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Background: Knee dislocations (KD) are limb threatening injuries known to cause significant dysfunction and disability. This review aims to summarize KD knowledge and uncover areas where more research is needed., Methods: The published literature was queried according to PRISMA guidelines. Studies eligible for inclusion were clinical studies of knee dislocations. Studies published before 1990, or that focused on patellofemoral dislocation were excluded., Results: A total of 132 studies involving 43,869 knee dislocations were analyzed. The majority of patients were young adult males, with high-velocity trauma, particularly motor vehicle accidents, being the most common cause. Substance use and alcohol involvement were commonly reported. The predominant KD types were KD III (54.8 %) and KD IV (20.5 %). Meniscal tears were observed in over 50 % of cases, while cartilage injuries were present in 26.7 %. Neurovascular complications were significant, with popliteal artery injuries in 7.8 % and peroneal nerve injuries in 15.3 % of patients. Acute ligament repairs (64.2 %) were more common than delayed repairs (35.8 %), although the average time to repair was 56.1 days. Complications included amputations (2.3 %), fatalities (1.9 %), compartment syndrome (2.7 %), deep infection (5.3 %), and heterotopic ossification (21.6 %). Despite these severe injuries, a substantial loss to follow-up (19 %) and underreporting of functional outcomes were noted, limiting the comprehensive assessment of long-term recovery. A notable percentage of patients did not return to work or sports, with many requiring a change in profession due to their injuries, but these outcomes were only reported in 10 or fewer studies., Conclusion: This study highlights the significant gaps in understanding the treatment strategies, financial burden, and long-term outcomes of knee dislocations. The incomplete data, particularly the high loss to follow-up rates and underreported functional outcomes, hinders the ability to make comprehensive assessments. Available results should thusly be interpreted with an understanding of the gaps in data, however return to sport and prior employment is often not achieved. Additionally, the potential influence of socioeconomic factors and substance abuse on treatment decisions and outcomes remains inadequately explored. Future research should focus on these areas to improve the management and prognosis of patients with knee dislocations, ensuring more accurate and thorough evaluations of long-term recovery and quality of life., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To evaluate the visual outcomes and identify prognostic factors in patients with ocular bird beak injuries treated at a tertiary eye care center in South India., Methods: We conducted a comprehensive analysis of patients with bird beak injuries, considering factors such as age, gender, mode of injury, and size of laceration. The affected eyes underwent detailed examinations using slit-lamp biomicroscopy, and B-scan ultrasonography was performed to assess the status of the posterior segment. Postoperatively, the best-corrected visual acuity (BCVA) was measured at the last follow-up visit., Results: Our findings demonstrated significant improvements in visual outcomes, including BCVA and uncorrected visual acuity (UCVA), over a follow-up period ranging from 1 week to 3 years (p < 0.05). No significant changes were observed in endophthalmitis, intraocular pressure (IOP), lens status, or retinal abnormalities during the study duration., Conclusion: This retrospective study highlight the potential for favorable long-term visual improvement in patients with ocular injuries caused by bird beaks and emphasize the importance of timely intervention. Delayed surgical treatment and the requirement for multiple surgeries within the first week were found to negatively impact visual acuity. Hence, it is crucial to raise public awareness, particularly in rural areas, to prevent these potentially devastating injuries and ensure early intervention for optimal visual recovery., Competing Interests: Declaration of competing interest no conflicting relationship exists for any author., (Copyright © 2024. Published by Elsevier Ltd.)

The immune activation ability of FimH, an adhesion protein in pili of Escherichia coli (E. coli), has been recently reported. However, studies on the immune activity of PapG, another major pili terminal protein, have not been well explored. In this study, the immune stimulatory effect of purified recombinant PapG was evaluated. PapG treatment promoted dramatic changes in dendritic morphology of the bone marrow-derived dendritic cells (BMDCs) and induced upregulation of co-stimulatory molecule levels, major histocompatibility complex (MHC) I and II expression, and pro-inflammatory cytokine production in BMDCs. To identify the stimulatory receptor of PapG, an in silico study was performed. PapG exhibited strong binding affinity with murine toll-like receptor 2 (TLR2). In addition, PapG-induced activation of splenic DC and its subsets was unsuccessful in TLR2-knock out mice. Combination of PapG and ovalbumin (OVA) elicited OVA-specific T cell proliferation and cytokine production and cytotoxicity that consequently promoted anti-cancer immune responses against OVA-expressing B16 melanoma. Furthermore, PapG treatment induced activation of peripheral blood DCs and its subsets in humans in a TLR2 dependent manner. PapG-stimulated human conventional DC2 promoted syngeneic T cell proliferation and activation. The findings of this study demonstrated that PapG could be a useful immune stimulator for immunotherapy against cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Fishing stands out as a widely enjoyed leisure pursuit. While ocular fishing injuries are infrequent, they carry the potential for severe ocular trauma, and safe extraction of a fish hook can pose challenges. We here in report a series of 21 cases of penetrating injury to the cornea by fish hook, detailing successful surgical interventions employed for their management. The report not only outlines different techniques for the removal of fish hooks but also provides clarification on terminologies associated with various components of a fish hook., Methods: This was a retrospective study conducted at tertiary eye care centers in South India. Our hospitals cater to the states of Telangana, Andhra Pradesh, and Odisha. All medical records of patients who attended the emergency department from the period of 2003 to 2023 were evaluated and all patients with fish hook injury were included in the study. This is the longest and largest study in India., Results: Twenty-one cases of ocular fish-hook injuries were presented to the emergency room between 2003 and 2023. Patients were between the ages of 9 and 59 years (mean, 29.4 years), and 90.4 % (19 out of 21) were males. Patient demographics, injury characteristics, surgical interventions, and visual outcomes were meticulously documented. Out of 21 cases, three cases (14.3 %) had blunt trauma, 17 cases (80.9 %) had penetrating injury and one case had lid laceration. Patients had better visual outcomes after the second surgery. Out of 21 cases, 7 (33.3 %) had post-operative visual acuity (VA) between 20/20 and 20/40. Three (14.3 %) had post-operative VA between 20/60 and 20/125. Five (23.8 %) had post-operative VA between 20/200 and 20/600. Six cases (28.6 %) had poor visual outcomes of which two had no perception of light (NPL), two had Hand movements and the other two had the perception of light present and projection of rays inaccurate CONCLUSION: This extensive case series underscores the complexity of ocular injuries caused by fish hooks and emphasizes significance of tailored surgical approaches for optimal visual outcomes. The hook can be successfully removed with minimal trauma to ocular structures by understanding structure of fish hook and by employing appropriate method of extraction., Competing Interests: Declaration of competing interest No conflicting relationship exists for any author, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Topic: The timing of primary repair of open-globe injury is variable in major trauma centers worldwide, and consensus on optimal timing is lacking., Clinical Relevance: Surgery is the mainstay of open-globe injury management, and appropriate timing of surgical repair may minimize the risk of potentially blinding complications such as endophthalmitis, thereby optimizing visual outcomes., Methods: A systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (International Prospective Register of Systematic Reviews identifier, CRD42023442972). The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and ISRCTN registries and ClinicalTrials.gov were searched from inception through October 29, 2023. Prospective and retrospective nonrandomized studies of patients with open-globe injury with a minimum of 1 month of follow-up after primary repair were included. Primary outcomes included visual acuity at last follow-up and the proportion of patients with endophthalmitis. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach., Results: Fifteen studies met inclusion criteria, reporting a total of 8497 eyes. The most common injury types were penetrating and intraocular foreign body (IOFB). Meta-analysis found that primary repair less than 24 hours after open-globe injury was associated with 0.30 odds of endophthalmitis compared with primary repair conducted more than 24 hours after trauma (odds ratio, 0.39; 95% confidence interval [CI], 0.19-0.79; I 2  = 95%; P = 0.01). No significant difference was found in reported visual outcomes between patients whose open-globe injuries were repaired more than, compared with less than, 24 hours after trauma (odds ratio, 0.89; 95% CI, 0.61-1.29; I 2  = 70%; P = 0.52). All included studies were retrospective and nonrandomized, demonstrating an overall low certainty of evidence on GRADE assessment., Discussion: Only retrospective data exist around the effect of timing of open-globe repair, resulting in low certainty of the available evidence. However, this review of current evidence, predominantly including penetrating and IOFB injuries, suggests that primary repair performed less than 24 hours after open-globe injury is associated with a reduced endophthalmitis rate compared with longer delays, consistent with delay to primary repair increasing endophthalmitis risk., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Disturbed sleep in patients with COPD impact quality of life and predict adverse outcomes., Research Question: To identify distinct phenotypic clusters of patients with COPD using objective sleep parameters and evaluate the associations between clusters and all-cause mortality to inform risk stratification., Study Design and Methods: A longitudinal observational cohort study using nationwide Veterans Health Administration data of patients with COPD investigated for sleep disorders. Sleep parameters were extracted from polysomnography physician interpretation using a validated natural language processing algorithm. We performed cluster analysis using an unsupervised machine learning algorithm (K-means) and examined the association between clusters and mortality using Cox regression analysis, adjusted for potential confounders, and visualized with Kaplan-Meier estimates., Results: Among 9992 patients with COPD and a clinically indicated baseline polysomnogram, we identified five distinct clusters based on age, comorbidity burden and sleep parameters. Overall mortality increased from 9.4 % to 42 % and short-term mortality (<5.3 years) ranged from 3.4 % to 24.3 % in Cluster 1 to 5. In Cluster 1 younger age, in 5 high comorbidity burden and in the other three clusters, total sleep time and sleep efficiency had significant associations with mortality., Interpretation: We identified five distinct clinical clusters and highlighted the significant association between total sleep time and sleep efficiency on mortality. The identified clusters highlight the importance of objective sleep parameters in determining mortality risk and phenotypic characterization in this population., Competing Interests: Declaration of competing interest None of the authors disclose any financial or personal relationship with other people or organizations that could inappropriately influence this work., (Published by Elsevier Ltd.)

Topic: Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management strategy after open-globe injury (OGI) remains controversial., Clinical Relevance: This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat., Methods: Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR)., Results: Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval [CI], 0.00%-0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%-0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%-0.33%). The ARR using a random effects model was -0.0010 (in favour of eye removal; 95% CI, -0.0031 [in favor of eye removal] to 0.0011 [in favor of primary repair]). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data., Discussion: Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. All rights reserved.)

Copper(L 2 Cu) and vanadium(L 2 VOCl) complexes of N-p-tolylbenzohydroxamic acid (LH) ligand have been investigated for DNA binding efficacy by multiple analytical, spectral, and computational techniques. The results revealed that complexes as groove binders as evidenced by UV absorption. Fluorescence studies including displacement assay using classical intercalator ethidium bromide as fluorescent probe also confirmed as groove binders. The viscometric analysis too supports the inferences as strong groove binders for both the complexes. Molecular docking too exposed DNA as a target to the complexes which precisely binds L 2 Cu, in the minor groove region while L 2 VOCl in major groove region. Molecular dynamic simulation performed on L 2 Cu complex revealing the interaction of complex with DNA within 20 ns time. The complex stacked into the nitrogen bases of oligonucleotides and the bonding features were intrinsically preserved for longer simulation times. In-vitro cytotoxicity study was undertaken employing MTT assay against the breast cancer cell line (MCF-7). Potential cytotoxic activities were observed for L 2 Cu and L 2 VOCl complexes with IC 50 values of showing 71 % and 74 % of inhibition respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Vitamin D plays a critical role in immunomodulation, and its deficiency is implicated in the pathogenesis of several autoimmune diseases. Nevertheless, its relationship with non-infectious uveitis (NIU), an inflammatory ocular disorder, remains inconclusive., Methods: A systematic search was conducted in three databases from database inception until May 8, 2023, to investigate the potential relationship between vitamin D deficiency and NIU. We included observational studies reporting the measurement of vitamin D levels in patients with NIU and healthy controls without restriction of language or date of publication. Three pairs of authors independently screened the title and abstracts for potential eligibility and then in full text. A third author resolved disagreements. Three pairs of independent reviewers abstracted the data from the fully reviewed records and evaluated the risk of bias. We followed The MOOSE and PRISMA guidelines. Random effects meta-analyses were used for primary analysis. Studies not included in the meta-analysis were summarized descriptively. This review was registered in PROSPERO: CRD42022308105., Findings: Of 933 records screened, 11 studies were included, and five were meta-analyzed, encompassing 354 cases and 5728 controls (mean participant age ranging from 7.1 to 58.9 years). Patients with vitamin D deficiency exhibited an Odds Ratio of 2.04 (95% CI = 1.55-2.68, P < 0.00001) for developing NIU compared to controls. Overall, potential sources of bias were low across most studies., Interpretation: Our findings suggest that vitamin D may play an essential role in the pathophysiology of NIU. While the included studies demonstrated generally low potential bias, additional rigorous prospective studies are necessary to confirm these findings and further elucidate the underlying mechanisms involved. Vitamin D supplementation could represent a possible therapeutic strategy for preventing or managing NIU if substantiated. Clinicians should consider screening for and addressing vitamin D deficiency in patients with or at risk for NIU., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: While the longer-term Obstructive Sleep apnea (OSA)-related intermittent hypoxia (IH) leads to various comorbidities, it has become increasingly evident that OSA confers protective advantages during and after acute myocardial infarction (AMI). We hypothesized in patients who were admitted with acute MI, the presence of OSA is associated with lower in-hospital mortality compared to those without a prior diagnosis of OSA., Methods: In this nationwide retrospective study utilizing Veterans Health Administration records, we included patients hospitalized for MI with a history of sleep disorders from 1999 to 2020. We divided patients into two cohorts: those with OSA and those without OSA. The primary outcome was in-hospital mortality during AMI hospitalization. We analyzed the data using logistic regression and calculated the odds ratio of in-hospital mortality., Results: Out of more than four million veterans with any sleep diagnosis, 76,359 patients were hospitalized with a diagnosis of AMI. We observed 30,116 with OSA (age, 64 ± 10 years; BMI, 33 ± 7 kg/m 2 ) and 43,480 without OSA (age, 68 ± 12 years; BMI, 29 ± 6 kg/m 2 ). The aOR of in-patient mortality (n = 333 (1.1%)) was lower in those with OSA (aOR, 0.43; 95% CI, 0.38 to 0.49) compared to without-OSA (n = 1,102, 2.5%). However, the OSA cohort had a higher proportion of the prolonged length of stay (28.1%)., Conclusions: Presence of OSA is associated with lower in-hospital mortality among patients admitted for AMI, after adjusting for various demographic and co-morbidity factors. This study highlights the complex relationship between OSA and cardiovascular health and highlights the need for further research in this area., Competing Interests: Conflict of interest The authors report NO conflict of interests relevant to this work., (Published by Elsevier Ltd.)

Rapid industrialization, improved standards of living, growing economies and ever-increasing population has led to the unprecedented exploitation of the finite and non-renewable resources of minerals in past years. It was observed that out of 100 BMT of raw materials processed annually only 10% is recycled back. This has resulted in a strenuous burden on natural or primary resources of minerals (such as ores) having limited availability. Moreover, severe environmental concerns have been raised by the huge piles of waste generated at landfill sites. To resolve these issues, 'Urban Mining' from waste or secondary resources in a Circular Economy' concept is the only sustainable solution. The objective of this review is to critically examine the availability, elemental composition, and the market potential of the selected secondary resources such as lignocellulosic/algal biomass, desalination water, sewage sludge, phosphogypsum, and e-waste for minerals sequestration. This review showed that, secondary resources have potential to partially replace the minerals required in different sectors such as macro and microelements in agriculture, rare earth elements (REEs) in electrical and electronics industry, metals in manufacturing sector and precious elements such as gold and platinum in ornamental industry. Further, inputs from the selected life cycle analysis (LCA) & techno economic analysis (TEA) were discussed which showed that although, urban mining has a potential to reduce the greenhouse gaseous (GHG) emissions in a sustainable manner however, process improvements through innovative, novel and cost-effective pathways are essentially required for its large-scale deployment at industrial scale in future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: None

Competing Interests: None.

Prone positioning is an immediately accessible, readily implementable intervention that was proposed initially as a method for improvement in gas exchange > 50 years ago. Initially implemented clinically as an empiric therapy for refractory hypoxemia, multiple clinical trials were performed on the use of prone positioning in various respiratory conditions, cumulating in the landmark Proning Severe ARDS Patients trial, which demonstrated mortality benefit in patients with severe ARDS. After this trial and the corresponding meta-analysis, expert consensus and societal guidelines recommended the use of prone positioning for the management of severe ARDS. The ongoing COVID-19 pandemic has brought prone positioning to the forefront of medicine, including widespread implementation of prone positioning in awake, spontaneously breathing, nonintubated patients with acute hypoxemic respiratory failure. Multiple clinical trials now have been performed to investigate the safety and effectiveness of prone positioning in these patients and have enhanced our understanding of the effects of the prone position in respiratory failure. In this review, we discuss the physiologic features, clinical outcome data, practical considerations, and lingering questions of prone positioning., (Copyright © 2022. Published by Elsevier Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is the most common (∼90% cases) pancreatic neoplasm and one of the most lethal cancer among all malignances. PDAC harbor aberrant oncogenic signaling that may result from the multiple genetic and epigenetic alterations such as the mutation in driver genes (KRAS, CDKN2A, p53), genomic amplification of regulatory genes (MYC, IGF2BP2, ROIK3), deregulation of chromatin-modifying proteins (HDAC, WDR5) among others. A key event is the formation of Pancreatic Intraepithelial Neoplasia (PanIN) that often results from the activating mutation in KRAS. Mutated KRAS can direct a variety of signaling pathways and modulate downstream targets including MYC, which play an important role in cancer progression. In this review, we discuss recent literature shedding light on the origins of PDAC from the perspective of major oncogenic signaling pathways. We highlight how MYC directly and indirectly, with cooperation with KRAS, affect epigenetic reprogramming and metastasis. Additionally, we summarize the recent findings from single cell genomic approaches that highlight heterogeneity in PDAC and tumor microenvironment, and provide molecular avenues for PDAC treatment in the future., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: At what rate does the RNA of SARS CoV-2 shed from cadavers? Although, there have been numerous studies which have demonstrated the persistence of the virus on dead bodies, there is a lack of conclusive evidence regarding the variation of viral RNA content in cadavers. This has led to a knowledge gap regarding the safe handling/management of COVID-19 decedents, posing a barrier in forensic investigations., Methods: In this study, we report the presence of RNA of SARS CoV-2 by real time RT-PCR, in nasopharyngeal swabs collected after death from two groups of bodies - one who died due to COVID-19 and the other who died due to other diagnoses. A prospective study on 199 corpses, who had tested positive for COVID-19 ante-mortem, was conducted at a tertiary care center. RNA testing was conducted at different time intervals (T1-T5)., Results: 112(56.3%) died primarily due to COVID-19 and 87(43.7%) died due to other diagnoses. 144(72.4%) were male and 55(27.6%) were female. A total of 115 (57.8%) tested positive for COVID-19 after death at different time points. The mean age was 50.7 ± 18.9 years and the length of hospitalization ranged from 1 to 50 days with a mean of 9.2 ± 7.6 days. Realtime RT-PCR positivity of SARS CoV-2 RNA decreases with time., Conclusion: We observed that real time RT-PCR positivity, indicating viral RNA detection, decreases with time. Therefore, it is advisable to follow appropriate COVID-19 precautions to carry out scientific studies, medico-legal investigations and mortuary services on suspected/confirmed COVID-19 corpses., Competing Interests: Conflict of interest All the authors report no conflict., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is an urgent need to detect depression using a non-intrusive approach that is reliable and accurate. In this paper, a simple and efficient unimodal depression detection approach based on speech is proposed, which is non-invasive, cost-effective and computationally inexpensive. A set of spectral, temporal and spectro-temporal features is derived from the speech signal of healthy and depressed subjects. To select a minimal subset of the relevant and non-redundant speech features to detect depression, a two-phase approach based on the nature-inspired wrapper-based feature selection Quantum-based Whale Optimization Algorithm (QWOA) is proposed. Experiments are performed on the publicly available Distress Analysis Interview Corpus Wizard-of-Oz (DAICWOZ) dataset and compared with three established univariate filtering techniques for feature selection and four well-known evolutionary algorithms. The proposed model outperforms all the univariate filter feature selection techniques and the evolutionary algorithms. It has low computational complexity in comparison to traditional wrapper-based evolutionary methods. The performance of the proposed approach is superior in comparison to existing unimodal and multimodal automated depression detection models. The combination of spectral, temporal and spectro-temporal speech features gave the best result with the LDA classifier. The performance achieved with the proposed approach, in terms of F1-score for the depressed class and the non-depressed class and error is 0.846, 0.932 and 0.094 respectively. Statistical tests demonstrate that the acoustic features selected using the proposed approach are non-redundant and discriminatory. Statistical tests also establish that the performance of the proposed approach is significantly better than that of the traditional wrapper-based evolutionary methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Safe, effective, and easily implementable treatments that reduce the progression of respiratory failure in COVID-19 are urgently needed. Despite the increased adoption of prone positioning during the pandemic, the effectiveness of this technique on progression of respiratory failure among nonintubated patients is unclear., Research Question: What is the effectiveness of smartphone-guided self-prone positioning recommendations and instructions compared with usual care in reducing progression of respiratory failure among nonintubated patients with COVID-19?, Study Design and Methods: Awake Prone Position for Early Hypoxemia in COVID-19 (APPEX-19) is a multicenter randomized clinical trial that randomized nonintubated adults with COVID-19 on < 6 L/min of supplemental oxygen to receive a smartphone-guided self-prone positioning intervention or usual care. The primary outcome was the composite of respiratory deterioration (an increase in supplemental oxygen requirement) or ICU transfer. Using a Bayesian statistical approach, the posterior probability of superiority within each treatment arm (superiority threshold 95%) was calculated., Results: The trial was stopped early for slow enrollment. A total of 293 participants were included in the modified intention-to-treat analysis (159 self-prone positioning intervention and 134 usual care). Among participants who self-reported body positioning (n = 139 [70 intervention, 69 usual care]), 71.4% in the intervention arm and 59.4% in the usual care arm attempted prone positioning. Thirty-one participants (posterior mean, 24.7%; 95% credible interval, 18.6-31.4) receiving usual care and 32 participants (posterior mean, 22.1%; 95% credible interval, 16.6-28.1) receiving the self-prone positioning intervention experienced the primary outcome; the posterior probability of superiority for the self-prone positioning intervention was 72.1%, less than the 95% threshold for superiority. Adverse events occurred in 26.9% of participants in the usual care arm and in 11.9% of participants in the intervention arm., Interpretation: Among nonintubated patients with COVID-19, smartphone-guided self-prone positioning recommendations and instructions did not promote strong adherence to prone positioning., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04344587; URL: www., Clinicaltrials: gov., (Copyright © 2022 American College of Chest Physicians. All rights reserved.)

Background: Venous thromboembolism (VTE) is a common complication in acute COVID-19 and those with hematologic malignancy (HM) may be at an even higher risk. We performed a retrospective analysis of patients with history of HM and acute COVID-19 to evaluate thrombotic and clinical outcomes., Methods: Patients with COVID-19 were identified by positive SARS-CoV-2 PCR test. Our primary endpoints were rate of VTE and CVA in patients with HM compared to the general population (GP). Secondary outcomes included composite thrombotic events (CVA + VTE), COVID-19 fatality, respiratory support, ICU admission rates, and length of ICU stay RESULTS: A total of 833 patients were evaluated, 709 in the GP cohort, 124 patients in the HM cohort. CVA was more prevalent in the HM cohort (5.4% vs. 1.6%, P = .011). Rates of VTE were numerically higher for the HM cohort (8.0% vs. 3.6%, P = .069). The composite thrombotic rate was increased in the HM cohort (13.4% vs. 5.2%, P = .005). Patients with HM had a higher inpatient fatality rate (35.5% vs. 11.3%, P < .001), required more respiratory support (74.6% vs. 46.5%, P < .001) and had a higher rate of ICU admission (31.9% vs. 12.1%, P = .001)., Conclusion: Our data demonstrated an increased rate of composite thrombotic (CVA + VTE) outcomes, indicating HM patients with acute COVID-19 are at increased risk of thrombosis. Irrespective of disease status, HM patients also have significantly increased need for intensive care, respiratory support, and have higher fatality rates., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.

Caregiving encompasses the nurturing, tasks, resources, and services that meet the day-to-day needs of children and youth with special health care needs (CYSHCN) at home. Many gaps exist in the strategies currently offered by the health care system to meet the caregiving needs of CYSHCN. The work of family caregivers of CYSHCN is known to be extensive, but it is so poorly understood that it has been described as "invisible". This invisibility leads to poor communication and gaps in understanding between professional health care providers and family caregivers. To address these gaps, health care researchers must work with family caregivers to incorporate their expertise on caregiving and create meaningful and sustainable research partnerships. A growing body of research is attempting to remedy the problem of caregiving invisibility and lay better foundations for successful integration between health care settings, family caregiving, professional caregiving, and community supports for families of CYSHCN. We identify high-priority gaps in CYSHCN caregiving research and propose research questions that are designed to accelerate growth in evidence-based understanding of the work of family caregivers of CYSHCN and how best to support them., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Concerns about potential risks of using contrast media in patients with chronic renal insufficiency limit the utilization of CT angiography in this population., Purpose: To evaluate the feasibility of abdominopelvic CTA with very low volumes of contrast media., Material and Methods: In this retrospective study, 20 patients with chronic renal insufficiency underwent high-pitch abdominopelvic (AP) CTA on a third-generation dual-source CT scanner with 30 mL of nonionic iodinated contrast. The homogeneity of intravascular attenuation at the suprarenal aorta, infrarenal aorta, and the right common iliac artery was measured. Image noise, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were used to assess objective image quality. Subjective image quality was evaluated on a 5-point scale (1 = unacceptable; 5 = excellent)., Results: Twelve male and eight female patients underwent CTA of the abdomen and pelvis at 80 kVp. Five CTAs also included the chest (CAP). The mean scan duration was 0.78 ± 0.19 s for AP and 0.96 ± 0.06 s for CAP CTAs. The mean ± SD of attenuation at suprarenal aorta, infrarenal aorta, and right common iliac artery were 235.1 ± 68.0, 249.2 ± 61.3, and 254.4 ± 67.7 HU, respectively. The attenuation was homogeneous across vascular levels (P = 0.06). All scans had diagnostic subjective image quality with the median (IQR) of 3.5 (1.75). CNR and SNR were homogeneous across vascular levels (P = 0.08 and P = 0.14, respectively)., Conclusion: Sub-second, high-pitch abdominopelvic CTA with a low volume of contrast in patients with chronic renal insufficiency is technically and clinically feasible with good diagnostic image quality and homogenous attenuation across vascular levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The pulp and biorefining industries produce their waste as lignin, which is one of the most abundant renewable resources. So far, lignin has been remained severely underutilized and generally burnt in a boiler as a low-value fuel. To demonstrate lignin's potential as a value-added product, we will review market opportunities for lignin related applications by utilizing the thermo-chemical/biological depolymerization strategies (with or without catalysts) and their comparative evaluation. The application of lignin and its derived aromatics in various sectors such as cement industry, bitumen modifier, energy materials, agriculture, nanocomposite, biomedical, H 2 source, biosensor and bioimaging have been summarized. This comprehensive review article also highlights the technical, economic, environmental, and socio-economic variable that affect the market value of lignin-derived by-products. The review shows the importance of lignin, and its derived products are a platform for future bioeconomy and sustainability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH., Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method., Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247)., Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39., Lay Summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51)., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: PARADIGM-HF demonstrated superiority of sacubitril/valsartan (sac/val) over enalapril in patients with heart failure with reduced ejection fraction (HFrEF). However, patients in clinical practice may differ in their characteristics and overall risk compared with patients in clinical trials, and additional outcomes can be observed in real world (RW). Hence, a systematic review was conducted to identify and describe RW data on sac/val., Methods: RW studies evaluating the effects of sac/val in adult patients with HFrEF with a sample size ≥100 were identified via MEDLINE® and Embase® from 2015 to January 2020. Citations were screened, critically appraised and relevant data were extracted., Results: A total of 68 unique studies were identified. Nearly half of the studies were conducted in Europe (n = 34), followed by the US (n = 15) and Asia (n = 11). Median follow-up period varied from 1 to 19 months. Mean age ranged between 48.7 and 79.0 years; patients were mostly male and in New York Heart Association (NYHA) functional class II/III, and mean left ventricular ejection fraction varied between 23%and 38%. Of studies performing comparisons, most reported superior efficacy of sac/val in reducing the risk of HF hospitalisations, all-cause hospitalisations, and all-cause mortality as compared to standard-of-care. Many studies reported significant improvements in NYHA functional class and reduction in biomarker levels post sac/val. Hypotension and hyperkalaemia were the most frequently reported adverse events., Conclusions: This comprehensive overview of currently available RW evidence on sac/val complements the evidence from randomised controlled trials, substantiating its effectiveness in heterogeneous real-world HF populations., Competing Interests: Declaration of competing interest The authors report no additional relationships that could be construed as a conflict of interest Michele Senni is the Chief of Cardiovascular Department and Cardiology 1, Unit ASST Papa Giovanni XXIII hospital, Bergamo, Italy and declares financial interest for consultancy with Novartis, Merck, Bayer, Vifor Pharma, Abbott, Boehringer Ingelheim, AstraZeneca, and Servier. Clare Proudfoot, Rachel Studer and Stefano Corda are employees and stockholders in Novartis Pharma AG. Tanvi Rajput, Ramandeep Jindal and Rumjhum Agrawal are employees of Novartis Healthcare Pvt. Ltd. This study was funded by Novartis Pharma AG., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Topic: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis., Clinical Relevance: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU., Methods: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process., Results: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis., Discussion: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Topic: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU)., Clinical Relevance: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition., Methods: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process., Results: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive., Discussion: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Schizophrenia is a complex neuropsychiatric disorder with significant genetic predisposition. In a subset of schizophrenia patients, mitochondrial dysfunction could be explained by the genomic defects like mitochondrial DNA Copy Number Variations, which are considered as a sensitive index of cellular oxidative stress. Given the high energy demands for neuronal functions, altered Mitochondrial DNA copy number (mtDNAcn) and consequent impaired mitochondrial physiology would significantly influence schizophrenia pathogenesis. In this context, we have made an attempt to study mitochondrial dysfunction in schizophrenia by assessing mtDNAcn in antipsychotic-naïve/free schizophrenia patients., Method: mtDNAcn was measured in 90 antipsychotic-naïve / free schizophrenia (SCZ) patients and 147 Healthy Controls (HC). The relative mtDNAcn was determined by quantitative real-time polymerase chain reaction (qPCR) using TaqMan® multiplex assay method., Result: A statistically significant difference between groups [t = 5.22, P < 0.001] was observed, with significantly lower mtDNAcn in SCZ compared to HC. The group differences persisted even after controlling for age and sex [F (4, 232) = 22.68, P < 0.001, η2 = 0.09]., Conclusion: Lower mtDNAcn in SCZ compared to HC suggests that mtDNAcn may hold potential to serve as an important proxy marker of mitochondrial function in antipsychotic-naïve/free SCZ patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

M1 metallopeptidases regulate many important biological processes such as angiogenesis, tumour growth, hormone regulation, and immune cell development. Knowledge of substrate specificity mechanism in this family is valuable. An M1 peptidase from Deinococcus radiodurans (M1dr) with preference for bulky hydrophobic residues at N-terminus of peptide substrates was recently reported. In contrast to Escherichia coli aminopeptidase N, a previously characterized M1 peptidase, M1dr exhibits reduced activity towards peptides with N-terminal Arg or Ala residue. In order to illuminate structural basis of substrate specificity, we report several crystal structures of M1dr with different amino acids bound to the active site. Structural analysis indicated that the enzyme makes subtle adjustments to multiple residues leading to significant volume change of the active site cavity to accommodate residues of varying sizes (Leu to Trp). This study further reveals that the low preference for Arg at N-terminus of peptide substrate arises from a non-productive conformation in which many of the Arg molecules bind where they block the proton donor essential for the peptidase reaction. Hence, this study illuminates the substrate-binding mechanism and also reveals the structural basis for the substrate specificity of M1dr enzyme., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Registries are integral to monitoring, surveying, treating, preventing and prognosticating trauma. The quantity and quality of data must justify a change or intervention in treatment and/or preventive strategies and must be collected while balancing the cost and time invested in the registry. This review documents the quality, completeness and operational and funding models for ocular trauma registries worldwide., Methods: The databases CENTRAL, MEDLINE, EMBASE and Informit Health Collection were searched using key word and mesh terms for: "Eye injury, "Ocular trauma", "Eye injury prevention", "Eye protection", "Registry". To find relevant unpublished articles and theses, clinicaltrials.gov, Trip, MedNar and Google Scholar were searched using the key words "eye injury" OR "ocular trauma" AND "registry*". No date or language restrictions were applied. The quality of registry data was assessed against published measures including design, operation and data quality., Results: The electronic search retrieved 528 distinct published articles; 61 articles were assessed for eligibility. Of the 61 articles identified, 28 were eligible to be included in the review, with cross-referencing identifying a further 7 articles. The source of most articles on ocular trauma registries was the United States, followed by Germany and China. Patient follow-up was conducted in 31 studies, with 6 months being the most frequently reported period. Issues with data quality included incomplete data such as presence or absence of eye protection and initial visual acuity. Attrition bias was controlled by the United States Eye Injury Register with follow-up. Patients without follow-up data were removed for some studies and this may have introduced bias., Conclusion: National, state and hospital-based ocular trauma registries have contributed significantly to our understanding of ocular trauma. The United States has the most frequently cited and well-resourced ocular trauma registries. It is anticipated that this review will guide the development of future registries for ocular trauma in order to inform evidence-based prevention strategies and, ultimately, improve visual outcomes. We recommend the development of a consensus guidelines for international ocular trauma registry that includes mechanism and context of injury and visual outcomes, to permit international comparison that can be implemented at low cost with secure data capture., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A 54-year old woman with primary osteoarthritis and a tibial bone marrow lesion underwent subchondroplasty with injectable calcium phosphate. Post-operatively, the patient's symptoms worsened, and she lost the ability to bear weight. Follow-up MRI revealed previously absent, diffuse STIR hyperintensity in the tibia extending far beyond the surgical site. Twelve months post-operatively, symptoms spontaneously resolved. As the prevalence of subchondroplasty grows it will be important to recognize potential complications. To the authors' best knowledge this is the first report of significantly worsening pain and difficulty bearing weight corresponding with diffuse hyperintense T2 signal in the tibia after a calcium phosphate subchondroplasty., (Copyright © 2019. Published by Elsevier Inc.)

Catheter associated infections (CAIs) are the major cause of nosocomial infections leading to increased morbidity, mortality rates and economical loss. Though the antibiotic coated surface modified catheters are reported to be effective in preventing CAIs, presence of sub-lethal concentrations of antibiotics in long term instilled catheters poses a risk of development and spread of drug resistant microbial strains. Herein, we have developed an antibiotic-free alternative strategy to coat catheter surfaces using pyrogallol (PG) and metal ions (Ag + /Mg 2+ ). Surface characteristics, antimicrobial and anti-biofilm properties with hemocompatibility of the coated catheters were studied. Structural characteristics of coated catheters were similar to the uncoated catheters with improved wettability. All the coated catheters with PG and different PG/metal ion combinations exhibited broad spectrum antibacterial activity. Catheters coated with PG/metal ions combination showed effective antibiofilm properties against MRSA strains. None of the coated catheters showed any significant hemolysis for rabbit erythrocytes. In addition, polypyrogallol (pPG) coating attenuated the hemolytic properties of silver without altering the antimicrobial properties. The inherent antimicrobial properties of the coating agent along with antimicrobial metal ions broaden the application landscape which includes coating of other medical devices, clean room construction and development of antimicrobial surfaces. The chemical formulation can also be used to design antiseptic solutions to prevent healthcare associated infections., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Spatial normalization of brain MR images is highly dependent on the choice of target brain template. Morphological differences caused by factors like genetic and environmental exposures, generates a necessity to construct population specific brain templates. Brain image analysis performed using brain templates from Caucasian population may not be appropriate for non-Caucasian population. In this study, our objective was to construct an Indian brain template from a large population (N = 157 subjects) and compare the morphometric parameters of this template with that of Chinese-56 and MNI-152 templates. In addition, using an independent MRI data of 15 Indian subjects, we also evaluated the potential registration accuracy differences using these three templates., Methods: Indian brain template was constructed using iterative routines as per established procedures. We compared our Indian template with standard MNI-152 template and Chinese template by measuring global brain features. We also examined accuracy of registration by aligning 15 new Indian brains to Indian, Chinese and MNI templates. Furthermore, we supported our measurement protocol with inter-rater and intra-rater reliability analysis., Results: Our results showed that there were significant differences in global brain features of Indian template in comparison with Chinese and MNI brain templates. The results of registration accuracy analysis revealed that fewer deformations are required when Indian brains are registered to Indian template as compared to Chinese and MNI templates., Conclusion: This study concludes that population specific Indian template is likely to be more appropriate for structural and functional image analysis of Indian population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The actin cytoskeleton is a complex network controlled by a vast array of intricately regulated actin-binding proteins. Human plastins (PLS1, PLS2, and PLS3) are evolutionary conserved proteins that non-covalently crosslink actin filaments into tight bundles. Through stabilization of such bundles, plastins contribute, in an isoform-specific manner, to the formation of kidney and intestinal microvilli, inner ear stereocilia, immune synapses, endocytic patches, adhesion contacts, and invadosomes of immune and cancer cells. All plastins comprise an N-terminal Ca 2+ -binding regulatory headpiece domain followed by two actin-binding domains (ABD1 and ABD2). Actin bundling occurs due to simultaneous binding of both ABDs to separate actin filaments. Bundling is negatively regulated by Ca 2+ , but the mechanism of this inhibition remains unknown. In this study, we found that the bundling abilities of PLS1 and PLS2 were similarly sensitive to Ca 2+ (pCa 50 ~6.4), whereas PLS3 was less sensitive (pCa 50 ~5.9). At the same time, all three isoforms bound to F-actin in a Ca 2+ -independent manner, suggesting that binding of only one of the ABDs is inhibited by Ca 2+ . Using limited proteolysis and mass spectrometry, we found that in the presence of Ca 2+ the EF-hands of human plastins bound to an immediately adjacent sequence homologous to canonical calmodulin-binding peptides. Furthermore, our data from differential centrifugation, Förster resonance energy transfer, native electrophoresis, and chemical crosslinking suggest that Ca 2+ does not affect ABD1 but inhibits the ability of ABD2 to interact with actin. A structural mechanism of signal transmission from Ca 2+ to ABD2 through EF-hands remains to be established., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Metabolic dysfunction accompanying traumatic brain injury (TBI) severely impairs the ability of injured neurons to comply with functional demands. This limits the success of rehabilitative strategies by compromising brain plasticity and function, and highlights the need for early interventions to promote energy homeostasis. We sought to examine whether the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) normalizes brain energy deficits and reestablishes more normal patterns of functional connectivity, while enhancing the effects of exercise during post-TBI period. Moderate fluid percussion injury (FPI) was performed and 7,8-DHF (5mg/kg, i.p.) was administered in animals subjected to FPI that either had access to voluntary wheel running for 7days after injury or were sedentary. Compared to sham-injured controls, TBI resulted in reduced hippocampal activation of the BDNF receptor TrkB and associated CREB, reduced levels of plasticity markers GAP-43 and Syn I, as well as impaired memory as indicated by the Barnes maze task. While 7,8-DHF treatment and exercise individually mitigated TBI-induced effects, administration of 7,8-DHF concurrently with exercise facilitated memory performance and augmented levels of markers of cell energy metabolism viz., PGC-1α, COII and AMPK. In parallel to these findings, resting-state functional MRI (fMRI) acquired at 2weeks after injury showed that 7,8-DHF with exercise enhanced hippocampal functional connectivity, and suggests 7,8-DHF and exercise to promote increases in functional connectivity. Together, these findings indicate that post-injury 7,8-DHF treatment promotes enhanced levels of cell metabolism, synaptic plasticity in combination with exercise increases in brain circuit function that facilitates greater physical rehabilitation after TBI., (Copyright © 2017. Published by Elsevier B.V.)