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Purpose: This case series investigated the implementation fidelity, feasibility, and effectiveness of integrating continuous heart rate monitoring with visual feedback into an established, intensive physical therapy camp for children with neuromotor disorders., Summary of Key Points: The provision of continuous visual feedback through color-coded, individually calculated heart rate zones was a feasible and effective intervention, encouraging pediatric gait camp participants to exercise at intensities that produced aerobic and functional gains. The use of technology facilitated participation with peers, an outcome equally as important as their endurance and functional improvements., Conclusions and Recommendations for Clinical Practice: Pediatric physical therapists play a crucial role in enhancing the well-being and physical fitness of children with disabilities. Encouraging regular exercise in a social environment fosters enjoyable, inclusive experiences while promoting overall health. It is important for clinicians in various pediatric rehabilitation settings to establish programs that offer such opportunities for children with neuromotor disorders., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Background: Wearable sensors have been heralded as revolutionary tools for healthcare. However, while data are easily acquired from sensors, users still grapple with questions about how sensors can meaningfully inform everyday clinical practice and research., Summary: We propose a simple, comprehensive framework for utilizing sensor data in healthcare. The framework includes three key processes that are applied together or separately to (1) automate traditional clinical measures, (2) illuminate novel correlates of disease and impairment, and (3) predict current and future outcomes. We demonstrate applications of the Automate-Illuminate-Predict framework using examples from rehabilitation medicine., Key Messages: Automate-Illuminate-Predict provides a universal approach to extract clinically meaningful data from wearable sensors. This framework can be applied across the care continuum to enhance patient care and inform personalized medicine through accessible, noninvasive technology., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers., Methods: Healthy volunteers ( N  = 200) aged 18-55 years and with body mass index of 18.5-29.9 kg/m 2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days., Results: The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC 0-1344 , AUC 0-∞ , and C max for both groups were entirely within the standard 80-125% bioequivalence acceptance range at 101.88% (93.31-111.23%), 105.38% (95.06-116.81%), and 91.29% (84.38-98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation., Conclusions: Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated., Clinical Trial Registration: NCT05203289.

Cognitive flexibility involves dynamic processes that allow adaptation of our thinking and behavior in response to changing contextual demands. Despite a large consensus about its beneficial effects, cognitive flexibility is still poorly understood. In this mini review, we examined the main conceptualizations and approaches for assessing cognitive flexibility: (1) neuropsychological tasks, (2) self-report questionnaires, and (3) neuroscientific approaches. The reviewed evidence shows that the definition and assessment of cognitive flexibility are not unified within the field and suggests that a more consensual and consistent conceptualization and operationalization of this important concept is needed. We propose that an integrative behavior-brain-context approach can help advance our understanding of cognitive flexibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hohl and Dolcos.)

Background: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx., Methods: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema., Results: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups., Conclusions: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model., Trial Registration: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408)., Competing Interests: Declaration of competing interest KH, MK, and TL are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. WS and AG are employees of Boehringer Ingelheim International. JMH has received grants to his institution for clinical trial conduct and personal fees for consultancy from Boehringer Ingelheim Pharma GmbH & Co. KG. CG, JVC, PB, and MM have nothing to declare., (Copyright © 2023. Published by Elsevier Ltd.)

N 1 -methylnicotinamide (NMN) has been proposed as endogenous biomarker for drug-drug interactions mediated by inhibition of multidrug and toxin extrusion proteins (MATEs) at the renal proximal tubule. We analyzed NMN in plasma and urine samples of two clinical trials investigating a new probe drug cocktail (consisting of digoxin, metformin, furosemide, and rosuvastatin) dedicated to clinically relevant drug transporters. In trial 1, NMN was investigated after single-dose treatment with individual cocktail components or after cocktail treatment. In trial 2, NMN was investigated after treatment with cocktail alone or with cocktail + inhibitor (cimetidine, a MATE inhibitor; or rifampin, verapamil, or probenecid, inhibitors of other transporters). In trial 1, NMN kinetics in plasma and urine were essentially not affected by individual cocktail components or after cocktail treatment. In trial 2, NMN renal clearance from 0 to 12 hours (CL R,0-12 ) geometric mean ratio (GMR) after cocktail + cimetidine vs. cocktail alone was 75% (90% confidence interval (CI): 65-87%). NMN CL R GMR after cocktail + verapamil, + rifampin, or + probenecid vs. cocktail alone was 99% (90% CI: 81-121%), 91% (90% CI: 75-111%), and 107% (90% CI: 91-126%), respectively. Compared with creatinine CL R and creatinine area under the plasma-concentration time curve, NMN CL R was more specific and more sensitive for renal MATE inhibition. Absence of impact of the cocktail on NMN in trial 1 allows for utilization of NMN in studies using this transporter cocktail. Trial 2 data support that NMN CL R is a specific and sensitive marker for MATE-mediated renal drug-drug interactions., (© 2023 Boehringer Ingelheim Pharma GmbH & Co. KG and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Research on risk assessment for domestic abuse has focused primarily on the predictive validity of specific tools; less attention has been paid to implementation of risk tools by practitioners. This paper presents findings from a mixed methods study in England and Wales. Multi-level modelling reveals an 'officer effect' whereby victims' responses to the Domestic Abuse, Stalking and Harassment and Honour-Based Violence (DASH) risk assessment are influenced by the specific officer that completes the assessment. Specifically, this officer effect is strongest in relation to questions intended to capture elements of controlling and coercive behaviour, and least apparent in relation to identifying physical injuries. We further present findings from field observations and interviews with first response officers that corroborate and help explain the officer effect. We discuss implications for the design of primary risk assessments, victim safeguarding, and the use of police data for predictive modelling., (© The Author(s) 2023.)

Purpose/background: Glycine transporter-1 inhibitors may ameliorate cognitive deficits in schizophrenia. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809., Methods/procedures: Interactions with cytochromes P450 (CYP) and P-glycoprotein (P-gp) were assessed in in vitro assays using human hepatocytes and Caco-2 cells, respectively. Pharmacokinetic characteristics of probe drugs were subsequently assessed in a Phase I, open-label, single-sequence crossover study in healthy male participants. Participants received a probe-drug cocktail containing midazolam (CYP3A4), warfarin (CYP2C9), and omeprazole (CYP2C19) and a separate dose of digoxin (P-gp), alone and on a background of steady-state BI 425809 25 mg once daily in 2 treatment periods. Adverse events were monitored., Findings/results: In vitro assays revealed concentration-dependent induction of CYP3A4 and inhibition of P-gp by BI 425809. In the clinical study, 12 of 13 participants completed both periods. With BI 425809, area under the plasma concentration curve from administration to the last measurement (AUC 0-tz ) and maximum plasma concentration ( Cmax ) for midazolam were lower than when administered alone. Adjusted geometric mean ratios (90% confidence interval) were 70.6% (63.9%-78.1%) for AUC 0-tz and 77.6% (67.3%-89.4%) for Cmax . For warfarin and digoxin, AUC 0-tz and Cmax were similar with and without BI 425809. For omeprazole, BI 425809 slightly reduced AUC 0-tz but not Cmax versus omeprazole alone. No new safety signals were identified., Implications/conclusions: These findings indicate induction of CYP3A4 by once-daily BI 425809 25 mg (the assumed highest therapeutic dose) and no meaningful effects on CYP2C9, CYP2C19, or P-gp in vivo., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Exoskeletons are externally worn motorized devices that assist with sit-to-stand and walking in individuals with motor and functional impairments. The Food & Drug Administration (FDA) has approved several of these technologies for clinical use however, there is limited evidence to guide optimal utilization in every day clinical practice. With the diversity of technologies & equipment available, it presents a challenge for clinicians to decide which device to use, when to initiate, how to implement these technologies with different patient presentations, and when to wean off the devices. Thus, we present a clinical utilization framework specific to exoskeletons with four aims.These aims are to assist with clinical decision making of when exoskeleton use is clinically indicated, identification of which device is most appropriate based on patient deficits and device characteristics, providing guidance on dosage parameters within a plan of care and guidance for reflection following utilization. This framework streamlines how clinicians can approach implementation through the synthesis of published evidence with appropriate clinical assessment & device selection to reflection for success and understanding of these innovative & complex technologies., (© 2022. The Author(s).)

Objective: To evaluate the combined effects of robotic exoskeleton and functional electrical stimulation (FES) training on muscle composition during over-ground gait training in persons with acute spinal cord injury (SCI)., Design: Randomized crossover pilot study., Setting: Inpatient-rehabilitation Hospital., Participants: Six individuals with acute SCI., Intervention: Participants were randomized to either receive training with the Ekso® Bionics exoskeleton combined with FES in addition to standard-of-care or standard-of-care alone., Outcome Measures: The main outcome measures for the study were quantified using magnetic resonance imaging (MRI), specifically, lower extremity muscle volume and intramuscular adipose tissue (IMAT). Static balance and fall risk were assessed using the Berg Balance Scale., Results: Significant improvements were observed in muscle volume in the exoskeleton intervention group when compared to only standard-of-care ( p  < 0.001). There was no significant difference between the groups in IMAT even though the intervention group saw a reduction in IMAT that trended towards statistical significance ( p  = 0.07). Static balance improved in both groups, with greater improvements seen in the intervention group., Conclusions: Early intervention with robotic exoskeleton may contribute to improved muscle function measured using MRI in individuals with acute SCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Hohl, Smith, Macaluso, Giffhorn, Prokup, O'Dell, Kleinschmidt, Elliott and Jayaraman.)

Background: Stroke is a leading cause of serious gait impairments and restoring walking ability is a major goal of physical therapy interventions. Soft robotic exosuits are portable, lightweight, and unobtrusive assistive devices designed to improve the mobility of post-stroke individuals through facilitation of more natural paretic limb function during walking training. However, it is unknown whether long-term gait training using soft robotic exosuits will clinically impact gait function and quality of movement post-stroke., Objective: The objective of this pilot study was to examine the therapeutic effects of soft robotic exosuit-augmented gait training on clinical and biomechanical gait outcomes in chronic post-stroke individuals., Methods: Five post-stroke individuals received high intensity gait training augmented with a soft robotic exosuit, delivered in 18 sessions over 6-8 weeks. Performance based clinical outcomes and biomechanical gait quality parameters were measured at baseline, midpoint, and completion., Results: Clinically meaningful improvements were observed in walking speed ([Formula: see text] < 0.05) and endurance ([Formula: see text] < 0.01) together with other traditional gait related outcomes. The gait quality measures including hip ([Formula: see text] < 0.01) and knee ([Formula: see text] < 0.05) flexion/extension exhibited an increase in range of motion in a symmetric manner ([Formula: see text] < 0.05). We also observed an increase in bilateral ankle angular velocities ([Formula: see text] < 0.05), suggesting biomechanical improvements in walking function., Conclusions: The results in this study offer preliminary evidence that a soft robotic exosuit can be a useful tool to augment high intensity gait training in a clinical setting. This study justifies more expanded research on soft exosuit technology with a larger post-stroke population for more reliable generalization. Trial registration This study is registered with ClinicalTrials.gov (ID: NCT04251091)., (© 2022. The Author(s).)

Longitudinal bone growth, achieved through endochondral ossification, is accomplished by a cartilaginous structure, the physis or growth plate, comprised of morphologically distinct zones related to chondrocyte function: resting, proliferating and hypertrophic zones. The resting zone is a stem cell-rich region that gives rise to the growth plate, and exhibits regenerative capabilities in response to injury. We discovered a FoxA2+group of long-term skeletal stem cells, situated at the top of resting zone, adjacent the secondary ossification center, distinct from the previously characterized PTHrP+ stem cells. Compared to PTHrP+ cells, FoxA2+ cells exhibit higher clonogenicity and longevity. FoxA2+ cells exhibit dual osteo-chondro-progenitor activity during early postnatal development (P0-P28) and chondrogenic potential beyond P28. When the growth plate is injured, FoxA2+ cells expand in response to trauma, and produce physeal cartilage for growth plate tissue regeneration., (© 2022. The Author(s).)

Currently, no dressings utilized in burn clinics provide adhesion, hydration or mechanical strength on the same order as human skin as well as the ability to be atraumatically removed. We report the synthesis, characterization, and in vivo evaluation of in situ polymerized and subsequent dissolvable hydrogels as burn wound dressings. Hydrogel dressings, from a small library of synthesized materials form in situ , exhibit storage moduli between 100-40 000 Pa, dissolve on-demand within 10 minutes to 90 minutes, swell up to 350%, and adhere to both burned and healthy human skin at 0.2-0.3 N cm -2 . Further, results from an in vivo porcine second degree burn model demonstrate functional performance with healing equivalent to conventional treatments with the added benefit of facile, in situ application and subsequent removal via dissolution.

Currently, no dressings are utilized after removal of polyps during a colonoscopy rendering these tissue sites susceptible to bleeding, sepsis, and perfusion. We report the design specifications, synthesis, and ex vivo evaluation of in situ polymerized hydrogels as colon wound dressings post polypectomy. The hydrogels exhibited varied properties to include moduli between 100 and 16 000 Pa, dissolution times between 4 h to 7 days or longer, swelling up to 200%, and adhesion to colon tissue from 0.1 to 0.4 N/cm 2 . The hydrogels displayed minimal cytotoxicity, prevented the migration/spread of bacteria, and exhibited rapid gelation, a requirement for application to the lumen of the colon via an endoscope. This work highlights the structure-property relationship of hydrogels prepared from N -hydroxysuccinimide functionalized PEG cross-linkers and hyperbranched polyethylenimines or 4-arm PEG-NH 2 star polymers, and their potential as colon wound dressings.

Qualitative evidence points to the engagement of religious coping strategies when facing adversity, and evidence also highlights the effectiveness of cognitive reappraisal in reducing the impact of distressing emotions on well-being. It has been suggested that religious practices could facilitate the use of reappraisal, by promoting reframing of negative cognitions to alter emotional states. However, the link between religiosity and reappraisal in influencing resilience against symptoms of distress is not known. The current study (N = 203) examined connections among these aspects, using self-reported measures of religious coping, habitual use of specific coping strategies (positive reappraisal) and perceived confidence in using coping strategies, as well as questionnaires assessing symptoms of distress (anxiety and depression). Results point to a mediating role of reappraisal and coping self-efficacy as part of mechanisms that provide a protecting role of religious coping against emotional distress. These results provide novel scientific evidence further validating millennia-old traditional coping practices and shed light on psychological factors influencing adaptive behaviors that promote increased resilience, reduce symptoms of distress, and maintain emotional well-being. These findings inform general counseling practices and counseling of religious clients alike., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Available evidence highlights the importance of emotion regulation (ER) in psychological well-being. However, translation of the beneficial effects of ER from laboratory to real-life remains scarce. Here, we present proof-of-principle evidence from a novel cognitive-emotional training intervention targeting the development of ER skills aimed at increasing resilience against emotional distress. This pilot intervention involved training military veterans over 5-8 weeks in applying two effective ER strategies [Focused Attention (FA) and Cognitive Reappraisal (CR)] to scenarios presenting emotional conflicts (constructed with both external and internal cues). Training was preceded and followed by neuropsychological, personality, and clinical assessments, and resting-state functional MRI data were also collected from a subsample of the participants. Results show enhanced executive function and psychological well-being following training, reflected in increased working memory (WM), post-traumatic growth (PTG), and general self-efficacy (GSE). Brain imaging results showed evidence of diminished bottom-up influences from emotional and perceptual brain regions, along with evidence of normalized functional connectivity in the large-scale functional networks following training. The latter was reflected in increased connectivity among cognitive and emotion control regions and across regions of self-referential and control networks. Overall, our results provide proof-of-concept evidence that resilience and well-being can be learned through ER training, and that training-related improvements manifested in both behavioral change and neuroplasticity can translate into real-life benefits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dolcos, Hu, Williams, Bogdan, Hohl, Berenbaum and Dolcos.)

Background and Objective: A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics., Methods: In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure., Results: The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC 0-tz ) by 248% and maximum plasma concentration (C max ) by 1025%. Probenecid increased furosemide AUC 0-tz by 172% and C max by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC 0-tz unaltered, C max  + 22%)., Conclusions: Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development., Clinical Trial Registration: EudraCT number 2017-001549-29.

Gyroscopic actuators are appealing for wearable applications due to their ability to provide overground balance support without obstructing the legs. Multiple wearable robots using this actuation principle have been proposed, but none has yet been evaluated with humans. Here we use the GyBAR, a backpack-like prototype portable robot, to investigate the hypothesis that the balance of both healthy and chronic stroke subjects can be augmented through moments applied to the upper body. We quantified balance performance in terms of each participant's ability to walk or remain standing on a narrow support surface oriented to challenge stability in either the frontal or the sagittal plane. By comparing candidate balance controllers, it was found that effective assistance did not require regulation to a reference posture. A rotational viscous field increased the distance healthy participants could walk along a 30mm-wide beam by a factor of 2.0, compared to when the GyBAR was worn but inactive. The same controller enabled individuals with chronic stroke to remain standing for a factor of 2.5 longer on a narrow block. Due to its wearability and versatility of control, the GyBAR could enable new therapy interventions for training and rehabilitation.

Research on risk assessment for domestic violence has to date focused primarily on the predictive power of individual risk factors and the statistical validity of risk assessment tools in predicting future physical assault in sub-sets of cases dealt with by the police. This study uses data from risk assessment forms from a random sample of cases of domestic violence reported to the police. An innovative latent trait model is used to test whether a cluster of risk factors associated with coercive control is most representative of the type of abuse that comes to the attention of the police. Factors associated with a course of coercive and controlling conduct, including perpetrators' threats, controlling behavior and sexual coercion, and victims' isolation and fear, had highest item loadings and were thus the most representative of the overall construct. Sub-lethal physical violence-choking and use of weapons-was also consistent with a course of controlling conduct. Whether a physical injury was sustained during the current incident, however, was not associated consistently either with the typical pattern of abuse or with other context-specific risk factors such as separation from the perpetrator. Implications for police practice and the design of risk assessment tools are discussed. We conclude that coercive control is the "golden thread" running through risk identification and assessment for domestic violence and that risk assessment tools structured around coercive control can help police officers move beyond an "incident-by-incident" response and toward identifying the dangerous patterns of behavior that precede domestic homicide.

Premise: Alkanna tinctoria (Boraginaceae) is an important medicinal herb with its main distribution across the Mediterranean region. To reveal its genetic variation and population structure, microsatellite markers were developed and validated in four Greek populations., Methods and Results: RNA-Seq data of the related species Arnebia euchroma and Echium plantagineum were assembled and mined to identify conserved ortholog sets containing simple sequence repeat motifs. Fifty potential loci were identified and then tested on A. tinctoria , of which 17 loci were polymorphic. The number of alleles ranged from one to nine, and the levels of observed and expected heterozygosity ranged from 0.000 to 1.000 and 0.000 to 0.820, respectively. Most of these loci could be successfully amplified in eight other species of Boraginaceae ( Alkanna graeca , A. hellenica , A. sfikasiana , Echium vulgare , E. plantagineum , Lithospermum officinale , Borago officinalis , and Anchusa officinalis )., Conclusions: This study provides the first set of microsatellite loci for studying the genetic variation and population structure of A. tinctoria and shows their potential usefulness in other Boraginaceae species., (© 2019 Ahmad et al. Applications in Plant Sciences is published by Wiley Periodicals, Inc. on behalf of the Botanical Society of America.)

Objective: To test the hypothesis that gait training with a hip-assistive robotic exoskeleton improves clinical outcomes and strengthens the descending corticospinal drive to the lower limb muscles in persons with chronic stroke., Methods: Fifty participants completed the randomized, single-blind, parallel study. Participants received over-ground gait training with the Honda Stride Management Assist (SMA) exoskeleton or intensity-matched functional gait training, delivered in 18 sessions over 6-8 weeks. Performance-based and self-reported clinical outcomes were measured at baseline, midpoint, and completion, and at a 3-month follow-up. Corticomotor excitability (CME) of 3 bilateral leg muscles was measured using transcranial magnetic stimulation., Results: The primary outcome, walking speed, improved for the SMA group by completion of the program (0.24 ± 0.14 m/s difference, p < 0.001). Compared to the functional group, SMA users had greater improvement in walking endurance (46.0% ± 27.4% vs 35.7% ± 20.8%, p = 0.033), took more steps during therapy days (4,366 ± 2,426 vs 3,028 ± 1,510; p = 0.013), and demonstrated larger changes in CME of the paretic rectus femoris (178% ± 75% vs 33% ± 32%, p = 0.010). Participants with hemorrhagic stroke demonstrated greater improvement in balance when using the SMA (24.7% ± 20% vs 6.8% ± 6.7%, p = 0.029)., Conclusions: Gait training with the SMA improved walking speed in persons with chronic stroke, and may promote greater walking endurance, balance, and CME than functional gait training., Clinicaltrialsgov Identifier: NCT01994395., Classification of Evidence: This study provides Class I evidence that gait training with a hip-assistive exoskeleton increases clinical outcomes and CME in persons with chronic stroke, but does not significantly improve walking speeds compared to intensity-matched functional gait training., (© 2018 American Academy of Neurology.)

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug-drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and C max , respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when co-administered in IPF patients., Competing Interests: Conflict of interest: L. Richeldi reports grants and personal fees (member of an advisory board) from InterMune, personal fees for consultancy from Sanofi-Aventis, ImmuneWorks, Celgene, Nitto and Bristol Myers Squibb, personal fees as member of an advisory board from Roche, Fibrogen and Promedior, personal fees for speaking from Shionogi, personal fees as a member of a steering committee from Boehringer Ingelheim, personal fees for editorial activity from DynaMed, outside the submitted work. Conflict of interest: S. Fletcher has nothing to disclose. Conflict of interest: H. Adamali has nothing to disclose. Conflict of interest: N. Chaudhuri reports grants (for a project) from Boehringer Ingelheim, personal fees (for speakers fees) from Boehringer Ingelheim, other funding for educational sponsorship from Roche and Boehringer Ingelheim, and personal fees (for advisory boards) from Roche, outside the submitted work. Conflict of interest: S. Wiebe is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: S. Wind is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. Conflict of interest: K. Hohl has nothing to disclose. Conflict of interest: A. Baker is an employee of Boehringer Ingelheim. Conflict of interest: R. Schlenker-Herceg has nothing to disclose. Conflict of interest: S. Stowasser is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: T.M. Maher has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB., (Copyright ©ERS 2019.)

Aims: Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin., Methods: In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC 0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and C max (maximum plasma concentration) of each probe drug., Results: Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC 0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for C max and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI., Conclusions: Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI., (© 2018 Boehringer Ingelheim Pharma GMBH and Co KG Biberach. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics., Methods: This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C max (maximum plasma concentration) and AUC 0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration)., Results: The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC 0-tz (90% CI 135-171%) and 154% for C max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC 0-tz (90% CI 102-132%) and 118% for C max (90% CI 98-142%)., Conclusion: The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845.

Nuclear replication of cytomegalovirus relies on elaborate mechanisms of nucleocytoplasmic egress of viral particles. Thus, the role of two essential and conserved viral nuclear egress proteins, pUL50 and pUL53, is pivotal. pUL50 and pUL53 heterodimerize and form a core nuclear egress complex (NEC), which is anchored to the inner nuclear membrane and provides a scaffold for the assembly of a multimeric viral-cellular NEC. Here, we report the crystal structure of the pUL50-pUL53 heterodimer (amino acids 1-175 and 50-292, respectively) at 2.44 Å resolution. Both proteins adopt a globular fold with mixed α and β secondary structure elements. pUL53-specific features include a zinc-binding site and a hook-like N-terminal extension, the latter representing a hallmark element of the pUL50-pUL53 interaction. The hook-like extension (amino acids 59-87) embraces pUL50 and contributes 1510 Å(2) to the total interface area (1880 Å(2)). The pUL50 structure overall resembles the recently published NMR structure of the murine cytomegalovirus homolog pM50 but reveals a considerable repositioning of the very C-terminal α-helix of pUL50 upon pUL53 binding. pUL53 shows structural resemblance with the GHKL domain of bacterial sensory histidine kinases. A close examination of the crystal structure indicates partial assembly of pUL50-pUL53 heterodimers to hexameric ring-like structures possibly providing additional scaffolding opportunities for NEC. In combination, the structural information on pUL50-pUL53 considerably improves our understanding of the mechanism of HCMV nuclear egress. It may also accelerate the validation of the NEC as a unique target for developing a novel type of antiviral drug and improved options of broad-spectrum antiherpesviral therapy., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: To evaluate the relative bioavailability of single pill combination (SPC) tablets of linagliptin and metformin compared with separate tablets co-administered in healthy Chinese subjects., Materials and Methods: This was an open-label, single-dose, randomized, two-period, crossover study in healthy Chinese subjects with two dose groups: linagliptin 2.5 mg/metformin 850 mg and linagliptin 2.5 mg/metformin 500 mg. Within each group (n=24), subjects received one dose of the SPC tablet in one period and one dose of the separate tablets in the other. Primary endpoints were area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72) and maximum plasma concentration (Cmax) for linagliptin, and AUC from 0 to the last quantifiable concentration (AUC0-tz) and Cmax for metformin., Results: With the linagliptin 2.5 mg/metformin 850 mg dose, the adjusted geometric mean ratio of the SPC to the separate tablets for linagliptin was 99.53% (90% confidence interval (CI): 94.75-104.55) for AUC0-72 and 101.93% (90% CI: 95.36-108.95) for Cmax; for metformin the ratio was 96.99% (90% CI: 90.62-103.81) for AUC0-tz and 94.64% (90% CI: 85.43-104.84) for Cmax. With the linagliptin 2.5 mg/metformin 500 mg dose, the ratio with linagliptin for AUC0-72 and Cmax was 100.81% (90% CI: 95.14-106.82) and 111.37% (90% CI: 100.40-123.54), respectively; the same statistical parameters with metformin for AUC0-tz and Cmax were 102.95% (90% CI: 96.24-110.12) and 102.46% (90% CI: 92.20-113.87), respectively., Conclusions: SPC tablets of linagliptin and metformin were bioequivalent to separate tablets co-administered in healthy Chinese subjects.

The indication of origin of sesame seeds and sesame oil is one of the important factors influencing its price, as it is produced in many regions worldwide and certain provenances are especially sought after. We joined stable carbon and hydrogen isotope analysis with DNA based molecular marker analysis to study their combined potential for the discrimination of different origins of sesame seeds. For the stable carbon and hydrogen isotope data a positive correlation between both isotope parameters was observed, indicating a dominant combined influence of climate and water availability. This enabled discrimination between sesame samples from tropical and subtropical/moderate climatic provenances. Carbon isotope values also showed differences between oil from black and white sesame seeds from identical locations, indicating higher water use efficiency of plants producing black seeds. DNA based markers gave independent evidence for geographic variation as well as provided information on the genetic relatedness of the investigated samples. Depending on the differences in ambient environmental conditions and in the genotypic fingerprint, a combination of both analytical methods is a very powerful tool to assess the declared geographic origin. To our knowledge this is the first paper on food authenticity combining the stable isotope analysis of bio-elements with DNA based markers and their combined statistical analysis.

Genome assembly remains a challenge for large and/or complex plant genomes due to their abundant repetitive regions resulting in studies focusing on gene space instead of the whole genome. Thus, DNA enrichment strategies facilitate the assembly by increasing the coverage and simultaneously reducing the complexity of the whole genome. In this paper we provide an easy, fast, and cost-effective variant of MRE-seq to obtain a plant's hypomethylome by an optimized methyl filtration protocol followed by next generation sequencing. The method is demonstrated on three plant species with knowingly large and/or complex (polyploid) genomes: Oryza sativa, Picea abies, and Crocus sativus. The identified hypomethylomes show clear enrichment for genes and their flanking regions and clear reduction of transposable elements. Additionally, genomic sequences around genes are captured including regulatory elements in introns and up- and downstream flanks. High similarity of the results obtained by a de novo assembly approach with a reference based mapping in rice supports the applicability for studying and understanding the genomes of nonmodel organisms. Hence we show the high potential of MRE-seq in a wide range of scenarios for the direct analysis of methylation differences, for example, between ecotypes, individuals, within or across species harbouring large, and complex genomes.