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To examine the effect of agitation, cognitive impairment, fatigue, and pain on physical therapy participation and outcomes during posttraumatic amnesia (PTA) after traumatic brain injury (TBI). Prospective longitudinal study. Inpatient rehabilitation hospital. Participants (N=77) with moderate-to-severe TBI who were deemed to be experiencing PTA using the Westmead Post-Traumatic Amnesia Scale. Not applicable. The Pittsburgh Rehabilitation Participation Scale and time in therapy (min) were recorded twice daily after routine physical therapy sessions during PTA. The FIM-motor (select items related to physical therapy) score rated on admission and after emergence from PTA was used to calculate FIM-motor change. Agitation was associated with lower participation in therapy. The presence of agitation and pain both predicted lower FIM-motor change at emergence from PTA. Higher levels of cognitive impairment and fatigue were also associated with lower participation and less time in therapy. The presence of agitation, fatigue, pain, and cognitive impairment impede rehabilitation success during PTA. This study strengthens the case for implementing environmental and behavioral recommendations, such as conducting therapy earlier in the day within a familiar space (ie, on the ward) and tailoring session duration to patient needs. This is with the aim of minimizing fatigue, agitation, and pain, while promoting cognitive recovery and arousal during PTA to maximize physical gains. Further research is warranted to examine the factors associated with rehabilitation success across other therapeutic disciplines. [ABSTRACT FROM AUTHOR]

Despite clinical guidelines recommending an interdisciplinary approach to persisting post-concussion symptom (PPCS) management, evaluations of interdisciplinary interventions remain scant. This pilot study aimed to explore the feasibility and preliminary efficacy of an interdisciplinary intervention for PPCSs. A single-case experimental design with randomisation to multiple baselines (2, 4, or 6 weeks) was repeated across 15 participants (53% female) with mild traumatic brain injury (mean age 38.3 years, SD 15.7). The 12-week treatment incorporated psychology, physiotherapy, and medical interventions. Feasibility outcomes included recruitment and retention rates, adverse events, treatment adherence and fidelity. Patient-centred secondary outcomes included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), assessed 3 times per week during the baseline and treatment phases, and at the 1- and 3-month follow-ups. Other secondary outcomes included measures of mood, sleep and fatigue, physical functioning, health-related quality of life, illness perceptions, and goal attainment. Changes in PPCSs were evaluated using systematic visual analysis and Tau- U. Clinically significant changes in secondary outcomes were explored descriptively. 16/26 individuals assessed for eligibility were enroled (61% recruitment rate); 15 completed the post-treatment follow-ups, and 13 completed the 1- and 3-month follow-up assessments (81% retention rate). High treatment adherence and competence in delivering treatments was observed. Moderate-large effect sizes for reducing PPCSs were observed in 12/15 cases, with 7/15 reaching statistical significance. Improvements were maintained at the 1- and 3-month follow-ups and were accompanied by reductions in fatigue, sleep difficulties, and mood symptoms, and changes in illness perceptions. All participants had clinically significant improvements in at least 1 outcome, with 81% of individual therapy goals achieved. This pilot study provided preliminary support for a subsequent randomised controlled trial (RCT), with satisfactory recruitment, retention, treatment compliance, and treatment fidelity. Improvement was evident on participant outcomes including symptom reduction and goal attainment, suggesting that progressing to a phase-II RCT is worthwhile. Findings highlight the potential benefit of individualized interdisciplinary treatments. [ABSTRACT FROM AUTHOR]

Abstract Objective To evaluate the cost-effectiveness of structured activities of daily living (ADL) retraining during posttraumatic amnesia (PTA) plus treatment as usual (TAU) vs TAU alone for inpatient rehabilitation following severe traumatic brain injury (TBI). Design Trial-based economic evaluation from a health-system perspective. Setting Inpatient rehabilitation center. Participants Participants (N=104) admitted to rehabilitation and in PTA for >7 days following severe TBI. Interventions Structured ADL retraining during PTA plus TAU vs TAU alone. Structured ADL retraining was manualized to minimize the risk of agitation and maximize functional improvement, following principles of errorless and procedural learning and targeting individualized therapy goals. TAU included physiotherapy and/or speech therapy during PTA plus ADL retraining after PTA emergence. Main Outcome Measures FIM total scores at baseline, PTA emergence, hospital discharge, or final follow-up (2mo postdischarge) where FIM total scores were calculated as the sum of 5 FIM motor self-care items and a FIM meal-preparation item. Results Structured ADL retraining during PTA significantly increased functional independence at PTA emergence (mean difference: 4.90, SE: 1.4, 95% confidence interval [CI]: 1.5, 8.3) and hospital discharge (mean difference: 5.22, SE: 1.4, 95% CI: 1.8, 8.7). Even in our most pessimistic scenario, structured ADL retraining was cost-saving as compared to TAU (mean: -$7762; 95% CI: -$8105, -$7419). Together, these results imply that structured ADL retraining dominates (less costly but no less effective) TAU when effectiveness is evaluated at PTA emergence and hospital discharge. Conclusions Structured ADL retraining during PTA yields net cost-savings to the health system and offers a cost-effective means of increasing functional independence at PTA emergence and hospital discharge. [ABSTRACT FROM AUTHOR]

• Sleep disturbance and fatigue are highly prevalent after acquired brain injury. • Cognitive behavioural therapy improves sleep disturbance and fatigue after injury. • This 8-week treatment is adapted to support individuals with cognitive impairments. • Benefits of cognitive behavioural therapy extend over and above health education. • Additional treatment benefits include improved self-efficacy and quality of life. Sleep disturbance and fatigue are highly prevalent after acquired brain injury (ABI) and are associated with poor functional outcomes. Cognitive behavioural therapy (CBT) is a promising treatment for sleep and fatigue problems after ABI, although comparison with an active control is needed to establish efficacy. We compared CBT for sleep disturbance and fatigue (CBT-SF) with a health education (HE) intervention to control for non-specific therapy effects. In a parallel-group, pilot randomised controlled trial, 51 individuals with traumatic brain injury (n = 22) and stroke (n = 29) and clinically significant sleep and/or fatigue problems were randomised 2:1 to 8 weeks of a CBT-SF (n = 34) or HE intervention (n = 17), both adapted for cognitive impairments. Participants were assessed at baseline, post-treatment, and 2 and 4 months post-treatment. The primary outcome was the Pittsburgh Sleep Quality Index; secondary outcomes included measures of fatigue, sleepiness, mood, quality of life, activity levels, self-efficacy and actigraphy sleep measures. The CBT-SF led to significantly greater improvements in sleep quality as compared with HE, during treatment and at 2 months [95% confidence interval (CI) -24.83; -7.71], as well as significant reductions in fatigue maintained at all time points, which were not evident with HE (95% CI -1.86; 0.23). HE led to delayed improvement in sleep quality at 4 months post-treatment and in depression (95% CI -1.37; -0.09) at 2 months post-treatment. CBT-SF led to significant gains in self-efficacy (95% CI 0.15; 0.53) and mental health (95% CI 1.82; 65.06). CBT-SF can be an effective treatment option for sleep disturbance and fatigue after ABI, over and above HE. HE may provide delayed benefit for sleep, possibly by improving mood. Australia New Zealand Clinical Trials Registry: ACTRN12617000879369 (registered 15/06/2017) and ACTRN12617000878370 (registered 15/06/2017). [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy of activities of daily living (ADL) retraining during posttraumatic amnesia (PTA) compared with ADL retraining commencing after emergence from PTA. Design Randomized controlled trial. Setting Inpatient rehabilitation center. Participants Participants with severe TBI (N=104), admitted to rehabilitation and remaining in PTA for >7 days, were randomized to receive either treatment as usual (TAU) with daily ADL retraining (treatment), or TAU alone (physiotherapy and/or necessary speech therapy) during PTA. Interventions ADL retraining was manualized, followed errorless and procedural learning principles, and included individualized goals. Both groups received occupational therapy as usual after PTA. Main Outcome Measures Primary outcome was the FIM completed at admission, PTA emergence, discharge, and 2-month follow-up. Secondary outcomes included length of rehabilitation inpatient stay, PTA duration, Agitated Behavior Scale scores, and Community Integration Questionnaire (CIQ) scores at follow-up. Groups did not significantly differ in baseline characteristics. Results On the primary outcome, FIM total change, random effects regression revealed a significant interaction of group and time ( P <.01). The treatment group had greater improvement in FIM scores from baseline to PTA emergence, which was maintained at discharge, but not at follow-up. Twenty-seven percent more of the treatment group reliably changed on FIM scores at PTA emergence. Group differences in length of stay, PTA duration, agitation, and CIQ scores were not significant; however, TAU trended toward longer length of stay and PTA duration. Conclusions Individuals in PTA can benefit from skill retraining. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy of adapted cognitive behavioral therapy (CBT) for sleep disturbance and fatigue in individuals with traumatic brain injury (TBI). Design Parallel 2-group randomized controlled trial. Setting Outpatient therapy. Participants Adults (N=24) with history of TBI and clinically significant sleep and/or fatigue complaints were randomly allocated to an 8-session adapted CBT intervention or a treatment as usual (TAU) condition. Interventions Cognitive behavior therapy. Main Outcome Measures The primary outcome was the Pittsburgh Sleep Quality Index (PSQI) posttreatment and at 2-month follow-up. Secondary measures included the Insomnia Severity Index, Fatigue Severity Scale, Brief Fatigue Inventory (BFI), Epworth Sleepiness Scale, and Hospital Anxiety and Depression Scale. Results At follow-up, CBT recipients reported better sleep quality than those receiving TAU (PSQI mean difference, 4.85; 95% confidence interval [CI], 2.56–7.14). Daily fatigue levels were significantly reduced in the CBT group (BFI difference, 1.54; 95% CI, 0.66–2.42). Secondary improvements were significant for depression. Large within-group effect sizes were evident across measures (Hedges g =1.14–1.93), with maintenance of gains 2 months after therapy cessation. Conclusions Adapted CBT produced greater and sustained improvements in sleep, daily fatigue levels, and depression compared with TAU. These pilot findings suggest that CBT is a promising treatment for sleep disturbance and fatigue after TBI. [ABSTRACT FROM AUTHOR]

Abstract: The reduction/oxidation (redox) potential of tissue is tightly regulated in order to maintain normal physiological processes, but is disrupted in disease states. Thus, the development of new tools to map tissue redox potential may be clinically important for the diagnosis of diseases that lead to redox imbalances. One promising area of chemical research is the development of redox-activated probes for mapping tissue through magnetic resonance imaging (MRI). In this review, we summarize several strategies for the design of redox-responsive MRI contrast agents. Our emphasis is on both lanthanide(III) and transition metal(II/III) ion complexes that provide contrast either as T 1 relaxivity MRI contrast agents or as paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents. These agents are redox-triggered by a variety of chemical reactions or switches including redox-activated thiol groups, and heterocyclic groups that interact with the metal ion or influence properties of other ancillary ligands. Metal ion centered redox is an approach which is ripe for development by coordination chemists. Redox-triggered metal ion approaches have great potential for creating large differences in magnetic properties that lead to changes in contrast. An attractive feature of these agents is the ease of fine-tuning the metal ion redox potential over a biologically relevant range. [Copyright &y& Elsevier]

Helicase B (RhlB) is one of the five DEAD box RNA-dependent ATPases found in Escherichia coli. Unique among these enzymes, RhIB requires an interaction with the partner protein RNase E for appreciable ATPase and RNA unwinding activities. To explore the basis for this activating effect, we have generated a di-cistronic vector that overexpresses a complex comprising RhlB and its recognition site within RNase E, corresponding to residues 696-762. Complex formation has been characterized by isothermal titration calorimetry, revealing an avid, enthalpy-favored interaction between the helicase and RNase E-(696- 762) with an equilibrium binding constant (Ka) of at least 1 × 108 M-1. We studied ATPase activity of mutants with substitutions within the ATP binding pocket of RhlB and on the putative interaction surface that mediates recognition of RNase E. For comparisons, corresponding mutations were prepared in two other E. coli DEAD box ATPases, RhlE and SrmB. Strikingly, substitutions at a phenylalanine near the Q-motif found in DEAD box proteins boosts the ATPase activity of Rh1B in the absence of RNA, but completely inhibits it in its presence. The data support the proposal that the protein-protein and RNA-binding surfaces both communicate allosterically with the ATPase catalytic center. We conjecture that this communication may govern the mechanical power and efficiency of the helicases, and is tuned in individual helicases in accordance with cellular function, [ABSTRACT FROM AUTHOR]

Summary: Eukaryotic TIP49a (Pontin) and TIP49b (Reptin) AAA+ ATPases play essential roles in key cellular processes. How their weak ATPase activity contributes to their important functions remains largely unknown and difficult to analyze because of the divergent properties of TIP49a and TIP49b proteins and of their homo- and hetero-oligomeric assemblies. To circumvent these complexities, we have analyzed the single ancient TIP49 ortholog found in the archaeon Methanopyrus kandleri (mkTIP49). All-atom homology modeling and molecular dynamics simulations validated by biochemical assays reveal highly conserved organizational principles and identify key residues for ATP hydrolysis. An unanticipated crosstalk between Walker B and Sensor I motifs impacts the dynamics of water molecules and highlights a critical role of trans-acting aspartates in the lytic water activation step that is essential for the associative mechanism of ATP hydrolysis. [ABSTRACT FROM AUTHOR]

Tuberculosis and other bacterial diseases represent a significant threat to human health. The DNA topoisomerases are excellent targets for chemotherapy, and DNA gyrase in particular is a well-validated target for antibacterial agents. Naphthoquinones (e.g. diospyrin and 7-methyljuglone) have been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis. We have found that these compounds are inhibitors of the supercoiling reaction catalyzed by M. tuberculosis gyrase and other gyrases. Our evidence strongly suggests that the compounds bind to the N-terminal domain of GyrB, which contains the ATPase active site, but are not competitive inhibitors of the ATPase reaction.Wepropose that naphthoquinones bind to GyrB at a novel site close to the ATPase site. This novel mode of action could be exploited to develop new antibacterial agents. [ABSTRACT FROM AUTHOR]

• A range of interventions are used worldwide to manage agitation after head injury. • Non-pharmacological strategies are favoured, although medication use remains high. • Clinicians with training and guidelines are more confident in managing agitation. • Only half of clinicians were satisfied with agitation management in their services. • Findings support the development of formal guidelines for managing agitation after head injury. Managing agitation is a significant challenge in the early stages of recovery after traumatic brain injury (TBI), and research investigating current practice during this period is lacking. This study examined how clinicians worldwide conceptualise, measure and manage agitation during early TBI recovery. A cross-sectional anonymous online survey was distributed via email, newsletters, conferences and social media to clinicians involved in early TBI care worldwide. Respondents were 331 clinicians (66% female) from 34 countries worldwide who worked in inpatient and outpatient settings in disciplines including medicine, nursing and allied health. Participants had an average of 13 years' clinical experience working specifically with an adult TBI population. Agitated behaviour was commonly defined as aggression and restlessness. Three quarters of clinicians reported that their services measure agitation, and clinicians in North America more frequently use standardised assessment tools. Common non-pharmacological approaches used across all regions surveyed included providing familiarising information (85%) and environmental cues (82%), managing patients in single rooms (81%) and reducing noise levels (80%). Most clinicians (90%) reported pharmacology use, particularly atypical antipsychotic agents. Clinicians' mean rating of confidence in managing agitation was 7 out of 10 (10 being excellent) and was higher for services that provided staff with written guidelines for agitation management. Only half of clinicians reported sufficient training for managing agitation and 52% were satisfied with current agitation management practices. Despite high rates of agitation measurement and management, many clinicians reported dissatisfaction with current agitation management and insufficient training. This study supports the development of international guidelines and training to ensure consistent and effective agitation management in early TBI care. [ABSTRACT FROM AUTHOR]