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Regular single and triple step arrays with different periodicities have been fabricated in ultrahigh vacuum on clean Si(557) surfaces at various thermal treatment procedures. The atomic structure of the triple step staircases has been studied with high resolution scanning tunneling microscopy (STM). The results of atomically resolved STM experiments demonstrate a number of possible triple step configurations on Si(hhm) surfaces. The triple step models consistent with atomically resolved STM data obtained on regular Si(223) and Si(556) triple step staircases are presented. Possible driving forces for self-assembling regular step arrays on large scale areas are discussed. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether dual task-related changes in walking speed were associated with recurrent falls in frail older adults. DESIGN: Twelve-month prospective cohort study. SETTING: Thirteen senior housing facilities. PARTICIPANTS: Two hundred thirteen subjects (mean age 84.4+/-5.5). MEASUREMENTS: Usual and dual-tasking walking speeds (m/s) were calculated on a 10-m straight walkway at baseline. Information on incident falls during the follow-up year was collected monthly, and participants were divided into three groups based on the occurrence of falls (0, 1, and >or=2). Recurrent falls were defined as two or more falls during the 12-month follow-up period. RESULTS: Twenty subjects (9.4%) were classified as recurrent fallers. The occurrence of recurrent falls was associated with age (crude odds ratio (OR)=1.11, P=.02), number of drugs (crude OR=1.28, P=.002), and walking speed under both walking conditions (crude OR=0.96, P=.002 for usual walking and crude OR=0.60, P=.005 for walking while counting backward). Multiple Poisson regression showed that only walking speed while dual tasking and number of drugs were associated with incident falls (incident rate ratio (IRR)=0.84, P=.045 and IRR=1.10, P=.004). CONCLUSION: Slower walking speed while counting backward was associated with recurrent falls, suggesting that changes in gait performance while dual tasking might be an inexpensive way of identifying frail older adults prone to falling. [ABSTRACT FROM AUTHOR]

OBJECTIVE: From a cognitive approach of locomotion, we studied the feasibility and the reproducibility of a clinical test of gait which is devoted to predict fall.METHODOLOGY: With a cross-sectional design, we studied the gait of 30 old subjects (average age 82.6±7.1 years). The gait course consisted of a 10m length in a well light room, with regular walking shoes. Two conditions were examined: walking with and without explicit cognitive task (mental arithmetic and verbal flow task). Time (seconds) and number of steps were collected by two operators Deviations and stops were video-taped. Number of figures was recorded with a tape recorder. The difficulty to perform gait conditions was estimated by each subject with a quotation ranging from 0 (easy gait) to 10 (difficult gait).RESULTS: Increases of time, steps, deviations and stops were observed when gait was associated to a cognitive task (6.4 seconds and 4.6 steps with mental arithmetic; 10.5 seconds and 6.7 steps with verbal flow task). All subjects managed this test. These results were reproducible across tests and operators. Walking with mental arithmetic was the most easy gait condition for subjects.CONCLUSIONS: The simplicity and the reproducibility of this test make it as adequate instrument of gait evaluation in geriatrics. Walking with mental arithmetic is the condition that must to be used. Validation of its predictive value for fall in frail elderly subjects remains to be shown. [Copyright &y& Elsevier]

Abstract Background Conflicting results have been reported regarding the relationship between stride time variability (STV) and walking speed. While some studies failed to establish any relationship, others reported either a linear or a non-linear relationship. We therefore sought to determine the extent to which decrease in self-selected walking speed influenced STV among healthy young adults. Methods The mean value, the standard deviation and the coefficient of variation of stride time, as well as the mean value of stride velocity were recorded while steady-state walking using the GAITRite® system in 29 healthy young adults who walked consecutively at 88%, 79%, 71%, 64%, 58%, 53%, 46% and 39% of their preferred walking speed. Results The decrease in stride velocity increased significantly mean values, SD and CoV of stride time (p < 0.001), whereas the repetition of trials (p = 0.534, p = 0.177 and p = 0.691 respectively for mean, SD, CoV); and step asymmetry (p = 0.971, p = 0.150 and p = 0.288 for mean, SD and CoV) had no significant effect. Additionally, the subject's effect was significant for all stride parameters (p < 0.001). The relationship between a decrease in walking speed and all stride parameters (i.e., mean values, SD and CoV of stride time) was significantly quadratic and showed higher STV at a slow speed (p < 0.001). Conclusion The results support the assumption that gait variability increases while walking speed decreases and, thus, gait might be more unstable when healthy subjects walk slower compared with their preferred walking speed. Furthermore, these results highlight that a decrease in walking speed can be a potential confounder while evaluating STV.

Abstract Background Little information exists about the involvement of attention in the control of gait rhythmicity. Variability of both stride time and stride length is closely related to the control of the rhythmic stepping mechanism. We sought 1) to determine whether backward counting while walking could provoke significant gait changes in mean values and coefficients of variation of stride velocity, stride time and stride length among healthy young adults; and 2) to establish whether change in stride-to-stride variability could be related to dual-task related stride velocity change, attention, or both. Methods Mean values and coefficients of variation of stride velocity, stride time and stride length were recorded using the Physilog®-system, at a self-selected walking speed in 49 healthy young adults (mean age 24.1 ± 2.8 years, women 49%) while walking alone and walking with simultaneous backward counting. Performance on backward counting was evaluated by recording the number of figures counted while sitting alone and while walking. Results Compared with walking alone, a significant dual-task-related decrease was found for the mean values of stride velocity (p < 0.001), along with a small but significant increase for the mean values and coefficients of variation of stride time (p < 0.001 and p = 0.015, respectively). Stride length parameters did not change significantly between both walking conditions. Dual-task-related increase of coefficient of variation of stride time was explained by changing stride velocity and variability between subjects but not by backward counting. The number of figures counted while walking decreased significantly compared to backward counting alone. Further, the dual-task related decrease of the number of enumerated figures was significantly higher than the dual-task related decrease of stride velocity (p = 0.013). Conclusion The observed performance-changes in gait and backward counting while dual tasking confirm that certain aspects of walking are attention-demanding in young adults. In the tested group of 49 young volunteers, dual tasking caused a small decrease in stride velocity and a slight increase in the stride-to-stride variability of stride time, while stride velocity variability was not affected by the attention-demanding task. The increase in stride time variability was apparently the result of a change in gait speed, but not a result of dual tasking. This suggests that young adults require minimal attention for the control of the rhythmic stepping mechanism while walking.

Abstract: There is accumulated evidence today that an electric pulse can drastically modify the physical properties of correlated materials. An electric pulse was shown for example to induce an insulator-to-metal transition in manganites or in organic Mott insulators. We report here the first experimental evidence of a non-volatile electric pulse-induced insulator-to-metal transition and possible superconductivity in the Mott insulator GaTa4Se8. This resistive switching is concomitant to an electronic phase separation induced by the pulse. This phenomena most probably differs from the thermal, electronic injection or ionic diffusion processes explaining the resistive switching in materials foreseen for non-volatile memory (RRAM) applications. [Copyright &y& Elsevier]

Abstract: The GAITRite® system is a validated portable gait analysis system that allows simple objective gait measurements. The limited length of the active area of the GAITRite® system may be a limitation in obtaining reliable measures of stride-to-stride variability. In contrast, the SMTEC® footswitches system provides a continuous measurement of temporal step parameters for a long distance and a long period (around 24h). The aim of the study was to examine the concurrent validity of the SMTEC® footswitches system with the GAITRite® system for the measurement of temporal steps parameters. Step, stride, swing and stance time were simultaneously recorded using SMTEC® and GAITRite® systems while walking at normal, slow and fast self-selected walking speed among 13 healthy young adults. The level of agreement between both systems was high as for the stride time with intra-class correlation coefficients (ICC) between 0.95 and 0.99 (P <0.001) and repeatability coefficients (RC) between 1.1% and 1.5% of mean values, whereas the lowest level of agreement was shown at fast self-selected walking speed and for stance time (ICC=0.52 with P <0.001 and RC=4.9%). Furthermore, the measurement of individual footstep data was excellent with an agreement ranging between −0.04 and 0.04s (Pitman''s test of difference in variance: r =−0.009, P =0.772). The present results suggest that the SMTEC® footswitches system provides a valid and reliable measurement of temporal gait parameters in healthy young adults. [Copyright &y& Elsevier]

Objectives: The development of falls prevention strategies is an essential health concern in elderly people. However, a global consensus does not exist for elderly subjects who live independently in the community. The aim of the study was to evaluate the benefit of an exercises program.Materials and methods: A control group (153 subjects) and an “Intervention” group (150 subjects) were tested before and after a 1-year prospective study. The “Intervention” group performed ten training sessions of physical activity, based on balance, muscular activity and coordination. We compared the incidence of falls, and the performances in several tests between the two groups.Results: The clinical features were similar between the two groups: mean age 71 years, 83% of females, subjects who were independent for activities of daily living. However, all subjects presented risk for factors for falls: 38% were not able to maintain the unipodal position more than five seconds, 29% had already fallen during the previous year. For the “Intervention” group, the comparison of the performances before and after the physical activity program showed significant increases (p < 0.001) for all the tests, and specifically for the unipodal position and for the exercises performed with eyes closed. After one year follow-up, the incidence rate of falls was lower in the “Intervention” group compared with the control group, but the difference was not significant (p = 0.32). However, falls occurred significantly latter in the “Intervention” group (p = 0.02).Conclusion: Ten training sessions of physical activity allowed to improve the performance of elderly people in several tests. This result suggests that a fall prevention program based on collective and regular exercises, may be efficient for elderly subjects who still have an active and independent way of live. [Copyright &y& Elsevier]

Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Some authors are employees in the companies involved in the studies and may have access to stock/share options. In particular Kuno Wuersch, Eric Johnson, Wilfried Frieauff, Kelley Penrrat, Dominique Brees, Valerie Dubost and Diethilde Theil in Novartis; Warren E. Glaab, Katerina Vlasakova in Merck & Co., Inc., Rahway, NJ, Unites States; Olivier Perrault and Mohamed Slaoui in Sanofi. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Drug-induced gastrointestinal toxicity is a frequent clinical adverse event that needs to be carefully monitored and managed to ensure patient compliance. While preclinical assessment of drug-induced gastrointestinal toxicity mostly relies on animal experimentation, intestinal organoids have gained increasing attention to identify gastrointestinal toxicants in vitro. Nonetheless, current in vitro protocols primarily assess structural alterations induced by drugs, whereas gastrointestinal adverse events can often stem from functional disturbances. Disruption of serotonin signaling in the gastrointestinal tract is associated with impaired motility, as well as nausea and vomiting. We aimed to investigate alterations of serotonin homeostasis in organoids derived from the canine small intestine as a driver of drug-induced gastrointestinal toxicity. Treatment of the organoids with a compound (NVS-1) inducing acute gastrointestinal toxicity in dogs as well as with three tyrosine kinase inhibitors with known preclinical and clinical gastrointestinal adverse effects (afatinib, crizotinib and vandetanib) led to increased supernatant serotonin levels. Mechanistic assays showed that, while NVS-1 and afatinib stimulate serotonin release, crizotinib and vandetanib inhibit serotonin re-uptake via direct inhibition of the serotonin re-uptake transporter. Using a data mining approach, we further suggest that inhibition of serotonin re-uptake could contribute to gastrointestinal toxicity observed with multiple marketed drugs. In conclusion, we present the implementation of a novel in vitro gastrointestinal toxicity endpoint that could complement current methods and serve as a mechanistic and predictive/screening tool for drug-induced gastrointestinal toxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. RC, SS, SW,VD, HSS, AV,FM own stocks from Novartis Pharma AG, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A limited understanding of the pathology underlying chronic wounds has hindered the development of effective diagnostic markers and pharmaceutical interventions. This study aimed to elucidate the molecular composition of various common chronic ulcer types to facilitate drug discovery strategies. We conducted a comprehensive analysis of leg ulcers (LUs), encompassing venous and arterial ulcers, foot ulcers (FUs), pressure ulcers (PUs), and compared them with surgical wound healing complications (WHCs). To explore the pathophysiological mechanisms and identify similarities or differences within wounds, we dissected wounds into distinct subregions, including the wound bed, border, and peri-wound areas, and compared them against intact skin. By correlating histopathology, RNA sequencing (RNA-Seq), and immunohistochemistry (IHC), we identified unique genes, pathways, and cell type abundance patterns in each wound type and subregion. These correlations aim to aid clinicians in selecting targeted treatment options and informing the design of future preclinical and clinical studies in wound healing. Notably, specific genes, such as PITX1 and UPP1, exhibited exclusive upregulation in LUs and FUs, potentially offering significant benefits to specialists in limb preservation and clinical treatment decisions. In contrast, comparisons between different wound subregions, regardless of wound type, revealed distinct expression profiles. The pleiotropic chemokine-like ligand GPR15L (C10orf99) and transmembrane serine proteases TMPRSS11A/D were significantly upregulated in wound border subregions. Interestingly, WHCs exhibited a nearly identical transcriptome to PUs, indicating clinical relevance. Histological examination revealed blood vessel occlusions with impaired angiogenesis in chronic wounds, alongside elevated expression of genes and immunoreactive markers related to blood vessel and lymphatic epithelial cells in wound bed subregions. Additionally, inflammatory and epithelial markers indicated heightened inflammatory responses in wound bed and border subregions and reduced wound bed epithelialization. In summary, chronic wounds from diverse anatomical sites share common aspects of wound pathophysiology but also exhibit distinct molecular differences. These unique molecular characteristics present promising opportunities for drug discovery and treatment, particularly for patients suffering from chronic wounds. The identified diagnostic markers hold the potential to enhance preclinical and clinical trials in the field of wound healing., (© 2023 Novartis Biomedical Research and The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

The possibility that ancestral environmental exposure could result in adaptive inherited effects in mammals has been long debated. Numerous rodent models of transgenerational responses to various environmental factors have been published but due to technical, operational and resource burden, most still await independent confirmation. A previous study reported multigenerational epigenetic adaptation of the hepatic wound healing response upon exposure to the hepatotoxicant carbon tetrachloride (CCl 4 ) in male rats. Here, we comprehensively investigate the transgenerational effects by repeating the original CCl 4 multigenerational study with increased power, pedigree tracing, F2 dose-response and suitable randomization schemes. Detailed pathology evaluations do not support adaptive phenotypic suppression of the hepatic wound healing response or a greater fitness of F2 animals with ancestral liver injury exposure. However, transcriptomic analyses identified genes whose expression correlates with ancestral liver injury, although the biological relevance of this apparent transgenerational transmission at the molecular level remains to be determined. This work overall highlights the need for independent evaluation of transgenerational epigenetic inheritance paradigms in mammals., (© 2023. Springer Nature Limited.)