Recruitment and baseline characteristics of young adults at risk of early-onset knee osteoarthritis after ACL reconstruction in the SUPER-Knee trial.

Objectives: The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants. Methods: The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18-40 years) with ongoing symptoms (ie, mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score subscales (KOOS4)) 9-36 months post-ACLR. The NNS was calculated as the number of prospective participants screened to enrol one person. At baseline, participants provided medical history, completed questionnaires (demographic, injury/surgery, rehabilitation characteristics) and underwent physical examination. Results: 1044 individuals were screened to identify 567 eligible people, from which 184 participants (63% male) enrolled. The sample of enrolled participants was multicultural (29% born outside Australia; 2% Indigenous Australians). The NNS was 5.7. For randomised participants, mean±SD age was 30±6 years. The mean body mass index was 27.3±5.2 kg/m2, with overweight (43%) and obesity (21%) common. Participants were, on average, 2.3 years post-ACLR. Over half completed <8 months of postoperative rehabilitation, with 56% having concurrent injury/surgery to meniscus and/or cartilage. The most affected KOOS (0=worst, 100=best) subscale was quality of life (mean 43.7±19.1). Conclusion: Young adults post-ACLR were willing to participate in a secondary osteoarthritis prevention trial. Sample size calculations should be multiplied by at least 5.7 to provide an estimate of the NNS. The SUPER-Knee cohort is ideally positioned to monitor and intervene in the early development and trajectory of osteoarthritis. Trial registration number: ACTRN12620001164987.

Identification of Micrococcin P2-Derivatives as Antibiotic Candidates against Two Gram-Positive Pathogens.

Thiopeptides exhibit potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. Micrococcins are among the structurally simpler thiopeptides, but they have not been exploited in detail. This research involved a computational simulation of micrococcin P2 (MP2) docking in parallel with the structure-activity relationship (SAR) studied. The incorporation of particular nitrogen heterocycles in the side chain of MP2 enhances the antimicrobial activity. Micrococcin analogues 6c and 6d thus proved to be more effective against impetigo and C. difficile infection (CDI), respectively, as compared to current first-line treatments. Compound 6c also showed a shorter treatment period than that of a first-line treatment for impetigo. This may be attributed to its ability to downregulate pro-inflammatory cytokines. Compound 6d had no observed recurrence for C. difficile and exerted a minimal impact on the beneficial gut microbiome. Their pharmacokinetic properties and low toxicity profile make these compounds ideal candidates for the treatment of impetigo and CDI and validate their involvement in preclinical development.

Novel Chlorin e6-Curcumin Derivatives as a Potential Photosensitizer: Synthesis, Characterization, and Anticancer Activity.

Novel series of chlorin e6-curcumin derivatives were designed and synthesized. All the synthesized compounds 16, 17, 18, and 19 were tested for their photodynamic treatment (PDT) efficacy against human pancreatic cancer cell lines: AsPC-1, MIA-PaCa-2, and PANC-1. The cellular uptake study was performed in the aforementioned cell lines using fluorescence-activated cell sorting (FACS). 17, among the synthesized compounds with IC50 values of 0.27, 0.42, and 0.21 µM against AsPC-1, MIA PaCa-2, and PANC-1 cell lines, respectively, demonstrated excellent cellular internalization capability and exhibited higher phototoxicity relative to the parent Ce6. The quantitative analyses using Annexin V-PI staining revealed that the 17-PDT-induced apoptosis was dose-dependent. In pancreatic cell lines, 17 reduced the expression of the anti-apoptotic protein, Bcl-2, and increased the pro-apoptotic protein, cytochrome C, which indicates the activation of intrinsic apoptosis, the primary cause of cancer cell death. Structure-activity relationship studies have shown that the incorporation of additional methyl ester moiety and conjugation to the enone moiety of curcumin enhances cellular uptake and PDT efficacy. Moreover, in vivo PDT testing in melanoma mouse models revealed that 17-PDT greatly reduced tumor growth. Therefore, 17 might be an effective photosensitizer for PDT anticancer therapy.

SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER) versus minimal intervention for young adults at risk of knee osteoarthritis after ACL reconstruction: SUPER-Knee randomised controlled trial protocol.

INTRODUCTION: Anterior cruciate ligament injury and reconstruction (ACLR) is often associated with pain, functional loss, poor quality of life and accelerated knee osteoarthritis development. The effectiveness of interventions to enhance outcomes for those at high risk of early-onset osteoarthritis is unknown. This study will investigate if SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER) is superior to a minimal intervention control for improving pain, function and quality of life in young adults with ongoing symptoms following ACLR. METHODS AND ANALYSIS: The SUPER-Knee Study is a parallel-group, assessor-blinded, randomised controlled trial. Following baseline assessment, 184 participants aged 18-40 years and 9-36 months post-ACLR with ongoing symptoms will be randomly allocated to one of two treatment groups (1:1 ratio). Ongoing symptoms will be defined as a mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score (KOOS4) subscales covering pain, symptoms, function in sports and recreational activities and knee-related quality of life. Participants randomised to SUPER will receive a 4-month individualised, physiotherapist-supervised strengthening and neuromuscular programme with education. Participants randomised to minimal intervention (ie, control group) will receive a printed best-practice guide for completing neuromuscular and strengthening exercises following ACLR. The primary outcome will be change in the KOOS4 from baseline to 4 months with a secondary endpoint at 12 months. Secondary outcomes include change in individual KOOS subscale scores, patient-perceived improvement, health-related quality of life, kinesiophobia, physical activity, thigh muscle strength, knee function and knee cartilage morphology (ie, lesions, thickness) and composition (T2 mapping) on MRI. Blinded intention-to-treat analyses will be performed. Findings will also inform cost-effectiveness analyses. ETHICS AND DISSEMINATION: This study is approved by the La Trobe University and Alfred Hospital Ethics Committees. Results will be presented in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12620001164987.

Modular hip exoskeleton improves walking function and reduces sedentary time in community-dwelling older adults.

BACKGROUND: Despite the benefits of physical activity for healthy physical and cognitive aging, 35% of adults over the age of 75 in the United States are inactive. Robotic exoskeleton-based exercise studies have shown benefits in improving walking function, but most are conducted in clinical settings with a neurologically impaired population. Emerging technology is starting to enable easy-to-use, lightweight, wearable robots, but their impact in the otherwise healthy older adult population remains mostly unknown. For the first time, this study investigates the feasibility and efficacy of using a lightweight, modular hip exoskeleton for in-community gait training in the older adult population to improve walking function. METHODS: Twelve adults over the age of 65 were enrolled in a gait training intervention involving twelve 30-min sessions using the Gait Enhancing and Motivating System for Hip in their own senior living community. RESULTS: Performance-based outcome measures suggest clinically significant improvements in balance, gait speed, and endurance following the exoskeleton training, and the device was safe and well tolerated. Gait speed below 1.0 m/s is an indicator of fall risk, and two out of the four participants below this threshold increased their self-selected gait speed over 1.0 m/s after intervention. Time spent in sedentary behavior also decreased significantly. CONCLUSIONS: This intervention resulted in greater improvements in speed and endurance than traditional exercise programs, in significantly less time. Together, our results demonstrated that exoskeleton-based gait training is an effective intervention and novel approach to encouraging older adults to exercise and reduce sedentary time, while improving walking function. Future work will focus on whether the device can be used independently long-term by older adults as an everyday exercise and community-use personal mobility device. Trial registration This study was retrospectively registered with ClinicalTrials.gov (ID: NCT05197127).

Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile.

The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.

Diversity-oriented routes to thiopeptide antibiotics: total synthesis and biological evaluation of micrococcin P2.

We report the first total synthesis of micrococcin P2 (MP2, 1) by a diversity-oriented route that incorporates a number of refinements relative to earlier syntheses. Biological data regarding the activity of 1 against a range of human pathogens are also provided. Furthermore, we disclose a chemical property of MP2 that greatly facilitates medicinal chemistry work in the micrococcin area and describe a method to obtain MP2 by fermentation in B. subtilis.

Association of breastfeeding and risk of metabolic syndrome and its components in postmenopausal parous women: Korea national health and nutrition examination survey (2010 ~ 2016).

BACKGROUND: Understanding the relationship between breastfeeding (BF) and metabolic syndrome (Mets) is important for maternal long-term health benefits and disease prevention. This study aimed to examine the association between BF and Mets and its components among postmenopausal parous Korean women. METHODS: This cross-sectional study on 10,356 Korean women used nationally representative data from the KNHANES from 2010 to 2016. Anthropometric, laboratory data and manual BP were measured. A multivariate logistic regression analysis was conducted to examine the association of BF with Mets and its components after adjusting for potential confounding variables. A p-value < 0.05 was to be considered statistically significant. RESULTS: Mets was present in 42% of the study participants. The BF group had low household income and education level. The prevalence of Mets in the BF group was higher than that in the non-BF group (42.69% vs. 34.76%, p <  0.001). BF was associated with increased risk of Mets (odds ratio [OR]: 1.4, 95% confidence interval [CI]: 1.18-1.65, p <  0.001). The BF group was at higher risks for diabetes (OR: 1.5, 95%CI: 1.14-1.98), hypertension (OR: 1.32, 95%CI: 1.03-1.68), hypertriglyceridemia (OR: 1.42, 95%CI: 1.02-1.99) and low high-density lipoprotein cholesterol (OR: 1.32, 95%CI: 1.06-1.65). CONCLUSION: In this study, BF did not affect decreasing the prevalence of Mets and its components.

RNN-Based On-Line Continuous Gait Phase Estimation from Shank-Mounted IMUs to Control Ankle Exoskeletons.

Several research groups have developed and studied powered ankle exoskeletons to improve energetics of healthy subjects and the mobility of elderly subjects, or to reduce asymmetry in gaits induced by strokes. To achieve optimal effect, the timing of assistive torque has been proved to be of crucial importance. Previous studies estimated the onset timings mostly by extrapolating the time horizon from past gait events observed with sensors. Such methods have inherently limited performance when subjects are not walking at steady frequencies. To overcome such limitation and allow the use of exoskeletons in various scenarios in a daily life, we propose to estimate the gait phase as a continuous variable progressing over a gait cycle, hence allowing immediate response to frequency changes rather than iteratively correcting it after each cycle. Our method uses recurrent neural networks to estimate gait phases out of an inertial measurement unit (IMU) every 10 ms. By replacing foot sensors with an IMU we can obtain rich enough information to estimate gait phase continuously as well as avoid physical damage in sensors from ground impacts. Our preliminary tests with 2 healthy subjects showed qualitatively positive outcomes regarding the gait phase estimation and the assistive torque control.

Natural gait event-based level walking assistance with a robotic hip exoskeleton.

In this paper, we present an assistance strategy for level walking by using a robotic hip exoskeleton. Our strategy utilizes a foot contact event estimated by an inertial measurement unit (IMU) on the pelvis. The gait cycle is composed of three phases. The transitions between the phases are established upon natural gait events that are inevitable and perceived reliably by sensors attached to our exoskeleton. The presented strategy provides a systematic way of adjusting the quantity of assistance that corresponds to the wearer's preference and needs, and also provides explicit principles for the initiation and termination of assistance. When a step begins, the maximum torque and duration of assistance are decided, and the torque profile for the entire step is designed in advance. We conduct experiments in order to investigate the effect on metabolic cost when walking on a motorized treadmill.

Gait performance and foot pressure distribution during wearable robot-assisted gait in elderly adults.

BACKGROUND: A robotic exoskeleton device is an intelligent system designed to improve gait performance and quality of life for the wearer. Robotic technology has developed rapidly in recent years, and several robot-assisted gait devices were developed to enhance gait function and activities of daily living in elderly adults and patients with gait disorders. In this study, we investigated the effects of the Gait-enhancing Mechatronic System (GEMS), a new wearable robotic hip-assist device developed by Samsung Electronics Co, Ltd., Korea, on gait performance and foot pressure distribution in elderly adults. METHODS: Thirty elderly adults who had no neurological or musculoskeletal abnormalities affecting gait participated in this study. A three-dimensional (3D) motion capture system, surface electromyography and the F-Scan system were used to collect data on spatiotemporal gait parameters, muscle activity and foot pressure distribution under three conditions: free gait without robot assistance (FG), robot-assisted gait with zero torque (RAG-Z) and robot-assisted gait (RAG). RESULTS: We found increased gait speed, cadence, stride length and single support time in the RAG condition. Reduced rectus femoris and medial gastrocnemius muscle activity throughout the terminal stance phase and reduced effort of the medial gastrocnemius muscle throughout the pre-swing phase were also observed in the RAG condition. In addition, walking with the assistance of GEMS resulted in a significant increase in foot pressure distribution, specifically in maximum force and peak pressure of the total foot, medial masks, anterior masks and posterior masks. CONCLUSION: The results of the present study reveal that GEMS may present an alternative way of restoring age-related changes in gait such as gait instability with muscle weakness, reduced step force and lower foot pressure in elderly adults. In addition, GEMS improved gait performance by improving push-off power and walking speed and reducing muscle activity in the lower extremities. TRIAL REGISTRATION: NCT02843828 .

Autonomous hip exoskeleton saves metabolic cost of walking uphill.

We have developed a hip joint exoskeleton to boost gait function in the elderly and rehabilitation of post-stroke patients. To quantitatively evaluate the impact of the power and mass of the exoskeleton, we measured the metabolic cost of walking on slopes of 0, 5, and 10% grade, once not wearing the exoskeleton and then wearing it. The exoskeleton reduced the metabolic cost by 13.5,15.5 and 9.8% (31.9, 51.6 and 45.6 W) at 0, 5, and 10% grade, respectively. The exoskeleton performance index was computed as 0.97, 1.24, and 1.24 at each grade, implicating that the hip exoskeleton was more effective on slopes than level ground in saving the metabolic cost.

Effects of assistance timing on metabolic cost, assistance power, and gait parameters for a hip-type exoskeleton.

There are many important factors in developing an exoskeleton for assisting human locomotion. For example, the weight should be sufficiently light, the assist torque should be high enough to assist joint motion, and the assistance timing should be just right. Understanding how these design parameters affect overall performance of a complex human-machine system is critical for the development of these types of systems. The present study introduces an assistance timing controller that regulates assistance timing such that peak joint velocity and peak assistance power are offset by a reference value for our hip-type exoskeleton. This is followed by measuring the manner in which various assistance timing references affect an important metric for performance, namely metabolic cost. The results indicate that net metabolic cost exhibits a concave up pattern with the most reduction of 21%, when compared to walking without the exoskeleton, at 0% assistance timing reference. The study also examines assistance timing's effect on gait parameters; increase in assistance timing reference increases step length, decreases cadence, and increases walk ratio (i.e. step length/cadence ratio) during treadmill walking.

Locomotion- and mechanics-mediated tactile sensing: antenna reconfiguration simplifies control during high-speed navigation in cockroaches.

Animals can expend energy to acquire sensory information by emitting signals and/or moving sensory structures. We propose that the energy from locomotion itself could permit control of a sensor, whereby animals use the energy from movement to reconfigure a passive sensor. We investigated high-speed, antenna-mediated tactile navigation in the cockroach Periplaneta americana. We discovered that the passive antennal flagellum can assume two principal mechanical states, such that the tip is either projecting backward or forward. Using a combination of behavioral and robotic experiments, we demonstrate that a switch in the antenna's state is mediated via the passive interactions between the sensor and its environment, and this switch strongly influences wall-tracking control. When the tip of the antenna is projected backward, the animals maintain greater body-to-wall distance with fewer body collisions and less leg-wall contact than when the tip is projecting forward. We hypothesized that distally pointing mechanosensory hairs at the tip of the antenna mediate the switch in state by interlocking with asperities in the wall surface. To test this hypothesis, we performed laser ablation of chemo-mechanosensory hairs and added artificial hairs to a robotic antenna. In both the natural and artificial systems, the presence of hairs categorically increased an antenna's probability of switching state. Antennal hairs, once thought to only play a role in sensing, are sufficient for mechanically reconfiguring the state of the entire antenna when coupled with forward motion. We show that the synergy between antennal mechanics, locomotion and the environment simplifies tactile sensing.

Kinetic and dynamic kinetic resolution of secondary alcohols with ionic-surfactant-coated Burkholderia cepacia lipase: substrate scope and enantioselectivity.

Forty-four different secondary alcohols, which can be classified into several types (II-IX), were tested as the substrates of ionic surfactant-coated Burkholderia cepacia lipase (ISCBCL) to see its substrate scope and enantioselectivity in kinetic and dynamic kinetic resolution (KR and DKR). They include 6 boron-containing alcohols, 24 chiral propargyl alcohols, and 14 diarylmethanols. The results from the studies on KR indicate that ISCBCL accepted most of them with high enantioselectivity at ambient temperature and with useful to high enantioselectivity at elevated temperatures. In particular, ISCBCL displayed high enantioselectivity toward sterically demanding secondary alcohols (types VIII and IX) which have two bulky substituents at the hydroxymethine center. DKR reactions were performed by the combination of ISCBCL with a ruthenium-based racemization catalyst at 25-60 °C. Forty-one secondary alcohols were tested for DKR. About half of them were transformed into their acetates of high enantiopurity (>90% ee) with good yields (>80%). It is concluded that ISCBCL appears to be a superb enzyme for the KR and DKR of secondary alcohols.

Serum 25-hydroxyvitamin D is associated with enhanced pneumococcal antibody levels in individuals with asthma.

Recent studies suggest that vitamin D modulates innate immunity and reduces the risk of microbial infections. Little is known about the role of vitamin D in antipneumococcal immunity in individuals with asthma. We determined the correlation between serum 25-hydroxyvitamin D (25[OH]D) levels and pneumococcal antibody levels in individuals with asthma, atopic dermatitis, or allergic rhinitis, and atopic sensitization status. A cross-sectional study was conducted for 21 subjects with asthma and 23 subjects without asthma. Pearson's correlation coefficient between serum 25(OH)D concentrations and the number of positive serotype-specific antibody levels was calculated among individuals with and without asthma, atopic dermatitis, and/or allergic rhinitis and atopic sensitization status. The overall correlation between serum 25(OH)D concentrations and positive pneumococcal antibody levels in all subjects regardless of asthma was not significant (r = -0.14; p = 0.38). Stratified analysis results showed that there was a positive correlation between serum 25(OH)D concentrations and positive pneumococcal antibody levels in asthmatic patients (r = 0.45; p < 0.05) and an inverse correlation was observed in nonasthmatic patients (r = -0.53; p < 0.05). These trends were similar for subjects with and without atopic dermatitis and/or allergic rhinitis (r = 0.58 and p = 0.008 versus r = -0.63 and p = 0.001). Despite similar trends in the correlation between serum 25(OH)D and pneumococcal antibody concentrations among those with and without atopic sensitization status (r = 0.27 and p = 0.19 versus r = -0.41 and p = 0.08), they did not reach statistical significance. The 25(OH)D may enhance humoral immunity against Streptococcus pneumonia in subjects with atopic conditions but not without atopic conditions. Atopic conditions may have an important effect modifier in the relationship between serum 25(OH)D concentrations and immune function.