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Maturational differences exist in cardiopulmonary and cerebrovascular function at sea‐level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea‐level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation (V̇E${\dot{V}}_{\rm{E}}$), end‐tidal partial pressures of oxygen (PETO2${P}_{{\rm{ETO}}_{\rm{2}}}$) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V̇E${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (−11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min−1vs. +13 beats min−1, P = 0.019). Between B1 and B4, adults increased V̇E${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V̇E${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆PETO2${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2 = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V̇E${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. Key points: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude.Children (ages 7–14) and adults (ages 23–44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week.Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults.PASP and CBF increased by a similar relative amount between children and adults at 3800 m.These results help us better understand age‐related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults. [ABSTRACT FROM AUTHOR]

The utmost goal of selecting an RNA-Seq alignment software is to perform accurate alignments with a robust algorithm, which is capable of detecting the various intricacies underlying read-mapping procedures and beyond. Most alignment software tools are typically pre-tuned with human or prokaryotic data, and therefore may not be suitable for applications to other organisms, such as plants. The rapidly growing plant RNA-Seq databases call for the assessment of the alignment tools on curated plant data, which will aid the calibration of these tools for applications to plant transcriptomic data. We therefore focused here on benchmarking RNA-Seq read alignment tools, using simulated data derived from the model organism Arabidopsis thaliana. We assessed the performance of five popular RNA-Seq alignment tools that are currently available, based on their usage (citation count). By introducing annotated single nucleotide polymorphisms (SNPs) from The Arabidopsis Information Resource (TAIR), we recorded alignment accuracy at both base-level and junction base-level resolutions for each alignment tool. In addition to assessing the performance of the alignment tools at their default settings, accuracies were also recorded by varying the values of numerous parameters, including the confidence threshold and the level of SNP introduction. The performances of the aligners were found consistent under various testing conditions at the base-level accuracy; however, the junction base-level assessment produced varying results depending upon the applied algorithm. At the read base-level assessment, the overall performance of the aligner STAR was superior to other aligners, with the overall accuracy reaching over 90% under different test conditions. On the other hand, at the junction base-level assessment, SubRead emerged as the most promising aligner, with an overall accuracy over 80% under most test conditions.

In his 1945 Nobel Prize acceptance speech, Sir Alexander Fleming warned of antimicrobial resistance (AMR) if the necessary precautions were not taken diligently. As the growing threat of AMR continues to loom over humanity, we must look forward to alternative diagnostic tools and preventive measures to thwart looming economic collapse and untold mortality worldwide. The integration of machine learning (ML) methodologies within the framework of such tools/pipelines presents a promising avenue, offering unprecedented insights into the underlying mechanisms of resistance and enabling the development of more targeted and effective treatments. This paper explores the applications of ML in predicting and understanding AMR, highlighting its potential in revolutionizing healthcare practices. From the utilization of supervised-learning approaches to analyze genetic signatures of antibiotic resistance to the development of tools and databases, such as the Comprehensive Antibiotic Resistance Database (CARD), ML is actively shaping the future of AMR research. However, the successful implementation of ML in this domain is not without challenges. The dependence on high-quality data, the risk of overfitting, model selection, and potential bias in training data are issues that must be systematically addressed. Despite these challenges, the synergy between ML and biomedical research shows great promise in combating the growing menace of antibiotic resistance.

In this paper, a novel foaming methodology consisting of turbulent mixing and thermally induced phase separation (TIPS) was used to generate scaffolds for tissue engineering. Air bubbles were mechanically introduced into a chitosan solution which forms the continuous polymer/liquid phase in the foam created. The air bubbles entrained in the foam act as a template for the macroporous architecture of the final scaffolds. Wet foams were crosslinked via glutaraldehyde and frozen at −20 °C to induce TIPS in order to limit film drainage, bubble coalescence and Ostwald ripening. The effects of production parameters, including mixing speed, surfactant concentration and chitosan concentration, on foaming are explored. Using this method, hydrogel scaffolds were successfully produced with up to 80% porosity, average pore sizes of 120 μm and readily tuneable compressive modulus in the range of 2.6 to 25 kPa relevant to soft tissue engineering applications. These scaffolds supported 3T3 fibroblast cell proliferation and penetration and therefore show significant potential for application in soft tissue engineering. [ABSTRACT FROM AUTHOR]

Titanium diboride (TiB2) is considered one of the most suitable candidate materials for applications as wettable cathodes in redesigned aluminium smelting cells. In this work, titanium diboride compacts have been produced from powders using a wet colloidal processing approach combined with pressureless sintering for densification. The approach has good potential to reduce the manufacturing cost compared to hot-pressing. Owing to the elevated cost of the raw materials, the possibility of mixing powders with different particle sizes (more expensive fine and less expensive coarse powder) has been explored. The outcome of this study is very promising, since using two different particle sizes improved the particle packing of the green material resulting in sintered densities around 80% of the theoretical density at 2000°C. [ABSTRACT FROM AUTHOR]

Dimethylamylamine (DMAA) was a forgotten pharmaceutical that was patented in 1944 as a nasal decongestant. DMAA has recently gained popularity as a dietary supplement, with claims of effectiveness as an athletic performance enhancer and weight loss aid. It is also sold as a recreational stimulant drug. DMAA is a sympathomimetic and potent pressor agent. This report describes 3 cases of cerebral hemorrhage in adults after the use of DMAA. The status of this substance as a synthetic or naturally occurring compound is also discussed. [ABSTRACT FROM AUTHOR]

PURPOSE: To assess the long-term ultrasonographic appearance of rupture of the Achilles tendon. SUBJECTS AND METHODS: We examined 70 patients at an average of 63 months (range 10-120 months) after rupture of the Achilles tendon. We assessed the patient's contralateral tendon and also performed ultrasonography on the Achilles tendon of 70 age- and sex-matched controls. We recorded the maximum transverse anteroposterior diameter, the presence of intratendinous alterations, and the presence of intratendinous calcification. RESULTS: The average maximum anteroposterior diameter of the ruptured tendon was 11.7 mm (SD = 2.10). The patients' normal tendons measured an average of 5.4 mm (SD = 0.9), and there was an average measure of 4.9 mm (SD = 0.5) (p = 0.0001) in the controls. There was no difference in the maximum anteroposterior diameter of the ruptured tendon depending on the method of treatment (conservative, open repair, percutaneous repair). Seventeen patients exhibited areas of hypoechogenicity in their ruptured tendon, two patients had areas of hypoechogenicity in their unruptured contralateral tendon, and 10 patients had calcification in their ruptured tendon. CONCLUSION: The anteroposterior diameter of the ruptured tendon was significantly greater than the nonruptured contralateral. However, when compared with a group of individually age- and sex-matched controls, the patients' contralateral tendons had significantly greater maximum anteroposterior diameter and had a greater prevalence of intratendinous alterations. This difference may represent a background of subclinical tendinopathy that may predispose to rupture. [ABSTRACT FROM AUTHOR]

Achilles tendinopathy is often treated surgically after failure of nonoperative management, but results are not uniformly excellent. We critically assessed the methods of 26 studies that reported surgical outcomes of patients with this condition. Using 10 previously published criteria, and blinded to study outcomes, we derived a 'methodology score' (0 to 100) for each study. This score was highly reproducible (r = 0.99, P < 0.01). Scores were generally low concerning the type of study, subject selection process, and outcome measures, which indicates methods deficiency in the way the study was designed, performed, and analyzed. We found a negative correlation between reported success rate and overall methods scores (r = -0.53, P < 0.01), and a positive correlation between year of publication and overall methods score (r = 0.70, P < 0.01). Study methods may influence reported surgical outcome, and we suggest guidelines for improving study design in this area of clinical research. We acknowledge that study methods have improved over the course of the past 20 years. [ABSTRACT FROM AUTHOR]

To raise compliance in a general practice based colorectal cancer screening programme by the use of a simple health educational leaflet. A randomised controlled trial of the leaflet's effect on completion of faecal occult blood tests. The leaflet explained the high frequency of colorectal cancer, the principles of screening, and addressed reasons for non-compliance. The British town of Market Harborough where most of the population are registered with a single practice. These comprised 1571 residents aged 61 to 70 years registered with the practice. Residents were invited to receive a free faecal occult blood test in a colorectal cancer screening programme. Half the population were randomly assigned to receive the educational leaflet about screening. Compliance in test and control groups, positive rate of stool testing, and pathology detected were measured. Compliance was higher in men who received the leaflet in those aged 61 to 65 years (36% v 27%, chi2 = 4.0, p < 0.05) and in men aged 66 to 70 years (39% v 23%, chi2 = 9.7, p < 0.01). In women, use of the leaflet did not affect compliance in those aged either 61 to 65 years (38% v 36%, chi2 = 0.1, NS) or 66 to 70 years (31% v 31%, chi2 = 0.0, NS). The positive rate of stool testing in patients observing the required dietary restrictions was 1.6%. A significant lesion was detected in 1.4% of people tested (2 carcinomas and 5 patients with adenomatous polyps). Health education leaflets addressing reasons for non-compliance significantly increased compliance in men and should be used in screening programmes. Reasons for the lack of success of the leaflet in women should be investigated and other interventions for raising compliance should be developed. [ABSTRACT FROM AUTHOR]

Integrating the voices of service users and providers in the design and delivery of health services increases the acceptability, relevance, and effectiveness of services. Such efforts are particularly important for youth opioid use treatments and services, which have failed to consider the unique needs of youth and families. Applying community-based participatory research (CBPR) and co-design can facilitate this process by contextualizing service user experiences at individual and community levels and supporting the collaborative design of innovative solutions for improving care. However, few studies demonstrate how to effectively integrate these methods and engage underserved populations in co-design. As such, this manuscript describes how our team wove CBPR and co-design methods to develop solutions for improving youth opioid use treatments and services in Canada. As per CBPR methods, national, provincial, and community partnerships were established to inform and support the project's activities. These partnerships were integral for recruiting service users (i.e., youth and caregivers) and service providers to co-design prototypes and support local testing and implementation. Co-design methods enabled understanding of the needs and experiences of youth, caregivers, and service providers, resulting in meaningful community-specific innovations. We used several engagement methods during the co-design process, including regular working group meetings, small group discussions, individual interviews and consultations, and feedback grids. Challenges involved the time commitment and resources needed for co-design, which were exacerbated by the COVID-19 pandemic and limited our ability to engage a diverse sample of youth and caregivers in the process. Strengths of the study included youth and caregiver involvement in the co-design process, which centered around their lived experiences; the therapeutic aspect of the process for participants; and the development of innovations that were accepted by design partners., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Turuba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cognitive decline in Alzheimer's disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity., Methods: To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma., Results: Similar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side., Conclusions: PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice., (© 2023. The Author(s).)

The progression of Alzheimer's disease (AD) correlates with the propagation of hyperphosphorylated tau (pTau) from the entorhinal cortex to the hippocampus and neocortex. Neutral sphingomyelinase2 (nSMase2) is critical in the biosynthesis of extracellular vesicles (EVs), which play a role in pTau propagation. We recently conjugated DPTIP, a potent nSMase2 inhibitor, to hydroxyl-PAMAM-dendrimer nanoparticles that can improve brain delivery. We showed that dendrimer-conjugated DPTIP (D-DPTIP) robustly inhibited the spread of pTau in an AAV-pTau propagation model. To further evaluate its efficacy, we tested D-DPTIP in the PS19 transgenic mouse model. Unexpectantly, D-DPTIP showed no beneficial effect. To understand this discrepancy, we assessed D-DPTIP's brain localization. Using immunofluorescence and fluorescence-activated cell-sorting, D-DPTIP was found to be primarily internalized by microglia, where it selectively inhibited microglial nSMase2 activity with no effect on other cell types. Furthermore, D-DPTIP inhibited microglia-derived EV release into plasma without affecting other brain-derived EVs. We hypothesize that microglial targeting allowed D-DPTIP to inhibit tau propagation in the AAV-hTau model, where microglial EVs play a central role in propagation. However, in PS19 mice, where tau propagation is independent of microglial EVs, it had a limited effect. Our findings confirm microglial targeting with hydroxyl-PAMAM dendrimers and highlight the importance of understanding cell-specific mechanisms when designing targeted AD therapies.

Background: Youth (ages 12-24) rarely access services and supports to address substance use concerns. Peer support can facilitate service engagement and has been associated with positive substance use recovery outcomes in adults, yet few studies have examined this role among youth specifically. As such, this qualitative study explored the role of peer support in providing substance use services to youth in British Columbia and how best to support them in their role., Methods: Participatory action research methods were used by partnering with youth who had lived/living experience of substance use, including peer support workers, to co-design the research protocol and materials. An initial focus group and subsequent interviews were held with 18 peer support workers who provide services to youth (ages 12-24) based on their own lived experience with mental health and/or substance use. The discussions were audio-recorded, transcribed verbatim, and analysed thematically using an inductive approach., Results: Peer support workers' core experiences providing substance use services to youth centred around supporting youth throughout the whole process. This was accomplished by meeting youth where they are at, providing individualized care, and bridging the gap between other services and supports. However, participants experienced multiple organizational barriers hindering their ability to support youth and stressed the importance of having an employer who understands the work you are doing. This involved having someone advocating for the peer support role to promote collaboration, empowering peers to set boundaries and define their own role, and providing adequate training and mentorship. Finally, peer support workers described how their lived experience bridges connection and de-stigmatization at the individual, organizational, and community level, which was unique to their role., Conclusions: Peer support plays a unique role in youths' substance use journeys, given their own lived experience and flexibility within their role. However, their position is often misunderstood by employers and other service providers, leaving peers with inadequate support, training, and mentorship to do their job. The findings from this study call for improved integration of peer support into service environments, as well as standardized training that is in-depth and continuous., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity., Methods: To determine the therapeutic benefit of inhibiting this elevation, we evaluated the efficacy of PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. Changes in brain ceramide and sphingomyelin levels, Tau content, histopathology, and nSMase2 target engagement were monitored, as well as changes in the number of brain-derived EVs in plasma and their Tau content. Additionally, we evaluated the ability of PDDC to impede tau propagation in a murine model where an adeno-associated virus(AAV) encoding for P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus and the contralateral transfer to the dentate gyrus was monitored., Results: Similar to human AD, PS19 mice exhibited increased brain ceramides and nSMase2 activity; both were completely normalized by PDDC treatment. PS19 mice exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all pathologic features of human AD. PDDC treatment significantly attenuated these aberrant changes. Mouse plasma isolated from PDDC-treated PS19 mice exhibited reduced levels of neuron- and microglia-derived EVs, the former carrying lower phosphorylated Tau(pTau) levels, compared to untreated mice. In the AAV tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly decreased tau spreading to the contralateral side., Conclusions: PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity leading to the slowing of tau spread in AD mice., Competing Interests: Competing interests: C.T., A.G.T., R.R., and N.J.H and B.S.S. are listed as inventors in patent applications filed by Johns Hopkins Technology Ventures covering novel compositions and utilities of nSMase2 inhibitors, including PDDC. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. Other authors declare that no conflict of interest exist.

Background: Substance use among youth is a longstanding global health concern that has dramatically risen in the era of highly toxic and unregulated drugs, including opioids. It is crucial to ensure that youth using unregulated opioids have access to evidence-based interventions, and yet, youth encounter critical gaps in the quality of such interventions. This study aims to address these gaps by identifying opportunities to improve the quality of opioid use services from the perspective of service providers, a perspective that has received scant attention., Methods: This community-based participatory study was conducted in four communities in British Columbia (Canada), a province that declared a public health overdose emergency in 2016. Human-centered co-design workshops were held to understand service providers' (n = 41) experiences, needs, and ideas for improving the quality of youth opioid use services/treatments in their community. Multi-site qualitative analysis was used to develop overarching experiences and needs themes that were further contextualized in each local community. A blended deductive and inductive thematic analysis was used to analyze the ideas data., Results: Three overarching themes were identified, reflecting service providers' goals to respond to youth in a timely and developmentally appropriate manner. However, this was significantly limited by organizational and systems-level barriers, revealing service providers' priorities for intra- and inter-organizational support and collaboration and systems-level innovation. Across communities, service providers identified 209 individual ideas to address these prioritized needs and improve the quality of youth opioid use services/treatments., Conclusion: These themes demonstrate a multi-level tension between macro-level systems and the meso-level organization of youth opioid use services, which undermine the quality of individual-level care service providers can deliver. These findings underscore the need for a coordinated multi-level response, such as developing youth-specific standards (macro-level), increasing inter-organizational activities and collaboration (meso-level), and creating programs that are specific to youths' needs (micro-level)., (© 2023. The Author(s).)

Purpose: A needs-based model of health systems planning uses a systematic estimate of service needs for a given population. Our objective was to derive annual prevalence estimates of specific mental disorders in the adult population of British Columbia, Canada and use a novel triangulation approach encompassing multiple data sources and stratifying these estimates by age, sex, and severity to inform Ministry partners, who commissioned this work., Methods: We performed systematic literature reviews and subsequent meta-analyses to derive an annual prevalence estimate for each mental disorder. We then generated age- and sex-specific estimates by triangulating published epidemiological studies, routinely collected province-wide health administrative data, and nationally representative health survey data sources. The age- and sex-specific estimates were further stratified by severity using the Global Burden of Disease severity distributions and published literature., Results: Anxiety disorders had the highest annual prevalence estimates (6.93%), followed by depressive disorders (6.42%). All other mental disorders had an annual prevalence of less than 1%. Prevalence estimates were consistently higher in younger age groups. Depressive disorders, anxiety disorders, and eating disorders were higher in women, while estimates for bipolar disorders, schizophrenia, and ADHD were slightly higher in men in younger age groups., Conclusion: We generated robust annual prevalence estimates stratified by age, sex, and severity using a triangulation approach. Variation by age, sex, and severity implies that these factors need to be considered when planning for mental health services. Our approach is replicable and can be used as a model for needs-based planning in other jurisdictions., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 + T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl( S )-2-(( S )-2-acetamido-3-(1 H -indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8 + T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP + , a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate ( 5i ) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP + derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.

Background: Substance use among youth (ages 12-24) is troublesome given the increasing risk of harms associated. Even more so, substance use services are largely underutilized among youth, most only accessing support when in crisis. Few studies have explored young people's help-seeking behaviours to address substance use concerns. To address this gap, this study explored how youth perceive and experience substance use services in British Columbia (BC), Canada., Methods: Participatory action research methods were used by partnering with BC youth (under the age of 30) from across the province who have lived and/or living experience of substance use to co-design the research protocol and materials. An initial focus group and interviews were held with 30 youth (ages 12-24) with lived and/or living experience of substance use, including alcohol, cannabis, and illicit substances. The discussions were audio-recorded, transcribed verbatim, and analyzed thematically using a data-driven approach., Results: Three main themes were identified and separated by phase of service interaction, starting with: Prevention/Early intervention, where youth described feeling unworthy of support; Service accessibility, where youth encountered many barriers finding relevant substance use services and information; and Service delivery, where youth highlighted the importance of meeting them where they are at, including supporting those who have milder treatment needs and/or do not meet the diagnosis criteria of a substance use disorder., Conclusions: Our results suggest a clear need to prioritize substance use prevention and early interventions specifically targeting youth and young adults. Youth and peers with lived and/or living experience should be involved in co-designing and co-delivering such programs to ensure their relevance and credibility among youth. The current disease model of care leaves many of the needs of this population unmet, calling for a more integrated youth-centred approach to address the multifarious concerns linked to young people's substance use and service outcomes and experiences., (© 2022. The Author(s).)

Background: Evidence continues to show that young people, ages 15-24, remain at significant risk of harms from non-medical opioid use and opioid use disorder (OUD), with experts calling for widespread implementation of developmentally-appropriate interventions. These recommendations include the involvement of caregivers in the prevention, early intervention, and treatment of young people using opioids. However, little research has investigated caregivers' experiences supporting young people, leaving critical gaps in understanding this role. The aim of this study is to explore caregivers' experiences accessing opioid use treatments with young people and their needs and ideas for improving such treatments., Methods: This study reports qualitative findings from Phase 1 of the Improving Treatment Together project, a multi-phase, multi-site community-based participatory study broadly aimed at co-designing opioid use treatments to improve the experiences and outcomes of young people using non-medical opioids. During Phase 1, a total of 27 caregivers (parents, guardians) participated in full-day workshops that were conducted in three communities in British Columbia, Canada. Following human-centred co-design methods, caregivers engaged in small and large group discussions of their experiences, needs, and ideas for improving opioid use treatments for young people. Discussions were audio-recorded, transcribed verbatim, and thematically analysed., Results: Across communities, caregivers' main experiences were defined as 'becoming our young people's case managers' and 'enduring a never-ending rollercoaster'. To improve these experiences, two needs themes were identified - expanding organizational and system-level capacity and wider-spread understanding of opioid use as a health issue. Caregivers brainstormed a total of 378 individual ideas to meet these needs, several of which spanned multiple needs themes., Conclusions: Caregivers' experiences, needs, and ideas reveal critical opportunities for improving the quality of interventions for opioid use among young people. This study represents a substantial contribution to the design and implementation of developmentally-appropriate and family-centred interventions for young people using opioids., (© 2022. The Author(s).)

Background: Adolescence and young adulthood is an important period for substance use initiation and related harms. In the context of the ongoing opioid crisis, the risks for youth (ages 16-29) who use opioids are particularly heightened. Despite recommendations to adopt a developmentally appropriate and comprehensive approach to reduce opioid-related harms among youth, data continue to show that youth are not adequately engaged in opioid treatments and encounter many barriers. The aim of this study is to identify youth-centered opportunities for improving opioid treatment services., Methods: This paper reports multi-site qualitative findings from youth participating in the 'Improving Treatment Together' project, a community-based participatory project being conducted in British Columbia and Alberta, two western Canadian provinces that have been dramatically impacted by the opioid crisis. Qualitative data were collected during three workshops with youth who used opioids and accessed opioid treatment services in the prior 12 months. These workshops were conducted in three communities following the core elements of human-centered co-design. A multi-site qualitative analysis was conducted to identify within- and between-site themes surrounding youths' needs for improving opioid treatment service experiences and outcomes., Results: Three overarching needs themes were identified from across the communities. The first reflected youths' difficulties finding and staying connected to opioid treatment services, with the overarching need theme suggesting opportunities to reduce organizational and systems-related barriers to care, such as waiting times and wider information about service availability. The second area of need was rooted in youths' feelings of judgment when accessing services. Consequently, opportunities to increase respectful and empathic interactions were the overarching need. The final theme was more nuanced across communities and reflected opportunities for an individualized approach to opioid treatment services that consider youths' unique basic safety, social, and health needs., Conclusions: This study identifies fundamental directions for the operationalization and implementation of youth-centered opioid treatment services. These directions are contextualized in youths' lived experiences accessing services in their local communities, with overarching themes from across sites strengthening their transferability to other settings., (© 2022. The Author(s).)

Objective: To estimate the prevalence of specific mental and substance use disorders (MSUDs), by age and sex, as a first step toward informing needs-based health systems planning by decision-makers., Methods: We developed a conceptual framework and a systematic methodology for combining available data sources to yield prevalence estimates for specific MSUDs. Data sources used included published, peer-reviewed literature from Canada and comparable countries, Canadian population survey data, and health administrative data from British Columbia. Several well-established methodologies including systematic review and meta-analyses of published prevalence estimates, modelling of age- and sex-specific distributions, and the Global Burden of Disease severity distribution model were incorporated in a novel mode of triangulation., Results: Using this novel approach, we obtained prevalence estimates for 10 MSUDs for British Columbia, Canada, as well as prevalence distributions across age groups, by sex., Conclusion: Obtaining reliable assessments of disorder prevalence and severity is a useful first step toward rationally estimating service need and plan health services. We propose a methodology to leverage existing information to obtain robust estimates in a timely manner and with sufficient granularity to, after adjusting for comorbidity and matching with severity-specific service bundles, inform need-based planning efforts for adult (15 years and older) mental health and substance use services.

Cognitive impairment is a common aspect of multiple sclerosis (MS) for which there are no treatments. Reduced brain N -acetylaspartylglutamate (NAAG) levels are linked to impaired cognition in various neurological diseases, including MS. NAAG levels are regulated by glutamate carboxypeptidase II (GCPII), which hydrolyzes the neuropeptide to N -acetyl-aspartate and glutamate. GCPII activity is upregulated multifold in microglia following neuroinflammation. Although several GCPII inhibitors, such as 2-PMPA, elevate brain NAAG levels and restore cognitive function in preclinical studies when given at high systemic doses or via direct brain injection, none are clinically available due to poor bioavailability and limited brain penetration. Hydroxyl-dendrimers have been successfully used to selectively deliver drugs to activated glia. Methods: We attached 2-PMPA to hydroxyl polyamidoamine (PAMAM) dendrimers (D-2PMPA) using a click chemistry approach. Cy5-labelled-D-2PMPA was used to visualize selective glial uptake in vitro and in vivo . D-2PMPA was evaluated for anti-inflammatory effects in LPS-treated glial cultures. In experimental autoimmune encephalomyelitis (EAE)-immunized mice, D-2PMPA was dosed biweekly starting at disease onset and cognition was assessed using the Barnes maze, and GCPII activity was measured in CD11b+ hippocampal cells. Results: D-2PMPA showed preferential uptake into microglia and robust anti-inflammatory activity, including elevations in NAAG, TGFβ, and mGluR3 in glial cultures. D-2PMPA significantly improved cognition in EAE mice, even though physical severity was unaffected. GCPII activity increased >20-fold in CD11b+ cells from EAE mice, which was significantly mitigated by D-2PMPA treatment. Conclusions: Hydroxyl dendrimers facilitate targeted drug delivery to activated microglia. These data support further development of D-2PMPA to attenuate elevated microglial GCPII activity and treat cognitive impairment in MS., Competing Interests: Competing Interests: Under license agreements involving Ashvattha Therapeutics, LLC and its subsidiary, Orpheris, Inc., and the Johns Hopkins University, Drs. Slusher, Kannan, and Rangaramanujam and the University are entitled to royalty distributions related to technology involved in the study discussed in this publication. Drs. Slusher (Board Member), Kannan (Co-founder, Board Member), and Rangaramanujam (Co-founder, Board Member) hold equity in Ashvattha Therapeutics Inc. Additionally, the study discussed in this publication was funded by and involved a dendrimer-drug manufactured by Ashvattha Therapeutics, LLC. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. AS, RS and SPK are co-inventors of patents licensed by Ashvattha, relating to the dendrimer platform. All other authors declare that there are no conflicts of interest., (© The author(s).)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease where muscle weakness and neuromuscular junction (NMJ) denervation precede motor neuron cell death. Although acetylcholine is the canonical neurotransmitter at the mammalian NMJ synapse, glutamate has recently been identified as a critical neurotransmitter for NMJ development and maintenance. One source of glutamate is through the catabolism of N-acetyl-aspartyl-glutamate (NAAG), which is found in mM concentrations in mammalian motoneurons, where it is released upon stimulation and hydrolyzed to glutamate by the glial enzyme glutamate carboxypeptidase II (GCPII). Using the SOD1 G93A model of ALS, we found an almost fourfold elevation of GCPII enzymatic activity in SOD1 G93A versus WT muscle and a robust increase in GCPII expression which was specifically associated with activated macrophages infiltrating the muscle. 2-(Phosphonomethyl)pentanedioic acid (2PMPA) is a potent GCPII inhibitor which robustly blocks glutamate release from NAAG but is highly polar with limited tissue penetration. To improve this, we covalently attached 2PMPA to a hydroxyl polyamidoamine (PAMAM-G4-OH) dendrimer delivery system (D-2PMPA) which is known to target activated macrophages in affected tissues. Systemic D-2PMPA therapy (20 mg/kg 2PMPA equivalent; IP 2 × /week) was found to localize in muscle macrophages in SOD1 G93A mice and completely normalize the enhanced GCPII activity. Although no changes in body weight or survival were observed, D-2PMPA significantly improved grip strength and inhibited the loss of NMJ innervation in the gastrocnemius muscles. Our finding that inhibiting elevated GCPII activity in SOD1 G93A muscle can prolong muscle function and delay NMJ denervation may have early therapeutic implications for ALS patients., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Extracellular Vesicles (EVs) are implicated in the spread of pathogenic proteinsin a growing number of neurological diseases. Given this, there is rising interest in developing inhibitors of Neutral Sphingomyelinase 2 (nSMase2), an enzyme critical in EV biogenesis. Our group recently discovered phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)carbamate (PDDC), the first potent, selective, orally-available, and brain-penetrable nSMase2 inhibitor, capable of dose-dependently reducing EVs release in vitro and in vivo. Herein, using multiplexed Surface Plasmon Resonance imaging (SPRi), we evaluated which brain cell-derived EVs were affected by PDDC following acute brain injury. Mice were fed PDDC-containing chow at doses which gave steady PDDC brain exposures exceeding its nSMase2 IC 50 . Mice were then administered an intra-striatal IL-1β injection and two hours later plasma and brain were collected. IL-1β injection significantly increased striatal nSMase2 activity which was completely normalized by PDDC. Using SPRi, we found that IL-1β-induced injury selectively increased plasma levels of CD171 + and PLP1 + EVs; this EV increase was normalized by PDDC. In contrast, GLAST1 + EVs were unchanged by IL-1β or PDDC. IL-1β injection selectively increased EVs released from activated versus non-activated microglia, indicated by the CD11b+/IB4 + ratio. The increase in EVs from CD11b + microglia was dramatically attenuated with PDDC. Taken together, our data demonstrate that following acute injury, brain nSMase2 activity is elevated. EVs released from neurons, oligodendrocytes, and activated microglial are increased in plasma and inhibition of nSMase2 with PDDC reduced these IL-1β-induced changes implicating nSMase2 inhibition as a therapeutic target for acute brain injury., (Copyright © 2021. Published by Elsevier Inc.)

Three key challenges to a whole-system approach to process improvement in health systems are the complexity of socio-technical activity, the capacity to change purposefully, and the consequent capacity to proactively manage and govern the system. The literature on healthcare improvement demonstrates the persistence of these problems. In this project, the Access-Risk-Knowledge (ARK) Platform, which supports the implementation of improvement projects, was deployed across three healthcare organisations to address risk management for the prevention and control of healthcare-associated infections (HCAIs). In each organisation, quality and safety experts initiated an ARK project and participated in a follow-up survey and focus group. The platform was then evaluated against a set of fifteen needs related to complex system transformation. While the results highlighted concerns about the platform's usability, feedback was generally positive regarding its effectiveness and potential value in supporting HCAI risk management. The ARK Platform addresses the majority of identified needs for system transformation; other needs were validated in the trial or are undergoing development. This trial provided a starting point for a knowledge-based solution to enhance organisational governance and develop shared knowledge through a Community of Practice that will contribute to sustaining and generalising that change.

Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APC min/+ mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Background: Opioid use is one of the most critical public health issues as highly potent opioids contribute to rising rates of accidental opioid-related toxicity deaths. This crisis has affected people from all age groups, including youth (ages 15-24) who are in a critical developmental period where the stakes of opioid use are especially high. Efforts to reduce the significant harms of opioid use have focused on the expansion of evidence-based treatments, including medications for opioid use disorder (e.g. buprenorphine). While these treatments are unequivocally life saving, recent evidence suggests that they may not align with youths' needs. Accordingly, the 'Improving Treatment Together' (ITT) project has been designed with the aim to improve youths' opioid treatment service experiences and outcomes by co-developing, implementing, and measuring youth-centred opioid use treatment service innovations. This manuscript describes the protocol for this multi-phase project., Methods: The ITT project follows community-based participatory research (CBPR) and strategically integrates co-design processes throughout its four phases. Upon establishing a project partnership between national, provincial and community-based organizations, Phase 1 follows four core elements of human-centred co-design (empathy, needs identification, ideation, prototyping) in nine separate workshops. These workshops will be held in four diverse communities with youth, caregivers and service providers who have accessed or delivered opioid treatment services. Phase 1 will culminate in the co-production of opioid treatment service innovations to be considered by the project's partners for further co-development, pilot testing, and wider implementation during the remaining phases of the project. Throughout each phase, the project will collect and analyse both qualitative and quantitative research and evaluation data to determine the project's impact., Discussion: This protocol provides a detailed description of the ITT project, with an emphasis on the project's application of co-design and CBPR processes, the planned research and implementation procedures, and the establishment of a unique partnership. To our knowledge, this is one of the first projects to integrate these participatory processes to the design, implementation and measurement of youth-centred opioid treatment services. Embedding these processes throughout each phase of the project will strengthen the relevance and feasibility of the project's service delivery innovations., (© 2021. The Author(s).)

Extracellular vesicles (EVs) are indispensable mediators of intercellular communication, but they can also assume a nefarious role by ferrying pathological cargo that contributes to neurological, oncological, inflammatory, and infectious diseases. The canonical pathway for generating EVs involves the endosomal sorting complexes required for transport (ESCRT) machinery, but an alternative pathway is induced by the enrichment of lipid membrane ceramides generated by neutral sphingomyelinase 2 (nSMase2). Inhibition of nSMase2 has become an attractive therapeutic strategy for inhibiting EV biogenesis, and a growing number of small-molecule nSMase2 inhibitors have shown promising therapeutic activity in preclinical disease models. This review outlines the function of EVs, their potential role in disease, the discovery and efficacy of nSMase2 inhibitors, and the path to translate these findings into therapeutics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.T., B.S.S., R.R., T.T. and N.J.H. are listed as inventors in patent applications filed by Johns Hopkins Technology Ventures covering novel compositions of nSMase2 inhibitors and their utility., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo . Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials.

While the peripheral nervous system is able to repair itself following injury and disease, recovery is often slow and incomplete, with no available treatments to enhance the effectiveness of regeneration. Using knock-out and transgenic overexpressor mice, we previously reported that BACE1, an aspartyl protease, as reported by Hemming et al. (PLoS One 4:12, 2009), negatively regulates peripheral nerve regeneration. Here, we investigated whether pharmacological inhibition of BACE may enhance peripheral nerve repair following traumatic nerve injury or neurodegenerative disease. BACE inhibitor-treated mice had increased numbers of regenerating axons and enhanced functional recovery after a sciatic nerve crush while inhibition increased axonal sprouting following a partial nerve injury. In the SOD1 G93A ALS mouse model, BACE inhibition increased axonal regeneration with improved muscle re-innervation. CHL1, a BACE1 substrate, was elevated in treated mice and may mediate enhanced regeneration. Our data demonstrates that pharmacological BACE inhibition accelerates peripheral axon regeneration after varied nerve injuries and could be used as a potential therapy.

Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl ( R )-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2- b ]pyridazin-8-yl)pyrrolidin-3-yl)carbamate 1 (PDDC) , the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.

Background: Effective strategies for participant retention are critical in health research to ensure validity, generalizability and efficient use of resources. Yet standardized guidelines for planning and reporting on retention efforts have been lacking. As with randomized controlled trial (RCT) and systematic review (SR) protocols, retention protocols are an opportunity to improve transparency and rigor. An RCT being conducted in British Columbia (BC), Canada provides a case example for developing a priori retention frameworks for use in protocol planning and reporting., Methods: The BC Healthy Connections Project RCT is examining the effectiveness of a nurse home-visiting program in improving child and maternal outcomes compared with existing services. Participants (N = 739) were girls and young women preparing to parent for the first time and experiencing socioeconomic disadvantage. Quantitative data were collected upon trial entry during pregnancy and during five follow-up interviews until participants' children reached age 2 years. A framework was developed to guide retention of this study population throughout the RCT. We reviewed relevant literature and mapped essential retention activities across the study planning, recruitment and maintenance phases. Interview completion rates were tracked., Results: Results from 3302 follow-up interviews (in-person/telephone) conducted over 4 years indicate high completion rates: 90% (n = 667) at 34 weeks gestation; and 91% (n = 676), 85% (n = 626), 80% (n = 594) and 83% (n = 613) at 2, 10, 18 and 24 months postpartum, respectively. Almost all participants (99%, n = 732) provided ongoing consent to access administrative health data. These results provide preliminary data on the success of the framework., Conclusions: Our retention results are encouraging given that participants were experiencing considerable socioeconomic disadvantage. Standardized retention planning and reporting may therefore be feasible for health research in general, using the framework we have developed. Use of standardized retention protocols should be encouraged in research to promote consistency across diverse studies, as now happens with RCT and SR protocols. Beyond this, successful retention approaches may help inform health policy-makers and practitioners who also need to better reach, engage and retain underserved populations., Trial Registration: ClinicalTrials.gov, NCT01672060. Registered on 24 August 2012.

Background: Given the emergent aging population, the identification of effective treatments for Alzheimer's disease (AD) is critical., Objective: We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model., Methods: Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4-5 months and cognitive performance was assessed using the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083., Results: JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings,postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment., Conclusion: These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD.

Study Design: This was a retrospective study of 2 different fusion techniques for the treatment of lumbar degenerative spondylolisthesis., Objective: To determine whether posterior lumbar interbody fusion (IF) is associated with improved patient-rated satisfaction and functional outcome when compared with posterolateral fusion (PLF)., Summary of Background Data: IF and PLF are widely used surgical approaches in the treatment of spondylolisthesis. Numerous studies have compared IF and PLF techniques, but inconsistent results, heterogeneous cohorts, and conflicting scientific evidence have made it difficult to reach a consensus on the optimal fusion technique., Materials and Methods: A consecutive cohort of 87 patients who had single-level degenerative spondylolisthesis and either PLF or IF were identified from a prospectively maintained database. Short Form-36 physical and mental component score, Oswestry Disability Index, back and leg pain, and complication rate were assessed to 24 months postoperatively. Patient characteristics, clinical outcome, and complications were compared between groups., Results: Of the 87 patients identified, 29 patients (33%) had PLF and 58 patients (67%) had IF. Patient follow-up was ≥85%. Foraminal stenosis (PLF, 13.8% vs. IF, 34.5%; P=0.046) was more common among the participants in the IF group. Intraoperative and postoperative complications were not different between groups (P>0.05). The reoperation rate was 3.4% in the PLF group and 10.3% in the IF group (P=0.416). Patients in the PLF group experienced similar gains in improvement in all outcome measures as those in the IF group (P>0.05). Four patients in the IF group and 3 in the PLF group were lacking evidence of radiographic fusion. These patients did have increased moderate back pain compared with patients demonstrating radiographic fusion but did not differ in any other postoperative outcomes measures., Conclusions: Type of fusion, IF or PLF, does not affect patient outcome or postoperative complication rates., Level of Evidence: Level IV.

The transformative and versatile role of cellulose nanomaterials (CNMs) as an enabling technology in the preparation of multiscale mesostructured ceramics, with pore sizes in the meso- (2-50 nm) and macroporosity (above 50 nm) range with controlled porous architecture across the structure is explored. CNMs have revolutionized functional advanced materials concepts and technology by using natural resources to derive superb properties. Its unique chemical and physical properties have inspired its exploitation as a reinforcement agent, stimuli responsive tool, and templating agent mostly for biologic and polymeric materials, as well as for metals and ceramics. CNMs can act as a sacrificial filler templating agent, a surface modifier agent, and as an aid for shaping macrostructures into bulk samples. A deep knowledge of the synergistic interaction mechanisms between CNMs and ceramic particles to assemble them in solution and into solid structures is key to advance this technology, and to develop a predictive understanding of synthesis and processing mechanisms that relates morphology evolution, processing, and final physical properties. The potential ease of processing and versatility of CNMs for functional ceramic technology, intimately linked to the CNMs' nature and properties, will make a significant impact with respect to the current state of the art., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Axons of the peripheral nervous system possess the capacity to regenerate following injury. Previously, we showed that genetically knocking out Beta-Site APP-Cleaving Enzyme 1 (BACE1) leads to increased nerve regeneration. Two cellular components, macrophages and neurons, contribute to enhanced nerve regeneration in BACE1 knockout mice. Here, we utilized a transgenic mouse model that overexpresses BACE1 in its neurons to investigate whether neuronal BACE1 has an inverse effect on regeneration following nerve injury. We performed a sciatic nerve crush in BACE1 transgenic mice and control wild-type littermates, and evaluated the extent of both morphological and physiological improvements over time. At the earliest time point of 3days, we observed a significant decrease in the length of axonal sprouts growing out from the crush site in BACE1 transgenic mice. At later times (10 and 15days post-crush), there were significant reductions in the number of myelinated axons in the sciatic nerve and the percentage of re-innervated neuromuscular junctions in the gastrocnemius muscle. Transgenic mice had a functional electrophysiological delay in the recovery up to 8weeks post-crush compared to controls. These results indicate that BACE1 activity levels have an inverse effect on peripheral nerve repair after injury. The results obtained in this study provide evidence that neuronal BACE1 activity levels impact peripheral nerve regeneration. This data has clinical relevance by highlighting a novel drug target to enhance peripheral nerve repair, an area which currently does not have any approved therapeutics., (Copyright © 2017 Elsevier Inc. All rights reserved.)

While the peripheral nervous system has the capacity to regenerate following a nerve injury, it is often at a slow rate and results in unsatisfactory recovery, leaving patients with reduced function. Many regeneration associated genes have been identified over the years, which may shed some insight into how we can manipulate this intrinsic regenerative ability to enhance repair following peripheral nerve injuries. Our lab has identified the membrane bound protease beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), or beta secretase, as a potential negative regulator of peripheral nerve regeneration. When beta secretase activity levels are abolished via a null mutation in mice, peripheral regeneration is enhanced following a sciatic nerve crush injury. Conversely, when activity levels are greatly increased by overexpressing beta secretase in mice, nerve regeneration and functional recovery are impaired after a sciatic nerve crush injury. In addition to our work, many substrates of beta secretase have been found to be involved in regulating neurite outgrowth and some have even been identified as regeneration associated genes. In this review, we set out to discuss BACE1 and its substrates with respect to axonal regeneration and speculate on the possibility of utilizing BACE1 inhibitors to enhance regeneration following acute nerve injury and potential uses in peripheral neuropathies., Competing Interests: None declared

Background: Waits for elective spine surgery are common in Canada. We examined whether a prolonged wait for surgery for lumbar degenerative spinal stenosis was detrimental to outcome., Methods: In this prospective observational study, we enrolled 166 consecutive patients referred to our centre for treatment of lumbar degenerative spinal stenosis between 2006 and 2010. Outcome measures were assessed at referral, preoperatively and until 24 months postoperatively. Primary outcome measures were the physical and mental component summary scores of the 36-Item Short-Form Health Survey and the Oswestry Disability Index. Secondary outcome measures included the symptom severity scale of the Zurich Claudication Questionnaire, a numeric rating scale for back and leg pain, and patient satisfaction with treatment. Wait time was defined as the time from referral to surgery., Results: The follow-up rate at 2 years was 85%. The median wait time was 349 days. All health-related quality of life measures deteriorated during the waiting period, but there was no significant correlation between wait time and magnitude of the change in outcome measure. At 6 months postoperatively, the Pearson correlation was significantly positive between wait time and change in disability (r = 0.223), Zurich Claudication Questionnaire score (r = 0.2) and leg pain score (r = 0.221). At 12 months, the correlation remained significant for change in disability (r = 0.205) and was significant for change in mental well-being (r = -0.224). At 12 months, patients with a shorter wait (≤ 12 months) showed greater improvement in mental well-being (mean difference in change [and 95% confidence interval (CI)] 5.7 [1.4-9.9]) and decrease in disability (-9.3 [95% CI -15.1 to -3.6]) and leg pain (-1.6 [95% CI -3.0 to -0.3]). There were no statistically significant differences in outcome or patient satisfaction with treatment between those with shorter and longer waits at 24 months., Interpretation: Patients awaiting spinal surgery experienced deterioration in health-related quality of life irrespective of the length of wait time. However, longer waits were associated with a delay in recovery during the first year after surgery.

Interventions, such as the use of percutaneous endoscopic gastrostomy (PEG) and non-invasive ventilation (NIV), are used in the management of people with motor neurone disease with the aim of improving quality of life and relieving symptoms. However, the number of people receiving these interventions varies across the UK. This study has looked at the involvement and knowledge of consultants, within specialist palliative care services, with these procedures, to ascertain if there were differences in attitudes to their use. Twenty-two consultants took part in a telephone audit. There appeared to be great variation in their involvement in and knowledge of the use of these interventions. The majority of services were involved in the care of people with MND, but often only in the terminal stages. There appears to be a need for the wider application of guidelines on the use of PEG and NIV, as well as the development of a collaborative approach with other services, including neurology and rehabilitation services.

Our objective was to study the use of opioid and other medication at the end of life for patients with ALS/MND under specialist palliative care. A retrospective study looked at the medication received by 62 patients with MND/ALS in the last 72 h of life in six hospices in the UK and Ireland. Medication is widely used in the last 24 h of life, and use of the parenteral route increases as death approaches. We found that the doses of opioids and other medication do not increase appreciably during this period. The mean dose of opioid in the last 24 h of life was 80 mg oral morphine equivalent/24 h. These results are further evidence that opioids can be used both effectively and safely to manage symptoms at the end of life for people with MND/ALS.

Aim: To study the effects of early weight bearing following acute repair of ruptured Achilles tendon., Methods: Using a comparative longitudinal study design, following repair of an Achilles tendon rupture, patients in Group 1 were immobilised with their ankle in gravity equinus, were encouraged to weight bear on the operated limb as soon as possible to full weight bearing, and received a single a cast change at 2 weeks, when the ankle was immobilised in a plantigrade position. Patients in Group 2 were immobilised with their ankle in full equinus, and received a cast change at 2 weeks, when the ankle was immobilised in mid equinus, and at 4 weeks, when the ankle was immobilised in a plantigrade position. They were advised to weight bear 4 weeks from the operation., Results: Patients in Group 1 attended less outpatient visits, completely discarded their crutches at an average of 2.5 weeks from the operation (Group 2: average of 5.7 weeks from the operation), (p=0.013), and a greater proportion of them were satisfied with the results of surgery. At ultrasound scan, the average thickness of the repaired tendon was 12.1 mm (SD 2), with no difference in the thickness of the ruptured tendon regardless of the method of postoperative management. There was no significant difference in isometric strength between the two groups of patients., Conclusion: Early weight bearing with the ankle plantigrade is not detrimental to the outcome of repair following rupture of the Achilles tendon.

Purpose: To study the effects of early weightbearing and ankle mobilization after acute repair of ruptured Achilles tendon., Study Design: Comparative longitudinal study., Methods: Patients in group 1 were postoperatively immobilized with their ankle in gravity equinus, they were encouraged to bear weight on the operated limb as soon as possible to full weightbearing, and they received a single cast change at 2 weeks, with the ankle accommodated in an anterior splint in a plantigrade position, allowing the ankle to be plantar flexed fully but not dorsiflexed above neutral. Patients in group 2 were immobilized with their ankle in full equinus with a cast change at 2 weeks, when the ankle was immobilized in mid equinus, and at 4 weeks, when the ankle was immobilized in a plantigrade position, and they were advised to bear weight., Results: Patients in group 1 attended fewer outpatient visits, completely discarded their crutches at an average of 2.5 weeks, and more were satisfied with the results of surgery. At ultrasonography, the average thickness of the repaired tendon was 12.1 mm, with no difference in the thickness of the ruptured tendon regardless of postoperative management. There was no significant difference in isometric strength between the two groups., Conclusions: Early weightbearing with the ankle plantigrade is not detrimental to the outcome of repair after acute rupture of the Achilles tendon and shortens the time needed for rehabilitation. However, strength deficit and muscle atrophy are not prevented.