Concurrent vestibular activation and postural training recalibrate somatosensory, vestibular and gaze stabilization processes.

Postural instability is a common symptom of vestibular dysfunction that impacts a person's day-to-day activities. Vestibular rehabilitation is effective in decreasing dizziness, visual symptoms and improving postural control through several mechanisms including sensory reweighting of the vestibular, visual and somatosensory systems. As part of the sensory reweighting mechanisms, vestibular activation exercises with headshaking influence vestibular-ocular reflex (VOR). However, combining challenging vestibular and postural tasks to facilitate more effective rehabilitation outcomes is under-utilized. Understanding how and why this may work is unknown. The aim of the study was to assess sensory reweighting of postural control processing and VOR after concurrent vestibular activation and weight shift training (WST) in healthy young adults. Forty-two participants (18-35years) were randomly assigned into four groups: No training/control (CTL), a novel visual feedback WST coupled with a concurrent, rhythmic active horizontal or vertical headshake activity (HHS and VHS), or the same WST with no headshake (NHS). Training was performed for five days. All groups performed baseline- and post-assessments using the video head impulse test, sensory organization test, force platform rotations and electro-oculography. Significantly decreased horizontal eye movement variability in the HHS group compared to the other groups suggests improved gaze stabilization (p = .024). Significantly decreased horizontal VOR gain (p = .040) and somatosensory downweighting (p = .050) were found in the combined headshake groups (HHS and VHS) compared to the other two groups (NHS and CTL). The training also showed a significantly faster automatic postural response (p = .003) with improved flexibility (p = .010) in the headshake groups. The concurrent training influences oculomotor function and suggests improved gaze stabilization through vestibular recalibration due to adaptation and possibly habituation. The novel protocol could be modified into progressive functional activities that would incorporate gaze stabilization exercises. The findings may have implications for future development of vestibular rehabilitation protocols.

Differential relationships between physical activity and pain phenotypes in individuals with spinal cord injury.

BACKGROUND: Chronic pain affects 70% of individuals with spinal cord injury (SCI) and leads to declines in health and quality of life. Neuropathic and nociceptive pain are phenotypes derived from different mechanisms that contribute to pain perception. The objective of this research was to investigate differential pain responses to moderate-to-vigorous physical activity (MVPA) in two chronic pain phenotypes: neuropathic and nociceptive pain. METHODS: Community-based physical activity levels were collected for one week in 17 individuals with SCI using a wrist-worn accelerometer, and daily pain ratings were assessed and categorized by phenotype. Physical activity levels were summarized to calculate minutes of MVPA. Correlational analyses were conducted to compare relationships between pain intensity and MVPA across individual participants and between pain phenotype groups. RESULTS: The neuropathic pain group revealed significant negative correlation between MVPA and pain intensity. In the nociceptive pain group, there was no significant correlation between MVPA and pain intensity. Further analysis revealed two subgroups of positive (N = 4) and negative (N = 3) correlations between MVPA and pain intensity. Pain location differed between the subgroups of nociceptive pain. Individuals with negative correlation experienced neck and upper back pain, whereas individuals with positive correlation experienced unilateral upper extremity pain. CONCLUSION: Differential relationships exist between pain phenotypes and MVPA in individuals with SCI. Pain location differed between the subgroups of nociceptive pain, which we presume may indicate the presence of nociplastic pain in some individuals. These results may contribute to the advancement of personalized pain management by targeting non-pharmacological interventions for specific pain phenotypes.Trial registration: ClinicalTrials.gov identifier: NCT05236933..

The Effects of Age and Height on Gait Smoothness in Adolescent Athletes.

(1) Background: Despite evidence of increased rates of sports injury during the years surrounding peak growth in adolescents, little is known regarding the relationship between adolescent growth and gait stability. The aim of this study was to gain a better understanding of how chronological age and height relate to gait stability in both male and female adolescents. (2) Methods: Participants (N = 67; females: n = 34, ages 8.7-15.9 years; males: n = 33, ages 10.0-16.7 years) completed two trials of treadmill walking at varying speeds: the preferred walking speed and 30% above and below. Trials were separated by a bout of fatiguing exercises. HarmonicRatios of the trunk, calculated from acceleration signals taken during walking, were used to quantify gait stability. Data were separated by sex and relationships between height and chronological age, and HarmonicRatios were assessed using multiple linear regression. (3) Results: Females' HarmonicRatios improved with chronological age both before and after fatigue. Males' HarmonicRatios increased with chronological age before fatigue; however, this effect was eliminated post-fatigue. Females' height was negatively associated with HarmonicRatios post-fatigue. Males' height was positively associated with HarmonicRatios pre-fatigue. (4) Conclusions: The study findings suggest sex differences in the effects of fatigue on gait stability during adolescence. In both sexes, HarmonicRatios increased with chronological age. These improvements were eliminated for males and altered for females with fatigue. The results of this study indicate the need for the reevaluation of sports progression based on chronological age in adolescents.

Using virtual reality-based neurocognitive testing and eye tracking to study naturalistic cognitive-motor performance.

Natural human behavior arises from continuous interactions between the cognitive and motor domains. However, assessments of cognitive abilities are typically conducted using pen and paper tests, i.e., in isolation from "real life" cognitive-motor behavior and in artificial contexts. In the current study, we aimed to assess cognitive-motor task performance in a more naturalistic setting while recording multiple motor and eye tracking signals. Specifically, we aimed to (i) delineate the contribution of cognitive and motor components to overall task performance and (ii) probe for a link between cognitive-motor performance and pupil size. To that end, we used a virtual reality (VR) adaptation of a well-established neurocognitive test for executive functions, the 'Color Trails Test' (CTT). The VR-CTT involves performing 3D reaching movements to follow a trail of numbered targets. To tease apart the cognitive and motor components of task performance, we included two additional conditions: a condition where participants only used their eyes to perform the CTT task (using an eye tracking device), incurring reduced motor demands, and a condition where participants manually tracked visually-cued targets without numbers on them, incurring reduced cognitive demands. Our results from a group of 30 older adults (>65) showed that reducing cognitive demands shortened completion times more extensively than reducing motor demands. Conditions with higher cognitive demands had longer target search time, as well as decreased movement execution velocity and head-hand coordination. We found larger pupil sizes in the more cognitively demanding conditions, and an inverse correlation between pupil size and completion times across individuals in all task conditions. Lastly, we found a possible link between VR-CTT performance measures and clinical signatures of participants (fallers versus non-fallers). In summary, performance and pupil parameters were mainly dependent on task cognitive load, while maintaining systematic interindividual differences. We suggest that this paradigm opens the possibility for more detailed profiling of individual cognitive-motor performance capabilities in older adults and other at-risk populations.

The Effects of Exoskeleton Assistance at the Ankle on Sensory Integration During Standing Balance.

Exoskeleton devices can reduce metabolic cost, increase walking speed, and augment load-carrying capacity. However, little is known about the effects of powered assistance on the sensory information required to achieve these tasks. To learn how to use an assistive device, humans must integrate novel sensory information into their internal model. This process may be disrupted by challenges to the sensory systems used for posture. We investigated the exoskeleton-induced changes to balance performance and sensory integration during quiet standing. We asked 11 unimpaired adults to perform a virtual reality-based test of sensory integration in balance (VRSIB) on two days while wearing the exoskeleton either unpowered, using proportional myoelectric control, or with regular shoes. We measured postural biomechanics, muscle activity, equilibrium scores, postural control strategy, and sensory ratios. Results showed improvement in balance performance when wearing the exoskeleton on firm ground. The opposite occurred when standing on an unstable platform with eyes closed or when the visual information was non-veridical. The balance performance was equivalent when the exoskeleton was powered versus unpowered in all conditions except when both the support surface and the visual information were altered. We argue that in stable ground conditions, the passive stiffness of the device dominates the postural task. In contrast, when the ground becomes unstable the passive stiffness negatively affects balance performance. Furthermore, when the visual input to the user is non-veridical, exoskeleton assistance can magnify erroneous muscle inputs and negatively impact the user's postural control.

The order of attentional focus instructions affects how postural control processes compensate for multisensory mismatch: a crossover study.

Directing attention during balance training can have an immediate and lasting impact on a patient's balance and ultimately decrease the risk of future falls. However, it is unclear how attention can best be utilized to improve postural control. The current study uses a 2 × 2 crossover design to investigate the potential impact of receiving multiple verbal instructions during a single session of sensorimotor control testing for balance. Twenty-eight healthy adults were tasked to balance on a rocker board while immersed in virtual reality (VR). The VR created a multisensory mismatch between visual VR motion and body motion. The strength of the relationship between visual motion and body motion was measured to assess visual dependence. Alpha and theta frequency bands in electroencephalography (EEG) recordings were also analyzed to identify potential neural correlates of visual dependence and postural stability. Participants were randomized into two groups: one group was first instructed to keep the board leveled (external focus) and then instructed to keep both feet leveled (internal focus) to help maintain stability. The other group was given these two instructions in reverse order. Analyses focused on time, instruction, and group effects from receiving multiple instructions. Results revealed that when participants are given external focus first, and internal focus second, they are more likely to demonstrate lower visual dependence and better postural stability throughout the entire session than participants given internal focus first and external focus second. However, channel-level EEG analyses did not reveal differences between the groups. Current findings suggest that the order of attentional focus instructions may influence how the postural control system resolves sensory incongruence during a single testing session.

The primary pharmacology of ceftazidime/avibactam: microbiology from clinical studies, and development of resistance during treatment.

As one of a series of thematically linked reviews of the primary pharmacology of the ß-lactam/ß-lactamase inhibitor combination, ceftazidime/avibactam, this article reviews the microbiological findings in drug-exposed patients. Earlier articles in the series focused on basic in vitro and in vivo translational biology (J Antimicrob Chemother 2022; 77: 2321-40 and 2341-52) and the development and mechanisms of resistance in vitro (J Antimicrob Chemother 2023: Epub ahead of print. doi: 10.1093/jac/dkac449). In clinical trials of ceftazidime/avibactam, combined favourable microbiological responses for evaluable patients infected at baseline by susceptible Enterobacterales or Pseudomonas aeruginosa were 86.1% (851/988). The corresponding percent favourable among patients infected by ceftazidime/avibactam-resistant pathogens was 58.8% (10/17), noting that the majority (15/17) of the resistant examples were P. aeruginosa. Microbiological response rates to comparator treatments in the same clinical trials ranged between 64% and 95%, depending on the type of infection and the analysis population. Uncontrolled case studies over a wide range of patients infected by antibiotic multiresistant Gram-negative bacteria have demonstrated that ceftazidime/avibactam can elicit microbiological clearance of ceftazidime/avibactam-susceptible strains. In case studies where a matched cohort of patients had been treated with antibacterial agents other than ceftazidime/avibactam, microbiological outcomes were comparable between treatments, mostly being observationally more favourable for ceftazidime/avibactam (recognizing that numbers were too small for definitive superiority assessments). Development of resistance to ceftazidime/avibactam during therapy is reviewed. The phenomenon has been reported multiple times, mostly in difficult-to-treat patients infected by KPC-producing Enterobacterales. Molecular mechanisms, when determined, have frequently been observed previously in vitro, such as the 'Ω-loop' D179Y (Asp179Tyr) substitution found in KPC variant enzymes. In human volunteers exposed to therapeutic levels of ceftazidime/avibactam, faecal numbers of Escherichia coli, other enterobacteria, lactobacilli, bifidobacteria, clostridia and Bacteroides spp. decreased. Clostridioides difficile was detected in the faeces, but this was of uncertain significance, because no unexposed controls were studied.

The primary pharmacology of ceftazidime/avibactam: resistance in vitro.

This article reviews resistance to ceftazidime/avibactam as an aspect of its primary pharmacology, linked thematically with recent reviews of the basic in vitro and in vivo translational biology of the combination (J Antimicrob Chemother 2022; 77: 2321-40 and 2341-52). In Enterobacterales or Pseudomonas aeruginosa, single-step exposures to 8×  MIC of ceftazidime/avibactam yielded frequencies of resistance from <∼0.5 × 10-9 to 2-8 × 10-9, depending on the host strain and the ß-lactamase harboured. ß-Lactamase structural gene mutations mostly affected the avibactam binding site through changes in the Ω-loop: e.g. Asp179Tyr (D179Y) in KPC-2. Other mutations included ones proposed to reduce the permeability to ceftazidime and/or avibactam through changes in outer membrane structure, up-regulated efflux, or both. The existence, or otherwise, of cross-resistance between ceftazidime/avibactam and other antibacterial agents was also reviewed as a key element of the preclinical primary pharmacology of the new agent. Cross-resistance between ceftazidime/avibactam and other ß-lactam-based antibacterial agents was caused by MBLs. Mechanism-based cross-resistance was not observed between ceftazidime/avibactam and fluoroquinolones, aminoglycosides or colistin. A low level of general co-resistance to ceftazidime/avibactam was observed in MDR Enterobacterales and P. aeruginosa. For example, among 2821 MDR Klebsiella spp., 3.4% were resistant to ceftazidime/avibactam, in contrast to 0.07% of 8177 non-MDR isolates. Much of this was caused by possession of MBLs. Among 1151 MDR, XDR and pandrug-resistant isolates of P. aeruginosa from the USA, 11.1% were resistant to ceftazidime/avibactam, in contrast to 3.0% of 7452 unselected isolates. In this case, the decreased proportion susceptible was not due to MBLs.

Economic Evaluation of the Protecting Teeth @ 3 Randomized Controlled Trial.

INTRODUCTION: An economic evaluation (EE) was conducted alongside a randomized controlled trial (the Protecting Teeth @ 3 Study [PT@3]), exploring the additional preventive value of fluoride varnish (FV) application at 6-monthly intervals in nursery schools compared to treatment as usual (TAU) in the same nurseries. TAU represented a multicomponent national child oral health improvement intervention, the Childsmile program, apart from nursery FV. METHODS: The EE was a within-trial cost-utility analysis (CUA) comparing the FV and TAU groups. The CUA was conducted from a National Health Service perspective and followed relevant methods guidance. Within-trial costs included intervention costs and health care resource use costs. Health outcomes were expressed in quality-adjusted life years (QALYs) accrued over the 2-y follow-up period. The Child Health Utility 9 Dimensions questionnaire was used to obtain utility scores. National reference costs were used, a discount rate of 1.5% for public health interventions was adopted, multiple imputation methods for missing data were employed, sensitivity analyses were conducted, and incremental cost-utility ratios were calculated. RESULTS: Data from 534 participants from the 2014-2015 PT@3 intake were used in the EE analyses, n = 265 (50%) in the FV arm and n = 269 (50%) in the TAU arm. Mean incremental cost per child in the FV arm was £68.37 (P = 0.382; 95% confidence interval [CI], -£18.04 to £143.82). Mean incremental QALY was -0.004 (P = 0.636; 95% CI, -0.016 to 0.007). The probability that the FV intervention was cost-effective at the UK £20,000 threshold was 11.3%. CONCLUSION: The results indicate that applying FV in nurseries in addition to TAU (all other components of Childsmile, apart from nursery FV) would not be deemed cost-effective given current UK thresholds. In view of previously proven clinical effectiveness and economic worthiness of the universal nursery toothbrushing component of Childsmile, continuation of the additional, targeted nursery FV component in its pre-COVID-19 form should be reviewed given its low probability of cost-effectiveness. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by child oral health policy makers and dental public health professionals. They can form part of the evidence to inform the Scottish, UK, and international guidance on community-based child oral health promotion programs.

Neuromotor changes in participants with a concussion history can be detected with a custom smartphone app.

Neuromotor dysfunction after a concussion is common, but balance tests used to assess neuromotor dysfunction are typically subjective. Current objective balance tests are either cost- or space-prohibitive, or utilize a static balance protocol, which may mask neuromotor dysfunction due to the simplicity of the task. To address this gap, our team developed an Android-based smartphone app (portable and cost-effective) that uses the sensors in the device (objective) to record movement profiles during a stepping-in-place task (dynamic movement). The purpose of this study was to examine the extent to which our custom smartphone app and protocol could discriminate neuromotor behavior between concussed and non-concussed participants. Data were collected at two university laboratories and two military sites. Participants included civilians and Service Members (N = 216) with and without a clinically diagnosed concussion. Kinematic and variability metrics were derived from a thigh angle time series while the participants completed a series of stepping-in-place tasks in three conditions: eyes open, eyes closed, and head shake. We observed that the standard deviation of the mean maximum angular velocity of the thigh was higher in the participants with a concussion history in the eyes closed and head shake conditions of the stepping-in-place task. Consistent with the optimal movement variability hypothesis, we showed that increased movement variability occurs in participants with a concussion history, for which our smartphone app and protocol were sensitive enough to capture.

Etiological spectrum and outcome of fever and inflammation of unknown origin. Does symptom duration matter?

OBJECTIVE: Evidence suggests that the symptom duration may affect the occurrence of certain fever (FUO) and inflammation (IUO) of unknown origin associated conditions. It is unclear if this could potentially guide diagnostic evaluations. We examined the association between symptom duration and diagnostic and prognostic outcomes in FUO/IUO. METHODS: We retrospectively analyzed a cohort of adult patients meeting criteria for FUO/IUO from a tertiary care center in Belgium between 2000 and 2019. The association between symptom duration and outcomes of interest were estimated by Cox proportional hazards models. RESULTS: Among 602 patients who met criteria for FUO/IUO (mean age 54 years, 43% female), 132 (22%) and 68 (11%) had symptoms for 3-12 months and >12 months, respectively. There were no significant differences in diagnosis or all-cause mortality between a symptom duration of <3 months and 3-12 months. In contrast, those who had a symptom duration of >12 months were less likely to receive a final diagnosis (aHR 0.42, 95% CI 0.30-0.60), in particular a diagnosis of infectious disorders (aHR 0.29, 95% CI 0.12-0.74), malignancies (aHR 0.11, 95% CI 0.03-0.46), and miscellaneous conditions (aHR 0.22, 95% CI 0.07-0.71), but no significant differences were seen in noninfectious inflammatory disorders (aHR 0.74, 95% CI 0.48-1.15) or all-cause mortality (aHR 0.55, 95% CI 0.19-1.54). CONCLUSIONS: The symptom duration may be used to guide the diagnostic workup among patients with FUO and IUO, in particular those with longstanding symptoms.

Association Between Traumatic Brain Injury and Subsequent Cardiovascular Disease Among Post-9/11-Era Veterans.

Importance: Traumatic brain injury (TBI) was common among US service members deployed to Iraq and Afghanistan. Although there is some evidence to suggest that TBI increases the risk of cardiovascular disease (CVD), prior reports were predominantly limited to cerebrovascular outcomes. The potential association of TBI with CVD has not been comprehensively examined in post-9/11-era veterans. Objective: To determine the association between TBI and subsequent CVD in post-9/11-era veterans. Design, Setting, and Participants: This was a retrospective cohort study conducted from October 1, 1999, to September 30, 2016. Participants were followed up until December 31, 2018. Included in the study were administrative data from the US Department of Veterans Affairs and the Department of Defense from the Long-term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. Participants were excluded if dates did not overlap with the study period. Data analysis was conducted between November 22, 2021, and June 28, 2022. Exposures: History of TBI as measured by diagnosis in health care records. Main Outcomes and Measures: Composite end point of CVD: coronary artery disease, stroke, peripheral artery disease, and cardiovascular death. Results: Of the 2 530 875 veterans from the consortium, after exclusions, a total of 1 559 928 veterans were included in the analysis. A total of 301 169 veterans (19.3%; median [IQR] age, 27 [23-34] years; 265 217 male participants [88.1]) with a TBI history and 1 258 759 veterans (80.7%; median [IQR] age, 29 [24-39] years; 1 012 159 male participants [80.4%]) without a TBI history were included for analysis. Participants were predominately young (1 058 054 [67.8%] <35 years at index date) and male (1 277 376 [81.9%]). Compared with participants without a history of TBI, diagnoses of mild TBI (hazard ratio [HR], 1.62; 95% CI, 1.58-1.66; P < .001), moderate to severe TBI (HR, 2.63; 95% CI, 2.51-2.76; P < .001), and penetrating TBI (HR, 4.60; 95% CI, 4.26-4.96; P < .001) were associated with CVD in adjusted models. In analyses of secondary outcomes, all severities of TBI were associated with the individual components of the composite outcome except penetrating TBI and CVD death. Conclusions and Relevance: Results of this cohort study suggest that US veterans with a TBI history were more likely to develop CVD compared with veterans without a TBI history. Given the relatively young age of the cohort, these results suggest that there may be an increased burden of CVD as these veterans age and develop other CVD risk factors. Future studies are needed to determine if the increased risk associated with TBI is modifiable.

The impact of external and internal focus of attention on visual dependence and EEG alpha oscillations during postural control.

BACKGROUND: The ability to maintain upright posture requires successful integration of multiple sensory inputs (visual, vestibular, and somatosensory). When one or more sensory systems become unreliable, the postural control system must "down-weight" (or reduce the influence of) those senses and rely on other senses to maintain postural stability. As individuals age, their ability to successfully reweight sensory inputs diminishes, leading to increased fall risk. The present study investigates whether manipulating attentional focus can improve the ability to prioritize different sensory inputs for postural control. METHODS: Forty-two healthy adults stood on a balance board while wearing a virtual reality (VR) head-mounted display. The VR environment created a multisensory conflict amongst the different sensory signals as participants were tasked with maintaining postural stability on the balance board. Postural sway and scalp electroencephalography (EEG) were measured to assess visual weighting and cortical activity changes. Participants were randomized into groups that received different instructions on where to focus their attention during the balance task. RESULTS: Following the instructions to direct attention toward the movement of the board (external focus group) was associated with lower visual weighting and better balance performance than when not given any instructions on attentional focus (control group). Following the instructions to direct attention towards movement of the feet (internal focus group) did not lead to any changes in visual weighting or balance performance. Both external and internal focus groups exhibited increased EEG alpha power (8-13 Hz) activity over the occipital cortex as compared to the control group. CONCLUSIONS: Current results suggest that directing one's attention externally, away from one's body, may optimize sensory integration for postural control when visual inputs are incongruent with somatosensory and vestibular inputs. Current findings may be helpful for clinicians and researchers in developing strategies to improve sensorimotor mechanisms for balance.

Disparities In Diabetes-Related Lower Extremity Amputations In The United States: A Systematic Review.

Disparities in rates of peripheral diabetic neuropathy and lower extremity amputation exist in the United States. To investigate the factors linked to this disparity, we performed a systematic review of the literature on the subject published during the period 2000-20. Nineteen observational studies were included. Disparities in rates of lower extremity amputation were reported according to patient race, ethnicity, sex, and age; across hospital referral regions, residential area characteristics, and income estimates; and on the basis of payer type and hospital characteristics. Several of these factors were interrelated. There was a reduction in major lower extremity amputation rates among Black, Hispanic, and White patients with diabetes over time, suggesting narrowing disparities in the odds of this procedure among Black and White patients. There is a need for a national strategy that integrates public awareness, screening, early initiated multidisciplinary care, and quality measures for peripheral artery disease management, as well as neighborhood-level public health interventions, to reduce the disproportionate burden of lower extremity amputation in underserved communities.

The primary pharmacology of ceftazidime/avibactam: in vitro translational biology.

Previous reviews of ceftazidime/avibactam have focused on in vitro molecular enzymology and microbiology or the clinically associated properties of the combination. Here we take a different approach. We initiate a series of linked reviews that analyse research on the combination that built the primary pharmacology data required to support the clinical and business risk decisions to perform randomized controlled Phase 3 clinical trials, and the additional microbiological research that was added to the above, and the safety and chemical manufacturing and controls data, that constituted successful regulatory licensing applications for ceftazidime/avibactam in multiple countries, including the USA and the EU. The aim of the series is to provide both a source of reference for clinicians and microbiologists to be able to use ceftazidime/avibactam to its best advantage for patients, but also a case study of bringing a novel ß-lactamase inhibitor (in combination with an established ß-lactam) through the microbiological aspects of clinical development and regulatory applications, updated finally with a review of resistance occurring in patients under treatment. This first article reviews the biochemistry, structural biology and basic microbiology of the combination, showing that avibactam inhibits the great majority of serine-dependent ß-lactamases in Enterobacterales and Pseudomonas aeruginosa to restore the in vitro antibacterial activity of ceftazidime. Translation to efficacy against infections in vivo is reviewed in the second co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2341-52).

The primary pharmacology of ceftazidime/avibactam: in vivo translational biology and pharmacokinetics/pharmacodynamics (PK/PD).

This review describes the translational in vivo and non-clinical pharmacokinetics/pharmacodynamics (PK/PD) research that supported clinical trialling and subsequently licensing approval of ceftazidime/avibactam, a new ß-lactam/ß-lactamase inhibitor combination aimed at the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. The review thematically follows on from the co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2321-40). Avibactam protected ceftazidime in animal models of infection with ceftazidime-resistant, ß-lactamase-producing bacteria. For example, a single subcutaneous dose of ceftazidime at 1024 mg/kg yielded little effect on the growth of ceftazidime-resistant, blaKPC-2-carrying Klebsiella pneumoniae in the thighs of neutropenic mice (final counts of 4 × 108 to 8 × 108 cfu/thigh). In contrast, co-administration of avibactam in a 4:1 ratio (ceftazidime:avibactam) was bactericidal in the same model (final counts of 2 × 104 to 3 × 104 cfu/thigh). In a rat abdominal abscess model, therapy with ceftazidime or ceftazidime/avibactam (4:1 w/w) against blaKPC-2-positive K. pneumoniae resulted in 9.3 versus 3.3 log cfu/abscess, respectively, after 52 h. With respect to PK/PD, in Monte Carlo simulations, attainment of unbound drug exposure targets (ceftazidime fT>8 mg/L and avibactam fT>1 mg/L, each for 50% of the dosing interval) for the labelled dose of ceftazidime/avibactam (2 and 0.5 g, respectively, q8h by 2 h IV infusion), including dose adjustments for patients with impaired renal function, ranged between 94.8% and 99.6% of patients, depending on the infection modelled.

Effect of Increasing Obstacle Distances Task on Postural Stability Variables During Gait Initiation in Older Nonfallers and Fallers.

OBJECTIVE: To compare the scaling of the postural stability variables between older nonfallers and fallers during gait initiation (GI) while stepping over increasing obstacle distances. DESIGN: Cross-sectional study. SETTING: University research laboratory. PARTICIPANTS: A sample of participants (N=24) divided into 2 groups: older nonfallers (n=12) and older fallers (n=12). Participants had no known neurologic, musculoskeletal, or cardiovascular conditions that could have affected their walking, and all were independent walkers. All the participants had an adequate cognitive function to participate as indicated by a score of more than 24 on the Mini-Mental State Examination. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary dependent variables were peak anterior-posterior (AP) center of mass (CoM)-center of pressure (CoP) separation during anticipatory postural adjustments (APAs), AP CoM-CoP separation at the toe-off, and peak AP CoM-CoP separation during the swing. Secondary dependent variables were AP trunk angle during GI. Within- and between-repeated measures analysis of variance was used to compare means between groups across different task conditions for all the dependent variables. RESULTS: There was a main effect of group for peak AP CoM-CoP separation during APA (P=.018), an interaction effect between group and condition for AP CoM-CoP separation at toe-off (P=.009), and a main effect of condition for peak AP CoM-CoP separation during the swing (P<.001). We also found a main effect of group for peak AP trunk angle during the swing (P=.028). CONCLUSIONS: For GI while stepping over increasing obstacle distances, older fallers adopt a more conservative strategy of AP CoM-CoP separation than nonfallers prior to toe-off and demonstrate increased peak AP trunk lean during the swing. AP CoM-CoP separation prior to toe-off during the GI task may be a critical marker to identify fallers and warrants additional investigation.

The trail less traveled: Analytical approach for creating shortened versions for virtual reality-based color trails test.

The Color Trails Test ("CTT") is among the most popular neuropsychological assessment tests of executive function, targeting sustained visual attention (Trails A), and divided attention (Trails B). During the pen-and-paper (P&P) test, the participant traces 25 consecutive numbered targets marked on a page, and the completion time is recorded. In many cases, multiple assessments are performed on the same individual, either under varying experimental conditions or at several timepoints. However, repeated testing often results in learning and fatigue effects, which confound test outcomes. To mitigate these effects, we set the grounds for developing shorter versions of the CTT (<25 targets), using virtual reality (VR) based CTT (VR-CTT). Our aim was to discover the minimal set of targets that is sufficient for maintaining concurrent validity with the CTT including differentiation between age groups, and the difference between Trails A and B. To this aim, healthy participants in three age groups (total N = 165; young, middle-aged, or older adults) performed both the P&P CTT, and one type of VR-CTT (immersive head-mounted-device VR, large-scale 3D VR, or tablet). A subset of 13 targets was highly correlated with overall task completion times in all age groups and platforms (r > 0.8). We tested construct validity and found that the shortened-CTT preserved differences between Trails A and B (p < 0.001), showed concurrent validity relative to the P&P scores (r > 0.5; p < 0.05), and differentiated between age groups (p < 0.05). These findings open the possibility for shortened "CTT-versions", to be used in repeated-measures experiments or longitudinal studies, with potential implications for shortening neurocognitive assessment protocols.

History of Mild Traumatic Brain Injury Affects Static Balance under Complex Multisensory Manipulations.

A recent study in active-duty military in the Coast Guard suggested that lifetime experience with mild traumatic brain injury (mTBI) was associated with subtle deficits in postural control when exposed to multi-sensory discordance (i.e., rotating visual stimulation). The present study extended postural assessments to veterans recruited from the community. Service veterans completed the Defense Veteran Brain Injury Center TBI Screening Tool, Post-Traumatic Stress Disorder (PTSD) Checklist (PCL-5), and Neurobehavioral Symptom Inventory (NSI). Postural control was assessed using a custom-designed, virtual-reality-based device, which assessed center of pressure sway in response to six conditions designed to test sensory integration by systematically combining three visual conditions (eyes open, eyes closed, and rotating scene) with two somatosensory conditions (firm or foam surface). Veterans screening positive for lifetime experience of mTBI (mTBI+) displayed similar postural sway to veterans without a lifetime experience of mTBI (mTBI-) on basic assessment of eyes open or closed on a firm and foam surface. mTBI+ veterans displayed greater sway than mTBI- veterans in response to rotating visual stimuli while on a foam surface. Similar to previous research, degree of sway was affected by the number of lifetime experiences of mTBI. Increased postural sway was not related to PTSD, NSI, or balance-specific symptom expression. In summary, veterans who experienced mTBI over their lifetime exhibited dysfunction in balance control as revealed by challenging conditions with multi-sensory discordance. These balance-related signs were independent of self-reported balance-related symptoms or other symptom domains measured by the NSI, which can provide a method for exposing otherwise covert dysfunction long after the experience of mTBI.