and regenerative medicine.50 developed the repulsion–adsorptionmodel, which made a significant contribution to understanding themechanism of hydrogel friction. In this model, when the interactionbetween the hydrogel and the substrate is repulsive, friction reductionmainly arises from lubrication by the fluid layer trapped betweenthe gel and the substrate. Such essentially hydrodynamic lubricationshows a close-to-linear dependence of the friction on the slidingvelocity, as expected for viscous shear stress in sheared Newtonianfluids. On the other hand, if the network polymers have a propensityto adsorb on the substrate, then another mechanism plays a role inaddition to the viscous force exhibited by the lubricating fluid layer:this is the elastic deformation force required to detach the adsorbingpolymers from the substrate during sliding. (Such detachment is dissipativebecause of its irreversible nature.)Gong et al.21 constructed layers of internallycross-linked and non-cross-linked PMPC brushes, some tens of nanometersthick, on mica substrates, where such internally cross-linked brusheshave the structure of a thin hydrogel layer, and measured the normaland shear interactions between them using an SFB. Although both brushes(μ ≈ 10–4) and cross-linked brushes(μ ≈ 10–3–10–4 depending on the vs) exhibit low CoFvalues .Hydration lubrication basedon hydrated boundary species (notedin previous sections) may also be used to reduce hydrogel friction.Iuster et al.Fvalues 5a,attri4Low-friction hydrogels haveclear applications in a variety ofbiomedical areas where lubrication is at a premium and thus are a promising topic in soft matter research. Their behaviormay also cast light on the friction mechanism of biological hydrogels,such as the articular cartilage described earlier. Different approacheshave been taken to prepare low-friction hydrogels.4.1–1. Kanekoet al.51 prepared triple-network (TN) hydrogelsby incorporating a third, weakly cross-linked network (negativelycharged) as well as DN hydrogels incorporating linear, non-cross-linked,negatively charged chains (DN-L) of the same polymers as the primarynetwork of the original DN hydrogel. The CoF values of such TN hydrogels(μ ≈ 10–3–10–4) and DN-L (10–2–10–3)hydrogels are significantly lower than that of DN hydrogels at thesame sliding velocity , an effect attributed to boundary lubrication. This approachwas also applied with biological tissue (degraded cartilage) to improveits wear resistance.56Double network (DN) hydrogels are a class of toughgels composed of a relatively rigid polyelectrolyte as the primarynetwork (rigid due to strong repulsion between charged monomers andhigher cross-linking) and an interpenetrating, loosely cross-linked,flexible neutral polymer as the secondary network. However, DN hydrogelshave large CoF values, μ ≈ 104.257 fabricated a polymer-filled macroporous hydrogel /poly(ethyleneglycol) (PEG)) together with a competitive photoresponsive guest.Irradiation by UV and visible light enables association and dissociationbetween α-CD and the guest molecules. This in turn releasesor recombines the PEG  on the hydrogel surface. Theresulting sliding CoF under UV of the hydrogel is ∼0.01, whichis ca. 3-fold lower than that of the hydrogels under visible light.To emulatethe porous structure of cartilage, where the pores are permeated bydifferent mobile biopolymers, Mu et al.4.358 grafted very thick (ca. tens of micrometers) polymer brusheson the surface of a stiff hydrogel. This hydrogel can maintain lowfriction (∼0.01–0.02) under high contact pressure (∼10MPa): the top, thick polymer brushes provide efficient lubrication,and the bottom, stiff hydrogel gives the load-bearing capability  continuously and enable suchlipids to accumulate at the surfaces. Inspired by this, hydrogelsincorporating liposomes were prepared,60 with the liposomes aggregated within microreservoirs, which couldcontinuously release lipids to create lipid-exposing boundary layers. Of the main modes to which thelubrication of healthy cartilage has been attributed, (a) lubricationarising from load-bearing interstitial fluid pressurization and (b)boundary lubrication, there is little one can do to treat fluid pressurizationin joints. However, boundary lubrication can indeed be modified, andsuitable vectors that can form efficiently lubricating boundary layersare thus at a premium. The use of liposomes  for intra-articularinjections is an area ripe for exploitation. Because liposomes arealso widely used as drug carriers, such lubrication vectors couldbe used at the same time for the controlled release of anti-inflammatoryor pain-reducing drugs, which could be an effective treatment, bothpalliative and disease-suppressing, for OA.2.Further on the topic of articular cartilage,lubricants, particularly liposomes, functionalized with targetingmoieties which can tightly bind to the cartilage surface should bedesigned. Such a system will avoid the loss of lubricants within thecirculatory system and out of the synovial membrane and maintain boundarylayers on the cartilage surface for extended periods.3.A related area to be explored concernsthe preparation of hydrogels with desirable mechanical properties(strong and tough) and high water content (up to 70–80%), suchas double-network hydrogels, incorporating highly hydrated lubricationvectors that would provide a reservoir to replenish boundary layersat the gel surface. Such layers may act through the hydration lubricationmechanism, resulting in extremely low friction and low wear and, unlikesurface-applied or surface grown layers, would be replenished as theywear, thereby providing long-term lubricity. An associated and challengingproblem to be resolved concerns the effective adherence of the lubricant-incorporatinghydrogels in their wet state either to biological tissues such ascartilage lesions or to biomedical devices whose use calls for lubricated surfaces.4.Biocompatibility is a key requirementfor the biological application of lubricants, whether directly onbiological tissues  or forlubricated hydrogel coatings for biomedical devices. The use of liposomesshould be further explored in this context because, almost uniquely,they are both naturally biocompatible because they are ubiquitousin living organisms and they can assemble to provide extremely lubriciousboundary layers via the hydration lubrication mechanism. Recent indicationssuggest that examining the ability of liposomes to form more robustand efficient boundary layers in combination with other biomacromoleculesis another direction that should be investigated.Our initial account of hydration lubrication was extended to thesurface of cartilage, a complex biohydrogel, where such a low frictionmechanism is believed to apply, and from that to lubrication of andby synthetic hydrogels. We conclude by considering a number of outstandingchallenges and opportunities in this area. These include the following:


Paederus beetle was improved after treatments. However, the patient developed generalized erythema with desquamation and scaling. The patient was successfully treated topically with moisturizing liquid soap and topical moisturizer with emollients and humectants, and triamcinolone lotion was applied on the bright red lesion. The patient was also treated with oral replacement solution and tropical azelaic cream was applied on the hyperpigmented kissing lesion. This case report shows the importance of a diagnostic practice with follow-up examination.Exfoliative erythroderma is rare but serious condition, which requires close supervision. We report a rare case of 28-year-old man with kissing lesions of Paederus dermatitis at his right side of neck. The rash caused by  Paederus beetles (family Staphylinidae). The lesion is local and unlikely to develop generalized abnormal skin presentations [Paederus dermatitis is one type of irritant contact dermatitis that occurs worldwide, especially in tropical and subtropical regions. Most of the patients develop localized blistering and inflammation after contacting with ntations . We repoPaederus beetle  [Paederus have been associated with Paederus dermatitis worldwide, however, Paederus fuscipes (Coleoptera: Staphylinidae) was mostly reported as the causative agent in Thailand [Paederus beetles have often attracted themselves to incandescent and fluorescent lights, which may explain why the patients especially from the urban area who sleep with light on have Paederus dermatitis [Paederus dermatitis is an acute irritant contact dermatitis caused by accidently crushing the 4H43O9N) . Althougaederin C4H43O9N [in vivo study has revealed that paederin enhances the expressions of toll-like receptor (TLR)-2 and interleukins (IL)-4, -5, and -13, which may be relevant to the disease severity in patients [On crushing the insect, patients are being exposed to paederin and experience self-limiting acute severe skin irritation, erythema, vesiculation, and crusting. Periorbital dermatitis and keratoconjunctivitis were less commonly reported . Moreovepatients .Treatment of Paederus dermatitis is initially done by washing the irritant area with soap and water, using cold wet compression and application of topical steroid. Preventing human-beetle contact is the primary prevention strategy by turning off the light and closing all windows and doors securely before sleep .We present atypical case of Paederus dermatitis as generalized erythroderma with desquamation. Further study is required to elucidate the molecular mechanisms related to exfoliative dermatitis in Paederus dermatitis patients.


Service refusal, where patients actively refuse clinicians’ recommendations for additional services needed to achieve safe and full recovery after discharge, is a key but often overlooked cause of readmissions. There is a dearth of literature on the extent of service refusal and providers’  observations regarding how to deal with these situations. As part of a larger, 10 VA site organizational case study of readmission, semi-structured interviews exploring causes of readmission were conducted with 21-41 staff members at each site (n=314). 41 providers identified Veteran service refusal and decision-making as causes of readmission. Providers acknowledged the need to honor patient autonomy/self-determination in decisions while at the same time worrying about potential adverse outcomes. Incongruence between Veterans’ and providers’ perceptions , goals, and discharge plans was also cited as a factor in service refusal. Frustration was also raised about initial acceptance of service followed by refusal at time of service delivery. Providers also felt readmissions increased even further when combined with lack of or inadequate caregiving arrangements/family support, lack of cognitive capacity, homelessness, or home care affordability. Findings point to the need for interventions to evaluate congruence between provider and patient assessment of self-care capabilities and provide more in-depth goal setting and motivational interviewing techniques to help patients reach more realistic post-discharge care goals.