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Biocatalysis has become an important component of modern organic chemistry, presenting an efficient and environmentally friendly approach to synthetic transformations. Advances in molecular biology, computational modeling, and protein engineering have unlocked the full potential of enzymes in various industrial applications. However, the inherent limitations of the natural building blocks have sparked a revolutionary shift. In vivo genetic incorporation of noncanonical amino acids exceeds the conventional 20 amino acids, opening new avenues for innovation. This review provides a comprehensive overview of applications of noncanonical amino acids in biocatalysis. We aim to examine the field from multiple perspectives, ranging from their impact on enzymatic reactions to the creation of novel active sites, and subsequent catalysis of new-to-nature reactions. Finally, we discuss the challenges, limitations, and promising opportunities within this dynamic research domain.

Increasing evidence indicates that disgust might compromise sexual functioning and can contribute to sexual problems. Although the stimuli and conditions that elicit disgust vary greatly across individuals, they cluster in three categories of disgust elicitors: Stimuli that are associated with an increased risk of the transmission of infectious diseases (pathogen disgust), stimuli that signal poor mating quality and may jeopardize reproductive success (sexual disgust), and behaviors that violate social norms (moral disgust). It has been argued that each of these categories of disgust may interfere with sexual responses. Thus far, research on the role of disgust in sexual contexts focused on external stimuli (e.g., sperm). Yet, recently it has been proposed that disgust can also become directed to features of the self. Such self-directed disgust may also apply to sexual contexts and contribute to sexual problems. As a first step to explore the relevance of self-disgust in sexual functioning, we tested if indeed particular sexual experiences have the ability to elicit self-disgust. Using a within subject design, participants (N = 124; all women) imagined themselves as well as others experiencing a series of sex-related scenarios, each relevant for one of the three categories of disgust, and subsequently rated their self-disgust. For all types of disgust, the scenarios evoked self-disgust, and the "self-perspective" elicited significantly more self-disgust than the "other-perspective." These findings support theoretical models pointing to the relevance of taking self-disgust into consideration as a factor that may compromise sexual functioning. Future research should test whether this also holds for men.

Introduction: Pain as a symptom of diabetic polyneuropathy (DPN) significantly lowers quality of life, increases mortality and is the main reason for patients with diabetes to seek medical attention. The number of people suffering from painful diabetic polyneuropathy (PDPN) has increased significantly over the past decades., Methods: The literature on the diagnosis and treatment of diabetic polyneuropathy was retrieved and summarized., Results: The etiology of PDPN is complex, with primary damage to peripheral nociceptors and altered spinal and supra-spinal modulation. To achieve better patient outcomes, the mode of diagnosis and treatment of PDPN evolves toward more precise pain-phenotyping and genotyping based on patient-specific characteristics, new diagnostic tools, and prior response to pharmacological treatments. According to the Toronto Diabetic Neuropathy Expert Group, a presumptive diagnosis of "probable PDPN" is sufficient to initiate treatment. Proper control of plasma glucose levels, and prevention of risk factors are essential in the treatment of PDPN. Mechanism-based pharmacological treatment should be initiated as early as possible. If symptomatic pharmacologic treatment fails, spinal cord stimulation (SCS) should be considered. In isolated cases, where symptomatic pharmacologic treatment and SCS are unsuccessful or cannot be used, sympathetic lumbar chain neurolysis and/or radiofrequency ablation (SLCN/SLCRF), dorsal root ganglion stimulation (DRGs) or posterior tibial nerve stimulation (PTNS) may be considered. However, it is recommended that these treatments be applied only in a study setting in a center of expertise., Conclusions: The diagnosis of PDPN evolves toward pheno-and genotyping and treatment should be mechanism-based., (© 2023 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Introduction: Cervical radicular pain is pain perceived in the upper limb, caused by irritation or compression of a cervical spine nerve, the roots of the nerve, or both., Methods: The literature on the diagnosis and treatment of cervical radicular pain was retrieved and summarized., Results: The diagnosis is made by combining elements from the patient's history, physical examination, and supplementary tests. The Spurling and shoulder abduction tests are the two most common examinations used to identify cervical radicular pain. MRI without contrast, CT scanning, and in some cases plain radiography can all be appropriate imaging techniques for nontraumatic cervical radiculopathy. MRI is recommended prior to interventional treatments. Exercise with or without other treatments can be beneficial. There is scant evidence for the use of paracetamol, nonsteroidal anti-inflammatory drugs, and neuropathic pain medications such as gabapentin, pregabalin, tricyclic antidepressants, and anticonvulsants for the treatment of radicular pain. Acute and subacute cervical radicular pain may respond well to epidural corticosteroid administration, preferentially using an interlaminar approach. By contrast, for chronic cervical radicular pain, the efficacy of epidural corticosteroid administration is limited. In these patients, pulsed radiofrequency treatment adjacent to the dorsal root ganglion may be considered., Conclusions: There is currently no gold standard for the diagnosis of cervical radicular pain. There is scant evidence for the use of medication. Epidural corticosteroid injection and pulsed radiofrequency adjacent to the dorsal root ganglion may be considered. [Correction added on 12 June 2023, after first online publication: The preceding sentence was corrected.]., (© 2023 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Sugar beet leaves can be a viable and economically interesting source of high-quality protein for the food industry. We investigated how storage conditions and leaf wounding at harvest affect the content and quality of the soluble protein. After collection, leaves were either stored intact or shredded to mimic wounding induced by commercial leaf harvesters. Leaf material was stored in small volumes at different temperatures to assess leaf physiology or in larger volumes to assess temperature development at different locations in the bins. Protein degradation was more pronounced at higher storage temperatures. Wounding accelerated the degradation of soluble protein at all temperatures. Both wounding and storage at higher temperatures greatly stimulated respiration activity and heat production. At temperatures below 5°C, ribulose-1,5-biphosphate carboxylase oxygenase (RuBisCO) in intact leaves was preserved for up to 3 weeks. At temperatures of 30-40°C, RuBisCO degradation occurred within 48 h. Degradation was more pronounced in shredded leaves. In 0.8-m 3 storage bins at ambient temperature, core temperatures rapidly increased, up to 25°C in intact leaves and up to 45°C in shredded leaves within 2-3 days. Immediate storage at 5°C greatly suppressed the temperature increase in intact but not in shredded leaves. The indirect effect of excessive wounding, that is, heat production, is discussed as the pivotal factor responsible for increased degradation of protein. For optimal retention of soluble protein levels and quality in harvested sugar beet leaves, it is advised to minimize wounding and to store the material at temperatures around -5°C. PRACTICAL APPLICATION: To preserve the soluble protein content and quality for at least 3 weeks, sugar beet leaves should be harvested with minimal wounding and stored at temperatures between 1 and 5°C. When aiming to store minimally wounded leaves in larger volumes, it must be ensured that the product temperature in the core of the biomass meets the temperature criterium or the cooling strategy must be adjusted. The principles of minimal wounding and low temperature storage are transferable to other leafy crops that are harvested for food protein., (© 2023 Wageningen Food & Biobased Research. Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Background: Fear-avoidance is one of the factors associated with chronic pain. However, it remains unclear whether the association between fear-avoidance and pain depends on sex. The present study aimed to investigate whether the association between fear-avoidance and pain intensity differed between men and women in chronic pain patients. Additionally, the potential confounding effect of affective experiences on the association between fear-avoidance and pain intensity was analyzed., Method: This cohort study included hospital referred chronic pain patients ( n = 45). Short momentary assessment questions according to the experience sampling method (ESM) were used to repeatedly assess patients' pain intensity, level of fear-avoidance and positive as well as negative affect during their daily life. Linear mixed-effects models were applied in the statistical analysis. Unadjusted and adjusted models were made, in which the latter corrected for statistically significant affective experiences and baseline variables, taking the Aikake Information Criterion into account to assess a better model of fit., Results: The results demonstrated an association between fear-avoidance and pain intensity that differed for men and women. In men ( n = 13), no association between these variables was found (-0.04 (95% CI: -0.14, 0.06) with a p -value of 0.48), whereas in women ( n = 32), an increase in fear-avoidance was associated with a (slight) increase in pain intensity (0.18 (95% CI 0.06, 0.30) with a p -value of 0.003). Affect did not confound the above-mentioned findings., Conclusion: Our data supports previous research highlighting the importance of sex differences in pain experience. These findings may be relevant for clinicians to consider more personalized (i.e., gender specific) pain management in chronic pain patients.

Leaf senescence can be induced by stress or aging, sometimes in a synergistic manner. It is generally acknowledged that the ability to withstand senescence-inducing conditions can provide plants with stress resilience. Although the signaling and transcriptional networks responsible for a delayed senescence phenotype, often referred to as a functional stay-green trait, have been actively investigated, very little is known about the subsequent metabolic adjustments conferring this aptitude to survival. First, using the individually darkened leaf (IDL) experimental setup, we compared IDLs of wild-type (WT) Arabidopsis (Arabidopsis thaliana) to several stay-green contexts, that is IDLs of two functional stay-green mutant lines, oresara1-2 (ore1-2) and an allele of phytochrome-interacting factor 5 (pif5), as well as to leaves from a WT plant entirely darkened (DP). We provide compelling evidence that arginine and ornithine, which accumulate in all stay-green contexts-likely due to the lack of induction of amino acids (AAs) transport-can delay the progression of senescence by fueling the Krebs cycle or the production of polyamines (PAs). Secondly, we show that the conversion of putrescine to spermidine (SPD) is controlled in an age-dependent manner. Thirdly, we demonstrate that SPD represses senescence via interference with ethylene signaling by stabilizing the ETHYLENE BINDING FACTOR1 and 2 (EBF1/2) complex. Taken together, our results identify arginine and ornithine as central metabolites influencing the stress- and age-dependent progression of leaf senescence. We propose that the regulatory loop between the pace of the AA export and the progression of leaf senescence provides the plant with a mechanism to fine-tune the induction of cell death in leaves, which, if triggered unnecessarily, can impede nutrient remobilization and thus plant growth and survival., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: Change on the Numeric Rating Scale (NRS) is based on subjective pain experience, hampering the establishment of clinically important improvement. An anchor-based method, the Patients' Global Impression of Change (PGIC), is often added to determine whether a patient has improved. A two-point change on the NRS has been shown to be equivalent to a moderate clinically important improvement in randomized controlled trials (RCT's) on medication effects. We contemplated whether these findings could be reproduced in cohort and data and in non-drug interventional RCT's., Methods: The NRS change was quantified by subtracting the NRS of baseline from the NRS at 6-month follow-up. Categorization of success/nonsuccess was applied on the PGIC, and their average NRS raw changes were calculated. The Spearman correlation coefficient quantified the overall relationship, while the discriminative ability was explored through the receiver operating characteristic curve. Data were stratified on design, sex, and pain intensity at baseline. Besides, the cohort evaluated treatment status at follow-up., Results: The records of 1661 patients were examined. Overall, the observed NRS change needed for moderate clinically important improvement was larger than the average two points. Yet, the changes in the cohort were smaller compared with the RCT's. Moreover, it modified with pain intensity at baseline and treatment statuses indicated differences in mean clinical importance of -4.15 (2.70) when finalized at 6 months and -2.16 (2.48) when treatment was ongoing., Conclusion: The moderate clinically important improvement varied substantially, representing heterogeneity in pain relief and its relation to treatment success in chronic pain patients., (© 2021 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Competing Interests: Competing interests: None declared.

Objective: Prevention of recurrent stroke in patients with embolic stroke of undetermined source (ESUS) is challenging. The advent of safer anticoagulation in the form of direct oral anticoagulants (DOACs) has prompted exploration of prophylactic anticoagulation for all ESUS patients, rather than anticoagulating just those with documented atrial fibrillation (AF). However, recent trials have failed to demonstrate a clinical benefit, while observing increased bleeding. We modeled the economic impact of anticoagulating ESUS patients without documented AF across multiple geographies., Methods: CRYSTAL-AF trial data were used to assess ischaemic stroke event rates in ESUS patients confirmed AF-free after long-term monitoring. Anticipated bleeding event rates (including both minor and major bleeds) with aspirin, dabigatran 150 mg, and rivaroxaban 20 mg were sourced from published meta-analyses, whilst a 30% ischaemic stroke reduction for both DOACs was assumed. Cost data for clinical events and pharmaceuticals were collected from the local payer perspective., Results: Compared with aspirin, dabigatran and rivaroxaban resulted in 17.9 and 29.9 additional bleeding events per 100 patients over a patient's lifetime, respectively. Despite incorporating into our model the proposed 30% reduction in ischaemic stroke risk, both DOACs were cost-additive over patient lifetime, as the costs of bleeding events and pharmaceuticals outweighed cost savings associated with the reduction in ischaemic strokes. DOACs added £5953-£7018 per patient (UK), €6683-€7368 (Netherlands), €4933-€9378 (Spain), AUD$5353-6539 (Australia) and $26,768-$32,259 (US) of payer cost depending on the agent prescribed. Additionally, in the U.S. patient pharmacy co-payments ranged from $2468-$12,844 depending on agent and patient plan. In all settings, cost-savings could not be demonstrated even when the modelling assumed 100% protection from recurrent ischaemic strokes, due to the very low underlying risk of recurrent ischaemic stroke in this population (1.27 per 100 patient-years)., Conclusions: Anticoagulation of non-AF patients may cause excess bleeds and add substantial costs for uncertain benefits, suggesting a personalised approach to anticoagulation in ESUS patients.

Near infrared (NIR) spectroscopy allows rapid estimation of quality traits in fresh fruit. Several portable spectrometers are available in the market as a low-cost solution to perform NIR spectroscopy. However, portable spectrometers, being lower in cost than a benchtop counterpart, do not cover the complete near infrared (NIR) spectral range. Often portable sensors either use silicon-based visible and NIR detector to cover 400-1000 nm, or InGaAs-based short wave infrared (SWIR) detector covering the 900-1700 nm. However, these two spectral regions carry complementary information, since the 400-1000 nm interval captures the color and 3rd overtones of most functional group vibrations, while the 1st and the 2nd overtones of the same transitions fall in the 1000-1700 nm range. To exploit such complementarity, sequential data fusion strategies were used to fuse the data from two portable spectrometers, i.e., Felix F750 (~400-1000 nm) and the DLP NIR Scan Nano (~900-1700 nm). In particular, two different sequential fusion approaches were used, namely sequential orthogonalized partial-least squares (SO-PLS) regression and sequential orthogonalized covariate selection (SO-CovSel). SO-PLS improved the prediction of moisture content (MC) and soluble solids content (SSC) in pear fruit, leading to an accuracy which was not obtainable with models built on any of the two spectral data set individually. Instead, SO-CovSel was used to select the key wavelengths from both the spectral ranges mostly correlated to quality parameters of pear fruit. Sequential fusion of the data from the two portable spectrometers led to an improved model prediction (higher R 2 and lower RMSEP) of MC and SSC in pear fruit: compared to the models built with the DLP NIR Scan Nano (the worst individual block) where SO-PLS showed an increase in R 2 p up to 56% and a corresponding 47% decrease in RMSEP. Differences were less pronounced to the use of Felix data alone, but still the R 2 p was increased by 2.5% and the RMSEP was reduced by 6.5%. Sequential data fusion is not limited to NIR data but it can be considered as a general tool for integrating information from multiple sensors., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to assess how Dutch neurologists and anesthesiologists diagnose and treat people with sciatica in secondary care and to evaluate their adherence to the newest guidelines., Methods: We conducted a cross-sectional survey. Respondents were asked about their current clinical practice related to sciatica. Three authors rated the respondents' adherence to the guidelines on a three-point Likert scale., Results: Eighty neurologists and 44 anesthesiologists completed the questionnaire. Neurologists diagnose their sciatica patients primarily using a magnetic resonance imaging (89%). Selective diagnostic nerve blocks are considered useful by 81% of the neurologists. Neurologists primarily treat patients with pain medication, and 40% of them think epidural steroid injections are effective in 40-60% of injected patients. Twenty-nine percent of neurologists refer patients to a neurosurgeon after 4 months. Anesthesiologists consider a selective diagnostic nerve root block to have a higher diagnostic value than mapping. The most reported side effect of epidural injections is exacerbation of pain (82%). Pulse radiofrequency is applied in 9-11% of acute cases. The results also indicate that Dutch neurologists and anesthesiologists follow an evidence-based approach that is strictly or broadly in line with the guideline., Conclusions: Neurologists treat sciatica patients initially with pain medication and physiotherapy, followed by epidural steroid injections and referral for surgery. Anesthesiologists treat sciatica patients with one or more steroid injections or may perform a selective nerve root block. Imaging, selective nerve root blocks, medication, physiotherapy, and pulse radiofrequency are topics of further research., (© 2021 S. Karger AG, Basel.)

Background and Objectives: Chronic pain affects many adults. To improve our daily practice, we need to understand multidisciplinary approaches, integrated treatment plans and the biopsychosocial context of these patients. To date, almost 15 000 chronic pain patients have been referred to the Maastricht University Pain Center in the Netherlands., Methods: This study describes 11 214 of these patients suffering from chronic pain. Chronic pain was analyzed using relevant Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials instruments., Results: Most patients were female (59.3%). The prevalence of low education was 59%, and unemployment/disability was 35.9%. The mean age was 55.6 years. Severe pain (Numerical Rating Sale score 7-10) was reported by 71.9% of the patients; psychological and quality of life values deteriorated when pain severity increased. Approximately 36% of patients showed severe signs of depression or anxiety, and 39% displayed high pain catastrophizing. Of all patients, 17.8% reported high values for pain severity, catastrophizing and anxiety or depression., Conclusions: Based on baseline biopsychosocial values, this study shows the complexity of patients referred to pain centers. Pain management with a biopsychosocial approach in an integrated multidisciplinary setting is indispensable. Above all, adjusted education on chronic pain and attention to its biopsychosocial aspects are deemed necessary., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: One popular procedure in the medical student selection process are multiple mini-interviews (MMIs), which are designed to assess social skills (e.g., empathy) by means of brief interview and role-play stations. However, it remains unclear whether MMIs reliably measure desired social skills or rather general performance differences that do not depend on specific social skills. Here, we provide a detailed investigation into the construct validity of MMIs, including the identification and quantification of performance facets (social skill-specific performance, station-specific performance, general performance) and their relations with other selection measures. Methods: We used data from three MMI samples ( N  = 376 applicants, 144 raters) that included six interview and role-play stations and multiple assessed social skills. Results: Bayesian generalizability analyses show that, the largest amount of reliable MMI variance was accounted for by station-specific and general performance differences between applicants. Furthermore, there were low or no correlations with other selection measures. Discussion: Our findings suggest that MMI ratings are less social skill-specific than originally conceptualized and are due more to general performance differences (across and within-stations). Future research should focus on the development of skill-specific MMI stations and on behavioral analyses on the extents to which performance differences are based on desirable skills versus undesired aspects.

Background: Medical education in the discipline of psychiatry and psychotherapy at the University of Münster was traditionally focused on the transfer of knowledge via lectures. According to the current guidelines, the medical curriculum was modified as from the winter semester 2016/2017 to be more competency-based and the changes were evaluated., Objective: Lectures and seminars were reduced to achieve a better linkage between theoretical and practical knowledge. Moreover, learning goals were formulated based on the German National Competence-based Catalogue of Learning Objectives in Medicine (NKLM) and entrustable professional activities (EPAs)., Material and Methods: Almost all previous lectures are now replaced by an inverted classroom concept with e‑learning. Theoretical knowledge is deepened by immediate multiple choice (MC) examinations and a seminar, which now focusses on specific practical EPAs. At the end of the semester, the students now undergo a practical, formative examination with simulated patients (actors) in addition to the former MC test. For evaluation, a representative sample of a semester cohort which took part in the previous curriculum and a similar cohort which attended the revised curriculum were investigated. Moreover, variables which might have an impact on the results were assessed, e. g. pre-existing psychiatric knowledge and motivation., Results: Students taught by the modified curriculum showed a significantly better practical performance and no reduction of theoretical knowledge. Relevant influencing factors were not identified., Conclusion: The results show that a competency-based modification of the curriculum in the discipline of psychiatry and psychotherapy leads to more practical abilities and thus helps future physicians to be more self-determined.

Aim: The aim of this study was to perform a cost-effectiveness analysis to establish the cost-effectiveness of sensor-augmented pump therapy (SAP) with automated insulin suspension vs continuous subcutaneous insulin infusion (CSII) alone in patients with type 1 diabetes in the Netherlands., Patients and Methods: The analysis was performed using the IQVIA CORE Diabetes Model (CDM) in two different patient cohorts: one with suboptimal glycemic control at baseline (mean age 27 years, mean baseline HbA1c 8.0% [64 mmol/mol]) and the other at increased risk of hypoglycemic events (mean age 18.6 years, mean baseline HbA1c 7.5% [58 mmol/mol]). Clinical input data were sourced from published literature, and the analysis was performed from the societal perspective., Results: In patients with suboptimal baseline glycemic control, SAP improved quality-adjusted life expectancy by 1.77 quality-adjusted life years (QALYs) vs CSII (15.54 QALYs vs 13.77 QALYs) with higher lifetime costs (EUR 189,855 vs EUR 150,366), resulting in an incremental cost-effectiveness ratio (ICER) of EUR 22,325 per QALY gained. In this cohort, sensitivity analyses showed that the influence of SAP on fear of hypoglycemia (FoH) and baseline HbA1c were key drivers of results. In patients at increased risk of hypoglycemia, the gain in quality-adjusted life expectancy with SAP vs CSII was 2.16 QALYs (16.70 QALYs vs 14.53 QALYs) with higher lifetime costs (EUR 204,013 vs EUR 171,032) leading to an ICER of EUR 15,243 per QALY gained. In this patient group, findings were most sensitive to changes in assumptions relating to the incidence of severe hypoglycemic events in the CSII arm., Conclusion: For type 1 diabetes patients in the Netherlands who do not achieve target HbA1c levels or who experience frequent severe hypoglycemic events on CSII, switching to SAP is likely to be cost-effective., Competing Interests: Disclosure Funding for the analysis was provided by Medtronic International Trading Sàrl. AD and SdP are current employees of Medtronic International Trading Sàrl, which manufactures SAP devices. BdB is a current employee of Medtronic Trading NL. SR is a current employee of HEVA HEOR, which has received consulting fees from Medtronic International Trading Sàrl. JS-P is a current employee of Ossian Health Economics and Communications, which has received consulting fees from Medtronic International Trading Sàrl. HWdV has previously received consulting fees/honoraria from Medtronic International Trading Sàrl. The authors report no other conflicts of interest in this work.

Objective: Ankle sprains are common injuries that may lead to long-term morbidity. Individuals with obesity are at increased risk for ankle sprains; however, prognostic associations between body mass index (BMI) and recovery are less well understood. This study investigated whether BMI status affects recovery from ankle sprains., Methods: We included individuals≥16 years old with grade 1 or 2 ankle sprains who sought emergency department treatment in Kingston, Ontario, Canada. Height in centimeters and weight in kilograms were measured at baseline by using a height rod and a standard medical column scale, respectively. BMI was calculated and categorized as non-overweight,<25.0kg/m 2 ; overweight, 25.0-29.9kg/m 2 ; and obese,≥30kg/m 2 . Recovery was assessed at 1, 3 and 6 months post-injury by the Foot and Ankle Outcome Score (FAOS). Continuous FAOS and binary recovery status were compared by BMI group at each assessment using a repeated measures linear mixed effects model and logistic regression, respectively., Results: In total, 504 individuals were recruited and 6-month follow-up data were collected for 80%. We observed no significant differences in recovery at 1 and 3 months post-injury. At 6 months, between 53% and 66% of the participants were considered to have recovered according to the FAOS. The mean difference in unadjusted FAOS between participants classified as obese and non-overweight was -23.02 (95% confidence interval, -38.99 to -7.05) but decreased after adjusting for confounders. The odds ratio for recovery was 0.60 (0.37-0.97) before adjustment and 0.74 (0.43-1.29) after adjustment. Six-month recovery was significantly lower for participants with obesity than non-overweight participants on the FAOS Pain and Function in Daily Living subscales but were not clinically meaningful., Conclusions: All BMI groups showed improvements from ankle sprain over time. However, at 6 months, a sizeable proportion of the participants had not fully recovered particularly among individuals classified as obese. The findings suggest that individuals with obesity may benefit from specialized interventions focused on symptom management and functional activity., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Although fibrosis and emphysema are in many ways on opposite ends of the pulmonary parenchymal disease spectrum, they seem to share common pathomechanistic steps. This is illustrated by the coexistence of both entities in lungs of individuals with combined pulmonary fibrosis and emphysema. Macroproteins elastin and collagen are major constituents of the pulmonary extracellular matrix. The prevailing paradigm states that emphysema is caused by an imbalance between destructive proteolytic and protective antiproteolytic enzymes leading to accelerated degradation of elastin fibers in the lungs. Rates of elastin breakdown, however, are equally enhanced in patients with idiopathic pulmonary fibrosis (IPF) and emphysema. Excessive accumulation of collagen is a hallmark of IPF. Surprisingly, collagen levels in the lung parenchyma of patients with emphysema are also higher than in controls. The concentration of elastin fibers is elevated in fibrotic lungs, despite accelerated elastinolysis, suggesting that elastin repair is also enhanced in IPF. Since elastin concentrations are reduced in emphysematous lungs, the factor of divergence between emphysema and fibrosis seems to be the degree of elastin repair. Multiple elastin repair steps can be deduced of which tropoelastin synthesis and crosslinking of tropoelastin polymers by the copper dependent enzyme lysyl oxidase seem to be the most important ones. We suspect that the distinction in the pathogeneses of lung fibrosis and emphysema depends on the local availability of copper to activate sufficient lysyl oxidase for elastin crosslinking, and suggest assessing the effects of inhalation therapy with copper plus heparin in emphysema and heparin monotherapy in IPF., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The triterpenes are one of the largest and most structurally diverse families of plant natural products. Many triterpene derivatives have been shown to possess medicinally relevant biological activity. However, thus far this potential has not translated into a plethora of triterpene-derived drugs in the clinic. This is arguably (at least partially) a consequence of limited practical synthetic access to this class of compound, a problem that can stifle the exploration of structure-activity relationships and development of lead candidates by traditional medicinal chemistry workflows. Despite their immense diversity, triterpenes are all derived from a single linear precursor, 2,3-oxidosqualene. Transient heterologous expression of biosynthetic enzymes in N. benthamiana can divert endogenous supplies of 2,3-oxidosqualene towards the production of new high-value triterpene products that are not naturally produced by this host. Agro-infiltration is an efficient and simple means of achieving transient expression in N. benthamiana. The process involves infiltration of plant leaves with a suspension of Agrobacterium tumefaciens carrying the expression construct(s) of interest. Co-infiltration of an additional A. tumefaciens strain carrying an expression construct encoding an enzyme that boosts precursor supply significantly increases yields. After a period of five days, the infiltrated leaf material can be harvested and processed to extract and isolate the resulting triterpene product(s). This is a process that is linearly and reliably scalable, simply by increasing the number of plants used in the experiment. Herein is described a protocol for rapid preparative-scale production of triterpenes utilizing this plant-based platform. The protocol utilizes an easily replicable vacuum infiltration apparatus, which allows the simultaneous infiltration of up to four plants, enabling batch-wise infiltration of hundreds of plants in a short period of time.

Objective: To explore the effectiveness of a 2-week client-centered rehabilitation intervention (tune-up) delivered 6 months after inpatient discharge on community reintegration at 1 year in people with stroke., Design: A multicenter randomized controlled trial with 2 groups: an intervention ("tune-up") group and a control group having the same exposure to assessment., Setting: Three research laboratories., Participants: Participants (N=103) with hemiparetic stroke recruited from inpatient rehabilitation units at the time of discharge., Interventions: Participants randomized to the tune-up group received 1-hour therapy sessions in their home 3times/wk for 2 weeks at 6 months postdischarge focusing on identified mobility-related goals. A second tune-up was provided at 12 months., Main Outcome Measures: Community reintegration measured by the Subjective Index of Physical and Social Outcome at 12 months and secondary outcomes included the Berg Balance Scale and measures of mobility and health-related quality of life up to 15 months., Results: At 12 months, both groups showed significant improvement in community reintegration (P<.05), a trend evident at all time points, with no difference between groups (mean difference, -0.5; 95% confidence interval, -1.8 to 2.7; P=.68). Similarly, a main effect of time reflected improvement in mobility-related and quality of life outcomes for both groups (P≤.0.5), but no group differences (P≥.30)., Conclusions: All participants in the tune-up group met or exceeded at least 1 mobility-related goal; however, the intervention did not differentially improve community reintegration. The improvements in mobility and quality of life over the 15-month postdischarge period may be secondary to high activity levels in both study groups and exposure to regular assessment., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

In plants, an individually darkened leaf initiates senescence much more rapidly than a leaf from a whole darkened plant. Combining transcriptomic and metabolomic approaches in Arabidopsis ( Arabidopsis thaliana ), we present an overview of the metabolic strategies that are employed in response to different darkening treatments. Under darkened plant conditions, the perception of carbon starvation drove a profound metabolic readjustment in which branched-chain amino acids and potentially monosaccharides released from cell wall loosening became important substrates for maintaining minimal ATP production. Concomitantly, the increased accumulation of amino acids with a high nitrogen-carbon ratio may provide a safety mechanism for the storage of metabolically derived cytotoxic ammonium and a pool of nitrogen for use upon returning to typical growth conditions. Conversely, in individually darkened leaf, the metabolic profiling that followed our 13 C-enrichment assays revealed a temporal and differential exchange of metabolites, including sugars and amino acids, between the darkened leaf and the rest of the plant. This active transport could be the basis for a progressive metabolic shift in the substrates fueling mitochondrial activities, which are central to the catabolic reactions facilitating the retrieval of nutrients from the senescing leaf. We propose a model illustrating the specific metabolic strategies employed by leaves in response to these two darkening treatments, which support either rapid senescence or a strong capacity for survival., (© 2018 American Society of Plant Biologists. All Rights Reserved.)

Objective: To investigate the extent to which physical performance measures of strength, balance, and mobility taken at discharge from inpatient stroke rehabilitation can predict health-related quality of life (HRQoL) and community reintegration after 6 months., Design: Longitudinal study., Setting: University laboratory., Participants: Adults (N=75) recruited within 1 month of discharge home from inpatient stroke rehabilitation., Interventions: Not applicable., Main Outcome Measures: 36-Item Short Form Health Survey (SF-36) for HRQoL and Subjective Index of Physical and Social Outcome (SIPSO) for community reintegration. Physical performance measures were the 6-minute walk test, timed Up and Go (TUG) test, Berg Balance Scale, Community Balance and Mobility Scale, and isokinetic torque and power of hip, knee, and ankle on the paretic and nonparetic sides. Other prognostic variables included age, sex, stroke type and location, comorbidities, and motor FIM score., Results: Separate stepwise linear regressions were performed using the SF-36 and SIPSO as dependent variables. The total paretic lower limb torque and 6-minute walk test predicted the SF-36 Physical Component Summary (adjusted R 2 =.30). The total paretic lower limb torque and TUG test predicted the SIPSO physical component (adjusted R 2 =.47). The total paretic lower limb torque significantly predicted the SF-36 Mental Component Summary, but the adjusted R 2 was low (.06). Similarly, the TUG test significantly predicted the SIPSO social component, but again the adjusted R 2 was low (.09)., Conclusions: Measures of physical performance including muscle strength and mobility at discharge can partially predict HRQoL and community reintegration 6 months later. Further research is necessary for more accurate predictions., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: There is an ongoing need for additional interventions in idiopathic pulmonary fibrosis (IPF) as antifibrotic drugs currently available only inhibit and do not stall disease progression. Vitamin K is a co-factor for the activation of coagulation factors. However, it is also required to activate proteins with functions outside of the coagulation cascade, such as matrix Gla protein (MGP), a defender against soft tissue calcification. Vitamin K antagonists are anticoagulants that are, for unknown reasons, associated with increased mortality in IPF. Areas covered: We advance the hypothesis that modulation of vitamin K-dependent MGP activation in IPF patients by either vitamin K antagonism or administration may result in acceleration and deceleration of fibrosis progression, respectively. Furthermore, shortfall in vitamin K could be suspected in IPF based on the high prevalence of certain co-morbidities, such as vascular calcification and lung cancer. Expert commentary: We hypothesize that vitamin K status is reduced in IPF patients. This, in combination with studies suggesting that vitamin K may play a role in lung fibrosis pathogenesis, would provide a rationale for conducting a clinical trial assessing the potential mitigating effects of vitamin K administration on progression of lung fibrosis, prevention of co-morbidities and mortality in IPF.

Surface water used for drinking water production is frequently monitored in The Netherlands using whole organism biomonitors, with for example Daphnia magna or Dreissena mussels, which respond to changes in the water quality. However, not all human-relevant toxic compounds can be detected by these biomonitors. Therefore, a new on-line biosensor has been developed, containing immobilized genetically modified bacteria, which respond to genotoxicity in the water by emitting luminescence. The performance of this sensor was tested under laboratory conditions, as well as under field conditions at a monitoring station along the river Meuse in The Netherlands. The sensor was robust and easy to clean, with inert materials, temperature control and nutrient feed for the reporter organisms. The bacteria were immobilized in sol-gel on either an optical fiber or a glass slide and then continuously exposed to water. Since the glass slide was more sensitive and robust, only this setup was used in the field. The sensor responded to spikes of genotoxic compounds in the water with a minimal detectable concentration of 0.01 mg/L mitomycin C in the laboratory and 0.1 mg/L mitomycin C in the field. With further optimization, which should include a reduction in daily maintenance, the sensor has the potential to become a useful addition to the currently available biomonitors., Competing Interests: The authors declare no conflict of interest.

Purpose: A qualitative inquiry was conducted to investigate the qualification requirements of medical doctors in different professional fields and from different perspectives. The inquiry was part of an empirical workplace analysis. Methods: Seventy-four structured interviews were conducted and analyzed to examine critical incidents and behaviors of medical doctors working in different professional fields (clinical theory, clinical practice, practitioner) and disciplines, and from three different perspectives (medical doctors, non-medical staff, and patients). In addition, the National Competency-based Catalogue of Learning Objectives for Medical Education (Nationaler Kompetenzbasierter Lernzielkatalog Medizin / NKLM) was used. Results: The results revealed eleven relevant competencies, which could be categorized into three superordinate competence clusters: interpersonal, work-related, and self-related. The perspectives of medical doctors and non-medical staff included all eleven competencies. However, the perspective of patients did not include one interpersonal and two self-related competencies. Nearly all of the critical behaviors mentioned are included in the NKLM. However, the NKLM also includes behaviors that were not mentioned in the interviews. Conclusions: The behavior-oriented interviews resulted in a requirement profile that is very similar in structure to other competency models in occupational contexts. Comparisons of the different perspectives predominantly revealed similarities. However, the patient perspective also revealed interesting differences compared to the perspectives of medical doctors and non-medical staff. The behavior-related results of the interviews can be directly used for the development of exercises in selection and personnel development contexts and for potential appraisals specific to different medical disciplines. In future steps, the results of this initial qualitative step are to be replicated and extended using quantitative studies and a representative sample. The main overall objective is the definition of relevant competencies both for the selection and development of medical students and for the design of potential appraisals as part of personnel development programs in different medical disciplines.

Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entrée to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines., (Copyright © 2017. Published by Elsevier Inc.)

Background & Aims: Gluten-free diet is the keystone of coeliac disease treatment. Despite adherence, some patients continue to suffer from symptoms that negatively influence health-related quality of life (HRQoL). Therefore we performed a systematic review and meta-analysis to assess the effect of gluten-free diet on HRQoL in coeliac disease. We specifically sought for determinants that negatively influenced HRQoL., Methods: We systematically searched PubMed, EMBASE, CINAHL, PsycINFO and Cochrane Library for studies assessing HRQoL in untreated or treated adults using validated HRQoL-questionnaires from 1960 to September 2015, comparing HRQoL: (1) before and after gluten-free diet initiation or (2) in patients and non-coeliac controls., Results: We included eighteen studies and sixteen were suitable for meta-analysis. Gluten-free diet significantly improves HRQoL, for psychological general well-being (PGWB)-Total (mean difference (MD) 7.34, 95% confidence interval (CI) [1.96; 12.72]; p = 0.008), SF-36 Mental Component Score (MCS) (MD 7.37, 95% CI [1.84; 12.90]; p = 0.009) and SF-36 Physical Component Score (PCS) (MD 5.72, 95% CI [1.50; 9.95]; p = 0.008). Treated patients had similar HRQoL compared with controls for PGWB-Total (MD -0.72, 95% CI [-2.71; 1.27]; p = 0.48), but significantly lower levels for SF-36 MCS (MD -4.09, 95% CI [-6.17; -2.01]; p = 0.0001) and PCS (MD -4.57, 95% CI [-6.97; -2.17]; p = 0.0002). Symptom-detected gluten-free diet adhering patients have lower HRQoL compared with screening-detected patients (MD -3.73, 95% CI [-6.77;-0.69]; p = 0.02) Strict adhering patients have better HRQoL compared with non-strict adhering patients for SF-36 MCS (MD 7.70, 95% CI [4.61; 10.79]; p < 0.00001) and for SF-36 PCS (MD 3.23, 95% CI [1.33; 5.14]; p = 0.0009)., Conclusions: Gluten-free diet significantly improves but does not normalize HRQoL in adults with coeliac disease. Dietary adherence improves HRQoL. Better (self-reported) dietary adherence results in higher HRQoL., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The functions of mitochondria during leaf senescence, a type of programmed cell death aimed at the massive retrieval of nutrients from the senescing organ to the rest of the plant, remain elusive. Here, combining experimental and analytical approaches, we showed that mitochondrial integrity in Arabidopsis (Arabidopsis thaliana) is conserved until the latest stages of leaf senescence, while their number drops by 30%. Adenylate phosphorylation state assays and mitochondrial respiratory measurements indicated that the leaf energy status also is maintained during this time period. Furthermore, after establishing a curated list of genes coding for products targeted to mitochondria, we analyzed in isolation their transcript profiles, focusing on several key mitochondrial functions, such as the tricarboxylic acid cycle, mitochondrial electron transfer chain, iron-sulfur cluster biosynthesis, transporters, as well as catabolic pathways. In tandem with a metabolomic approach, our data indicated that mitochondrial metabolism was reorganized to support the selective catabolism of both amino acids and fatty acids. Such adjustments would ensure the replenishment of α-ketoglutarate and glutamate, which provide the carbon backbones for nitrogen remobilization. Glutamate, being the substrate of the strongly up-regulated cytosolic glutamine synthase, is likely to become a metabolically limiting factor in the latest stages of developmental leaf senescence. Finally, an evolutionary age analysis revealed that, while branched-chain amino acid and proline catabolism are very old mitochondrial functions particularly enriched at the latest stages of leaf senescence, auxin metabolism appears to be rather newly acquired. In summation, our work shows that, during developmental leaf senescence, mitochondria orchestrate catabolic processes by becoming increasingly central energy and metabolic hubs., (© 2016 American Society of Plant Biologists. All Rights Reserved.)

Background: The Community Balance and Mobility Scale (CB&M) is increasingly used to evaluate walking balance following stroke., Objective: This study applied Rasch analysis to evaluate and refine the CB&M for use in ambulatory community-dwelling adults following stroke., Methods: The CB&M content was linked to task demands and motor skill classifications. Rasch analysis was used to evaluate internal construct validity (structural validity) and refine the CB&M for use with ambulatory community-dwelling adults following stroke. The CB&M data were collected at 3 time points: at discharge from inpatient rehabilitation and at 6 and 12 months postdischarge (N=238). Rasch analysis evaluated scale dimensionality, item and person fit, item response bias, scoring hierarchy, and targeting. Disordered scoring hierarchy was resolved by collapsing scoring categories. Highly correlated and "misfitting" items were removed. Sensitivity to change was evaluated with standardized response means (SRMs) and one-way repeated-measures analysis of variance., Results: The CB&M was primarily linked to closed body transport task demands. Significant item-trait interaction, disordered scoring hierarchies, and multidimensionality were found. Scoring categories were collapsed in 15/19 items, and 5 misfitting items were removed. The resulting stroke-specific 14-item unidimensional CB&M (CB&MStroke) fit Rasch model expectations, with no item response bias, acceptable targeting (13% floor effects and 0% ceiling effects), and moderate-to-strong sensitivity to change at 6 months postdischarge (SRM=0.63; 95% confidence interval=-1.523, -0.142) and 12 months postdischarge (SRM=0.73; 95% confidence interval=-2.318, -0.760)., Limitations: Findings are limited to a modest-sized sample of individuals with mild-to-moderate balance impairment following stroke., Conclusions: The CB&MStroke shows promise as a clinical scale for measuring change in walking balance in ambulatory community-dwelling adults poststroke. Future studies are recommended in a larger sample to validate and further refine the scale for use in this clinical population., (© 2016 American Physical Therapy Association.)

Objective: Inserting peripheral venous catheters (PVCs) has been identified as a core competency for medical students. Because the performance - even of hygienic standards - of both students and novice physicians is frequently inadequate, medical faculties must focus on competence-based learning objectives and deliberate practice, features that are combined in mastery learning. Our aim was to determine the competency of students in inserting PVCs before and after an educational intervention., Design: This study comprised a skills assessment with pre- and post-tests of a group of third-year students who received a simulation-based intervention. A newly established curriculum involved one hour of practice at inserting PVCs on simulators. Students were required to pass a test (total 21 points, pass mark 20 points) developed on the concept of mastery learning. An unannounced follow-up test was performed one week (8 days) after the intervention., Setting: The simulation center of the medical faculty in Muenster., Participants: Third-year students who received the intervention., Results: One hundred and nine complete data sets were obtained from 133 students (82.5%). Most students (97.2%) passed the test after the intervention (mean score increase from 15.56 to 20.50, P<0.001). There was a significant decrease in students' performance after one week (8 days): only 74.5% of participants passed this retest (mean score reduction from 20.50 to 20.06, P<0.001)., Conclusion: Mastery learning is an effective form of teaching practical skills to medical students, allowing a thorough preparation for the challenges of daily clinical practice.

Aims: Up to 30% of insulin-treated type 2 diabetes patients are unable to achieve HbA1c targets despite optimization of insulin multiple daily injections (MDI). For these patients the use of continuous subcutaneous insulin infusion (CSII) represents a useful but under-utilized alternative. The aim of the present analysis was to examine the cost-effectiveness of initiating CSII in type 2 diabetes patients failing to achieve good glycemic control on MDI in the Netherlands., Methods: Long-term projections were made using the IMS CORE Diabetes Model. Clinical input data were sourced from the OpT2mise trial. The analysis was performed over a lifetime time horizon. The discount rates applied to future costs and clinical outcomes were 4% and 1.5% per annum, respectively., Results: CSII was associated with improved quality-adjusted life expectancy compared with MDI (9.38 quality-adjusted life years [QALYs] vs 8.95 QALYs, respectively). The breakdown of costs indicated that ∼50% of costs were attributable to diabetes-related complications. Higher acquisition costs of CSII vs MDI were partially offset by the reduction in complications. The ICER was estimated at EUR 62,895 per QALY gained and EUR 60,474 per QALY gained when indirect costs were included., Conclusions: In the Netherlands, CSII represents a cost-effective option in patients with type 2 diabetes who continue to have poorly-controlled HbA1c despite optimization of MDI. Since the ICER falls below the willingness-to-pay threshold of EUR 80,000 per QALY gained, CSII is likely to represent good-value for money in the treatment of poorly-controlled T2D patients compared with MDI.

Propionibacterium acnes has been repeatedly suggested as a candidate causative agent of sarcoidosis. It is the only microorganism that has been isolated from sarcoid lesions by bacterial culture so far and this has been described in Japanese patients only. We report two non-Japanese patients in whom mediastinoscopy was performed in order to obtain lymph node tissue for histopathology, which was suggestive for sarcoidosis. Bacterial culture of these uncontaminated mediastinal lymph nodes revealed P. acnes in both patients. As shown in these two cases, P. acnes can be isolated from sterile biopsied sarcoid lymph nodes of non-Japanese patients and supports the belief that there is an etiologic link between P. acnes sarcoidosis. Further elucidation could provide an opening to novel strategies using antibiotics for treating sarcoidosis.

Recent advances in the use of inertial measurement units (IMUs) for motion analysis suggest the possibility of using this technology for the monitoring of daily activities of individuals during rehabilitation post-stroke. Previous studies have utilized features extracted from accelerometer and gyroscope signals to develop classification models capable of identifying activities performed within large datasets. In this study, nine k-nearest neighbor cross-validated classifiers were developed using frequency-features derived from shank-mounted IMUs on the less-affected and affected limbs of subjects with stroke. These classifiers were evaluated for two separate datasets of post-stroke gait; the first a classification of three separate gait activities (overground walking, stair ascent, and stair descent), and the second a classification of five gait activities, overground walking, stair ascent, and descent with a distinction between stepping pattern used while negotiating stairs (step-over-step (SOS) and step-by-step (SBS)). The comparison showed the highest classification accuracy, 100% for the three-activities and 94% for the five-activities, was obtained using a classifier composed of features derived from accelerometer and gyroscope measurements from both IMUs on less-affected and affected limbs., (Copyright © 2015 IPEM. Published by Elsevier Ltd. All rights reserved.)

Background: A decline in walking capacity and high energy cost can limit mobility following stroke. Mechanical energy exchange between lower limb and trunk segments can reflect gait inefficiencies, but reveals little about active energy flow between adjacent segments through muscle actions. This study evaluated mechanical energy expenditures (MEEs) during walking in stroke and healthy groups to understand movement control and explore the impact of walking speed on mechanical energy exchanges., Methods: Thirteen adults with hemiparesis and six healthy controls walked at self-selected speed. Power curves for each lower limb joint were segmented into concentric and eccentric sources of muscle power and transfer/no-transfer modes to calculate MEEs during stance., Findings: MEEs were lower in the stroke group on the affected side compared to the less affected side and compared to controls. Specifically, the affected plantarflexors transferred less energy distally via concentric action in late stance compared to the less affected side. However, the stroke group generated greater energy at the ankle in the absence of transfer compared to controls. Less concentrically transferred energy through midstance and absorbed in late stance was evident by the knee extensors bilaterally in stroke. At the hip, the total energy (no transfer) was reduced on the affected side. Classifying stroke subjects by walking speed (<.6m/s, >.6m/s) revealed disruptions in harnessing energy through motion and transfer energy across segments in the slower group., Interpretation: The limited ability of those with stroke to exploit intersegmental energy transfer to optimize efficiency may limit endurance and functional independence., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Repetitive peripheral magnetic stimulation (RPMS) is a painless and noninvasive method to produce afferents via the depolarization of the peripheral nervous system. A few studies tested RPMS after-effects on cerebral plasticity and motor recovery in stroke individuals, but evidences remain limited., Objectives: This study aimed to explore whether RPMS could mediate improvements in corticomotor and clinical outcomes associated with ankle impairments in chronic stroke., Methods: Eighteen subjects with chronic stroke were randomly allocated to RPMS or sham group and compared to 14 healthy subjects. Stimulation was applied over the paretic tibialis anterior (TA). Ankle impairments on the paretic side and ipsilesional TA cortical motor representation were tested clinically and by transcranial magnetic stimulation (TMS), respectively., Results: In the RPMS group, ankle dorsiflexion mobility and maximal isometric strength increased and resistance to plantar flexor stretch decreased. The magnitude of change seemed to be related to cortical and corticospinal integrity. Sham stimulation yielded no effect. Changes in TMS outcome and their relationships with clinical improvements were limited., Conclusions: RPMS improved ankle impairments in chronic stroke likely by a dynamic influence of sensory inputs on synaptic plasticity. The neurophysiological mechanisms potentially underlying the clinical effects are unclear. More studies are warranted to test the spinal and hemispheric changes responsible for the clinical improvements with emphasis on circuits spared by the lesion.

Glutathione transferases (GSTs) represent a widespread multigenic enzyme family able to modify a broad range of molecules. These notably include secondary metabolites and exogenous substrates often referred to as xenobiotics, usually for their detoxification, subsequent transport or export. To achieve this, these enzymes can bind non-substrate ligands (ligandin function) and/or catalyze the conjugation of glutathione onto the targeted molecules, the latter activity being exhibited by GSTs having a serine or a tyrosine as catalytic residues. Besides, other GST members possess a catalytic cysteine residue, a substitution that radically changes enzyme properties. Instead of promoting GSH-conjugation reactions, cysteine-containing GSTs (Cys-GSTs) are able to perform deglutathionylation reactions similarly to glutaredoxins but the targets are usually different since glutaredoxin substrates are mostly oxidized proteins and Cys-GST substrates are metabolites. The Cys-GSTs are found in most organisms and form several classes. While Beta and Omega GSTs and chloride intracellular channel proteins (CLICs) are not found in plants, these organisms possess microsomal ProstaGlandin E-Synthase type 2, glutathionyl hydroquinone reductases, Lambda, Iota and Hemerythrin GSTs and dehydroascorbate reductases (DHARs); the four last classes being restricted to the green lineage. In plants, whereas the role of DHARs is clearly associated to the reduction of dehydroascorbate to ascorbate, the physiological roles of other Cys-GSTs remain largely unknown. In this context, a genomic and phylogenetic analysis of Cys-GSTs in photosynthetic organisms provides an updated classification that is discussed in the light of the recent literature about the functional and structural properties of Cys-GSTs. Considering the antioxidant potencies of phenolic compounds and more generally of secondary metabolites, the connection of GSTs with secondary metabolism may be interesting from a pharmacological perspective.

Phytochrome is thought to control the induction of leaf senescence directly, however, the signalling and molecular mechanisms remain unclear. In the present study, an ecophysiological approach was used to establish a functional connection between phytochrome signalling and the physiological processes underlying the induction of leaf senescence in response to shade. With shade it is important to distinguish between complete and partial shading, during which either the whole or only a part of the plant is shaded, respectively. It is first shown here that, while PHYB is required to maintain chlorophyll content in a completely shaded plant, only PHYA is involved in maintaining the leaf chlorophyll content in response to partial plant shading. Second, it is shown that leaf yellowing associated with strong partial shading in phyA-mutant plants actually correlates to a decreased biosynthesis of chlorophyll rather than to an increase of its degradation. Third, it is shown that the physiological impact of this decreased biosynthesis of chlorophyll in strongly shaded phyA-mutant leaves is accompanied by a decreased capacity to adjust the Light Compensation Point. However, the increased leaf yellowing in phyA-mutant plants is not accompanied by an increase of senescence-specific molecular markers, which argues against a direct role of PHYA in inducing leaf senescence in response to partial shade. In conclusion, it is proposed that PHYA, but not PHYB, is essential for fine-tuning the chlorophyll biosynthetic pathway in response to partial shading. In turn, this mechanism allows the shaded leaf to adjust its photosynthetic machinery to very low irradiances, thus maintaining a positive carbon balance and repressing the induction of leaf senescence, which can occur under prolonged periods of shade., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

This study explored the relationships between motor cortical control of ankle dorsiflexors and clinical impairments of volitional ankle dorsiflexion in people with chronic stroke. Eighteen persons with stroke and 14 controls were evaluated. Clinical tools were used to assess ankle dorsiflexion amplitude and isometric strength. Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) tested the functional integrity of cortical circuits controlling the tibialis anterior (TA). All clinical scores and most TMS outcomes were impaired in people with chronic stroke. The lower clinical scores were related to the reduction of the strength of corticospinal projections onto spinal motoneurons. Concurrent TMS and clinical testing in chronic stroke provided original data demonstrating relationships between the integrity of cortical and corticospinal components of TA motor control and volitional ankle tasks. Our study proposes that volitional ankle mobilization in chronic stroke may be explained by the residual abnormal M1 circuits which may be responsive for rehabilitation intervention. This should be confirmed in longitudinal studies with larger samples to determine whether TMS outcomes associated with lower limb muscles are predictive of clinical changes or vice versa., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: Translate the Essentials of Magnetism II© (EOMII; Dutch Nurses' Association, Utrecht, The Netherlands) and assess its psychometric properties in a culture different from its origin., Background: The EOMII, developed in the USA, measures the extent to which organizations/units provide healthy, productive and satisfying work environments. As many healthcare organizations are facing difficulties in attracting and retaining staff nurses, the EOMII provides the opportunity to assess the health and effectiveness of work environments., Methods: A three-phased (respectively N = 13, N = 74 and N = 2542) combined descriptive and correlational design was undertaken for translation and evaluation validity and psychometric qualities of the EOMII for Dutch hospitals (December 2009-January 2010). We performed forward-backward translation, face and content validation via cross-sectional survey research, and semi-structured interviews on relevance, clarity, and recognizability of instruments' items. Psychometric testing included principal component analysis using varimax rotation, item-total statistics, and reliability in terms of internal consistency (Cronbach's α) for the total scale and its subscales., Results: Face validity was confirmed. Items were recognizable, relevant and clear. Confirmatory factor analysis indicated that five of eight subscales formed clear factors. Three original subscales contained two factors. Item-total correlations ranged from 0.43 to 0.83. One item correlated weakly (0.24) with its subscale. Cronbach's α for the entire scale was 0.92 and ranged from 0.58 to 0.92 for eight subscales., Conclusions: Dutch-translated EOMII (D-EOMII) demonstrated acceptable reliability and validity for assessing hospital staff nurses' work environment., Implications for Nursing and Health Policy: The D-EOMII can be useful and effective in identifying areas in which change is needed for a hospital to pursue an excellent work environment that attracts and retains well-qualified nurses., (© 2013 International Council of Nurses.)

Background: Tolerance of ambiguity, or the extent to which ambiguous situations are perceived as desirable, is an important component of the attitudes and behaviors of medical students. However, few studies have compared this trait across the years of medical school. General practitioners are considered to have a higher ambiguity tolerance than specialists. We compared ambiguity tolerance between general practitioners and medical students., Methods: We designed a cross-sectional study to evaluate the ambiguity tolerance of 622 medical students in the first to sixth academic years. We compared this with the ambiguity tolerance of 30 general practitioners. We used the inventory for measuring ambiguity tolerance (IMA) developed by Reis (1997), which includes three measures of ambiguity tolerance: openness to new experiences, social conflicts, and perception of insoluble problems., Results: We obtained a total of 564 complete data sets (return rate 90.1%) from medical students and 29 questionnaires (return rate 96.7%) from general practitioners. In relation to the reference groups defined by Reis (1997), medical students had poor ambiguity tolerance on all three scales. No differences were found between those in the first and the sixth academic years, although we did observe gender-specific differences in ambiguity tolerance. We found no differences in ambiguity tolerance between general practitioners and medical students., Conclusions: The ambiguity tolerance of the students that we assessed was below average, and appeared to be stable throughout the course of their studies. In contrast to our expectations, the general practitioners did not have a higher level of ambiguity tolerance than the students did.

Recombinant human erythropoietin (rHuEPO) is an agent commonly used by athletes with the aim to improve performance in endurance sports. However, the scientific community continues to debate the risks, benefits and its mechanism of action when used as a doping agent. This paper provides a brief overview on the pros and cons of rHuEPO use, as discussed by a group of scientist with diverse background, at the 17th Conference of the European Society for Clinical Hemorheology and Microcirculation in Pecs, Hungary. Among multiple topics, panel members challenged the common belief that the increased circulating hemoglobin concentration is the simple key to the improved sporting performance. Rather, hemorheologists developed the concept of optimal hematocrit (Hct), a Hct value that represents the optimal balance between the oxygen transport capacity of blood and blood viscosity. While guideline-directed transfusion therapy is advantageous under pathological conditions, such as severe anemia related to chronic kidney disease, its beneficial effects on endurance in healthy athletes remains questionable. Further studies are warranted in the field evaluating the effects of rHuEPO that are independent of increasing hemoglobin concentration, such as peripheral vasodilation and tissue metabolic changes.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This study aims to validate a commercially available inertial sensor based motion capture system, Xsens MVN BIOMECH using its native protocols, against a camera-based motion capture system for the measurement of joint angular kinematics. Performance was evaluated by comparing waveform similarity using range of motion, mean error and a new formulation of the coefficient of multiple correlation (CMC). Three dimensional joint angles of the lower limbs were determined for ten healthy subjects while they performed three daily activities: level walking, stair ascent, and stair descent. Under all three walking conditions, the Xsens system most accurately determined the flexion/extension joint angle (CMC > 0.96) for all joints. The joint angle measurements associated with the other two joint axes had lower correlation including complex CMC values. The poor correlation in the other two joint axes is most likely due to differences in the anatomical frame definition of limb segments used by the Xsens and Optotrak systems. Implementation of a protocol to align these two systems is necessary when comparing joint angle waveforms measured by the Xsens and other motion capture systems.

This study describes and contrasts the kinematics and kinetics of stair ambulation in people with chronic stroke and healthy control subjects. Three-dimensional motion data were collected from 10 persons with stroke (7 males) and 10 sex and age-matched older adults as they ascended and descended an instrumented staircase at self-selected speed with and without a handrail. Ankle, knee and hip joint angle and moment profiles were generated during stance and range of motion and peak moments were contrasted between groups, sides (stroke only) and condition. Cadence was lower in stroke than controls, although the kinematic profiles appeared similar during ascent and decent. Notable differences in joint kinetics were evident as the peak extensor moments were typically lower on the affected side in stroke compared with controls and the less affected side. These differences accounted for the lower magnitude net extensor support moment. The lower affected side hip abductor moments likely limited lateral stability. Handrail use tended to reduce the peak moments on the affected side only leading to more side-to-side differences than occurred without the handrail. The findings reveal differences in task performance between stroke and healthy groups that help inform rehabilitation practice.

This paper represents the first step in developing an inertial sensor system that is capable of assessing post-stroke gait in terms of walking speed and temporal gait symmetry. Two inertial sensors were attached at the midpoint of each shank to measure the accelerations and angular velocity during walking. Despite the abnormalities in hemiparetic gait, the angular velocity of most of the testing subjects (12 out of 13) exhibited similar characteristics as those from a healthy population, enabling walking speed estimation and gait event detection based on the pendulum walking model. The results from a standardized 10-meter walk test demonstrated that the IMU-based method has an excellent agreement with the clinically used stopwatch method. The gait symmetry results were comparable with previous studies. The gait segmentation failed when the angular velocity deviates significantly from the healthy groups' profile. With further development and concurrent validations, the inertial sensor-based system may eventually become a useful tool for continually monitoring spatio-temporal gait parameters post stroke in a natural environment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study., Patients and Methods: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out., Results: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures., Conclusion: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

This study validated the feasibility of inertial sensors in estimating lower limb joint kinematics during stair ambulation in healthy older adults and stroke survivors. Three dimensional motion data were collected using an inertial sensor-based system from 9 persons with stroke and 9 healthy older adults as they ascended and descended a staircase at a self-selected pace. The measured joint angles were compared with a laboratory-based motion capture system by computing differences in range of motion (RoM), grand mean error, standard deviation, and coefficients of multiple correlations. For stroke survivors, differences in RoM measurements between these two systems were determined to be 3.3 ± 8.1°, while the highest correlations were found in the estimation of sagittal plane joint angles after offset correction. Results suggest that the inertial sensor system is suitable for estimating major joint angles in healthy older adults as well as the RoM for stroke survivors. New calibration procedures are necessary for applying the technology to a stroke population.