Collagen Tubular Airway-on-Chip for Extended Epithelial Culture and Investigation of Ventilation Dynamics.

The lower respiratory tract is a hierarchical network of compliant tubular structures that are made from extracellular matrix proteins with a wall lined by an epithelium. While microfluidic airway-on-a-chip models incorporate the effects of shear and stretch on the epithelium, week-long air-liquid-interface culture at physiological shear stresses, the circular cross-section, and compliance of native airway walls have yet to be recapitulated. To overcome these limitations, a collagen tube-based airway model is presented. The lumen is lined with a confluent epithelium during two-week continuous perfusion with warm, humid air while presenting culture medium from the outside and compensating for evaporation. The model recapitulates human small airways in extracellular matrix composition and mechanical microenvironment, allowing for the first time dynamic studies of elastocapillary phenomena associated with regular breathing and mechanical ventilation, as well as their impacts on the epithelium. A case study reveales increasing damage to the epithelium during repetitive collapse and reopening cycles as opposed to overdistension, suggesting expiratory flow resistance to reduce atelectasis. The model is expected to promote systematic comparisons between different clinically used ventilation strategies and, more broadly, to enhance human organ-on-a-chip platforms for a variety of tubular tissues.

Ultrasonographic Identification of Shell Surface Types in Commercially Available Silicone Gel-Filled Breast Implants.

BACKGROUND: Breast implant safety issues have resulted in the need for global product recalls and medical device tracing. Conventional methods of breast implant tracing, have to date proven to be unsuccessful. This study aims to evaluate the effectiveness of high-resolution ultrasound (HRUS) screening in identifying implanted breast devices. METHODS: Data from 113 female patients undergoing preoperative ultrasound screening for secondary breast surgery between 2019 and 2022 was prospectively reviewed to evaluate the effectiveness of HRUS imaging with the aid of a sonographic surface catalog to identify the surface and brand type of implanted breast devices. To corroborate the findings and assess the reproducibility of the approach, further evaluations were replicated in New Zealand white rabbits and compared with the results found in humans. RESULTS: In the human recipients, implant surface and brand types were correctly identified by ultrasound imaging in 99% (112 of 113) and 96% (69 of 72) of the cases, either consultation-only or revision, respectively. This constituted an overall success rate of 98% (181 of 185). Furthermore, in a corroborating New Zealand white rabbit model where full-scale commercial implants were introduced and monitored over many months, from the total 28 analyzed, the surface was accurately identified in a total of 27 cases (the one failure being before generation of a sonograph surface catalogue), demonstrating an overall success rate of 96.4%. CONCLUSION: HRUS is, therefore, a valid and first-hand tool for breast implant imaging that can correctly evaluate both surface type and brand type alongside other variables such as implant placement, positioning, flipping, or rupture. CLINICAL RELEVANCE STATEMENT: HRUS is a valid and first-hand tool for the identification and traceability of breast implants that evaluates surface type and brand type. This low-cost, accessible, and reproducible practice provides patients with peace of mind and surgeons with a promising diagnostic tool.

Collection of menopause data in studies of women living with HIV: A systematic literature review.

OBJECTIVES: An increasing number of women living with HIV are transitioning through midlife and menopause. Women living with HIV may experience earlier menopause and a higher symptom burden than women without HIV, but more evidence is needed. Data collection on menopause in women living with HIV is scarce and often not standardized. We sought to assess how menopause data are collected in cohorts and studies of women living with HIV. METHODS: This was a literature review conducted within the PubMed database. We included original studies and cohorts assessing menopause and/or menopausal symptoms in women living with HIV. Study characteristics and menopause data collection, including the definition of menopause, symptom assessment tools, and measurement of biomedical parameters, were noted and summarized systematically in data tables. RESULTS: We included 40 articles describing 37 separate studies published between 2000 and 2023; 27 of these were conducted in high-income countries, the majority in the USA (n = 16). Ten studies were from low- and middle-income countries; four of these were conducted in Brazil. In 20 studies, menopause was defined according to the World Health Organization's definition of over 12 months of amenorrhea. Twelve studies used the Menopause Rating Scale to characterize menopausal symptoms, five studies used other specified symptom assessment tools, and 12 studies used a study-specific tool. CONCLUSIONS: Menopause data collection in women living with HIV is heterogeneous. We propose that standardized tools should be used to enable comparisons between studies and countries, thereby improving the quality of research and clinical treatment. Further research into the validity of menopausal symptom scoring tools is warranted.

Identification of high-risk patients for referral through machine learning assisting the decision making to manage minor ailments in community pharmacies.

Background: Data analysis techniques such as machine learning have been used for assisting in triage and the diagnosis of health problems. Nevertheless, it has not been used yet to assist community pharmacists with services such as the Minor Ailment Services These services have been implemented to reduce the burden of primary care consultations in general medical practitioners (GPs) and to allow a better utilization of community pharmacists' skills. However, there is a need to refer high-risk patients to GPs. Aim: To develop a predictive model for high-risk patients that need referral assisting community pharmacists' triage through a minor ailment service. Method: An ongoing pragmatic type 3 effectiveness-implementation hybrid study was undertaken at a national level in Spanish community pharmacies since October 2020. Pharmacists recruited patients presenting with minor ailments and followed them 10 days after the consultation. The main outcome measured was appropriate medical referral (in accordance with previously co-designed protocols). Nine machine learning models were tested (three statistical, three black box and three tree models) to assist pharmacists in the detection of high-risk individuals in need of referral. Results: Over 14'000 patients were included in the study. Most patients were female (68.1%). With no previous treatment for the specific minor ailment (68.0%) presented. A percentage of patients had referral criteria (13.8%) however, not all of these patients were referred by the pharmacist to the GP (8.5%). The pharmacists were using their clinical expertise not to refer these patients. The primary prediction model was the radial support vector machine (RSVM) with an accuracy of 0.934 (CI95 = [0.926,0.942]), Cohen's kappa of 0.630, recall equal to 0.975 and an area under the curve of 0.897. Twenty variables (out of 61 evaluated) were included in the model. radial support vector machine could predict 95.2% of the true negatives and 74.8% of the true positives. When evaluating the performance for the 25 patient's profiles most frequent in the study, the model was considered appropriate for 56% of them. Conclusion: A RSVM model was obtained to assist in the differentiation of patients that can be managed in community pharmacy from those who are at risk and should be evaluated by GPs. This tool potentially increases patients' safety by increasing pharmacists' ability to differentiate minor ailments from other medical conditions.

Endobronchial Ultrasound-guided Sampling of Centrally Located Intrapulmonary Tumors Provides Suitable Material for Diagnostic and Molecular Testing.

BACKGROUND: Curvilinear endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a key diagnostic and staging procedure for patients with suspected lung cancer. However, sampling centrally located intrapulmonary tumors is feasible but less well established. METHODS: We retrospectively evaluated the diagnostic utility of EBUS-TBNA in patients who underwent sampling of centrally located intrapulmonary tumors. Diagnostic accuracy, sample suitability for molecular testing, and complications were assessed. RESULTS: Between January 2015 and April 2021, 102 EBUS-TBNA procedures sampled centrally located intrapulmonary tumors in 99 patients. The median age was 70 [interquartile range, 63 to 75] years and 51% (51/99) were male. The commonest site was the right upper lobe (n=42/99; 42%). The median tumor size was 29 [interquartile range, 21 to 35] mm. The diagnostic yield was 88/102 (86%) with a false negative rate of 14% (14/102). In addition to intrapulmonary tumor sampling, lymph nodes were sampled in 65/102 procedures and 30/65(46%) were positive for lung cancer. Cancer was diagnosed in 87/99 (88%) cases. When requested, molecular testing was adequate in ≥94% of samples. Complications included minor bleeding in 6/102 (6%) with 2 requiring cold saline instillation, desaturation in 1/102 (1%), and tachycardia in 1/102(1%). One procedure was abandoned due to patient tachycardia. Delayed complications occurred in 1 patient who was hospitalized ≤7 days with pneumonia. CONCLUSION: EBUS-TBNA sampling of centrally located intrapulmonary tumors provides similar diagnostic accuracy to lymph node sampling, provides suitable material for molecular testing, and has a low complication rate.

E-cigarette aerosol exposure of pulmonary surfactant impairs its surface tension reducing function.

INTRODUCTION: E-cigarette (EC) and vaping use continue to remain popular amongst teenage and young adult populations, despite several reports of vaping associated lung injury. One of the first compounds that EC aerosols comes into contact within the lungs during a deep inhalation is pulmonary surfactant. Impairment of surfactant's critical surface tension reducing activity can contribute to lung dysfunction. Currently, information on how EC aerosols impacts pulmonary surfactant remains limited. We hypothesized that exposure to EC aerosol impairs the surface tension reducing ability of surfactant. METHODS: Bovine Lipid Extract Surfactant (BLES) was used as a model surfactant in a direct exposure syringe system. BLES (2ml) was placed in a syringe (30ml) attached to an EC. The generated aerosol was drawn into the syringe and then expelled, repeated 30 times. Biophysical analysis after exposure was completed using a constrained drop surfactometer (CDS). RESULTS: Minimum surface tensions increased significantly after exposure to the EC aerosol across 20 compression/expansion cycles. Mixing of non-aerosolized e-liquid did not result in significant changes. Variation in device used, addition of nicotine, or temperature of the aerosol had no additional effect. Two e-liquid flavours, menthol and red wedding, had further detrimental effects, resulting in significantly higher surface tension than the vehicle exposed BLES. Menthol exposed BLES has the highest minimum surface tensions across all 20 compression/expansion cycles. Alteration of surfactant properties through interaction with the produced aerosol was observed with a basic e-liquid vehicle, however additional compounds produced by added flavourings appeared to be able to increase inhibition. CONCLUSION: EC aerosols alter surfactant function through increases in minimum surface tension. This impairment may contribute to lung dysfunction and susceptibility to further injury.

Snapshot of ultrasound imaging in basic anatomy and physiology teaching in the United Kingdom and Republic of Ireland: perceptions, obstacles, and solutions.

We have used ultrasound imaging and technology as a tool for nonclinical teaching of basic physiological concepts for several years and are aware anecdotally that only a few others in the United Kingdom and Republic of Ireland (UK/ROI) are also using ultrasound with this intention in physiology and anatomy teaching. To better understand what areas ultrasound is used for by others, along with what barriers might exist to its use, we reached out to colleagues in UK/ROI institutions instructing on anatomy and physiology courses by asking them to complete a survey regarding their experiences. Relatively few institutions (9%) reported using the technology in this way but covered physiology and anatomy teaching in most major body systems. The perception of responding educators overall is that, overwhelmingly, ultrasound offers a useful addition to the teaching of physiology and anatomy and is very popular with students. Barriers to its implementation were identified, including unfamiliarity with equipment and potential uses. Lack of funding for equipment and staff, issues with class sizes, and lack of curriculum time were also identified. Despite these potential impediments, most nonusers were interested in finding out about the uses of ultrasound as a teaching tool. We conclude that the teaching community would benefit from wider dissemination of local practices.NEW & NOTEWORTHY We surveyed UK and Republic of Ireland institutions to establish the extent of ultrasound use in teaching undergraduate modules with significant anatomy or physiology content. Responses indicate that although ultrasound is used for a wide variety of systems, only a small proportion of courses use ultrasound for teaching. There is widespread interest in its use, with the main barriers being unfamiliarity with potential uses and the technology. We endorse further dissemination of this teaching practice.

The impact of the COVID-19 pandemic on pleural infection incidence: a UK multicentre retrospective analysis.

There was a significant reduction in pleural infection incidence, by almost a third, in the year following the start of the #COVID19 pandemic. Public health measures enforced during this period are likely to have played a significant role. https://bit.ly/3QAPPR9.

Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.

Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are 'loss of function' mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling. In our analysis we identify discordant genomic alleles present across all families as well as differentially abundant molecular features across the omics technologies. The analysis was focused on univariate modeling to discriminate the two phenotypic groups, but was unable to identify statistically significant candidate molecular markers. Our study highlights the issues caused by a large amount of inter-individual variation, and supports the emerging hypothesis that cerebral demyelination is a complex mix of environmental factors and/or heterogeneous genomic alleles. We confirm previous observations about the role of immune response, specifically auto-immunity and the potential role of PFN1 protein overabundance in CALD in a subset of the families. We envision our methodology as well as dataset has utility to the field for reproducing previous or enabling future modifier investigations.

Somatic mosaicism of sex chromosomes in the blood and brain.

In the blood, mosaic somatic aneuploidy (mSA) of all chromosomes has been found to be associated with adverse health outcomes, including hematological cancer. Sex chromosome mSA in the blood has been found to occur at a higher rate than autosomal mSA. Mosaic loss of the Y chromosome is the most common copy number alteration in males, and has been found to be associated with Alzheimer's disease (AD) in blood lymphocytes. mSA of the sex chromosomes has also been identified in the brain; however, little is known about its frequency across individuals. Using WGS data from 362 males and 719 females from the ROSMAP cohort, we quantified the relative rate of sex chromosome mSA in the dorsolateral prefrontal cortex (DLPFC), cerebellum and whole blood. To ascertain the functionality of observed sex chromosome mosaicism in the DLPFC, we examined its correlation with chromosome X and Y gene expression as well as neuropathological and clinical characteristics of AD and cognitive ageing. In males, we found that mSA of the Y chromosome occurs more frequently in blood than in the DLPFC or cerebellum. In the DLPFC, the presence of at least one APOE4 allele was associated with a reduction in read depth of the Y chromosome (p = 1.9e-02). In the female DLPFC, a reduction in chromosome X read depth was associated with reduced cognition at the last clinical visit and faster rate of cognitive decline (p = 7.8e-03; p = 1.9e-02). mSA of all sex chromosomes in the DLPFC were associated with aggregate measures of gene expression, implying functional impact. Our results provide insight into the relative rate of mSA between tissues and suggest that Y and female X chromosome read depth in the DLPFC is modestly associated with late AD risk factors and cognitive pathologies.

Identification and SAR exploration of a novel series of Legumain inhibitors.

This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in vitro experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i, a highly potent inhibitor with excellent physiochemical properties.

The Dynamics of Blood Drop Release from Swinging Objects in the Creation of Cast-off Bloodstain Patterns.

Although the characteristics of cast-off bloodstain patterns are well known, the physics of the mechanism by which they are created is poorly understood. The aim of this work was to describe the process by which blood droplets disengage from swinging objects. Cast-off droplets were recorded using high-speed digital video photography, and the resulting cast-off patterns were analyzed to draw inferences about the trajectories of individual drops. Blood on the object's distal end formed ligaments, which subsequently disintegrated into droplets. Initial droplet trajectories were approximately tangential to the trajectory of the location on the object from which the droplet was released. The application of the laws of physics to the mechanism of cast-off is discussed, and the process of drop formation is compared to that of passive drop formation. A technical description of cast-off is proposed, and a diagram to aid investigators in interpreting cast-off patterns at crime scenes is offered.

Integration of genomics and metabolomics for prioritization of rare disease variants: a 2018 literature review.

Many inborn errors of metabolism (IEMs) are amenable to treatment; therefore, early diagnosis and treatment is imperative. Despite recent advances, the genetic basis of many metabolic phenotypes remains unknown. For discovery purposes, whole exome sequencing (WES) variant prioritization coupled with clinical and bioinformatics expertise is the primary method used to identify novel disease-causing variants; however, causation is often difficult to establish due to the number of plausible variants. Integrated analysis of untargeted metabolomics (UM) and WES or whole genome sequencing (WGS) data is a promising systematic approach for identifying disease-causing variants. In this review, we provide a literature-based overview of UM methods utilizing liquid chromatography mass spectrometry (LC-MS), and assess approaches to integrating WES/WGS and LC-MS UM data for the discovery and prioritization of variants causing IEMs. To embed this integrated -omics approach in the clinic, expansion of gene-metabolite annotations and metabolomic feature-to-metabolite mapping methods are needed.

Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease-modifying antirheumatic drugs are available, there is still a medical need for novel drugs that control disease progression. As only 10% of experimental drug candidates for treatment of RA that enter phase I trials are eventually registered by the Food and Drug Administration, there is an immediate need for translational tools to facilitate early decision-making in drug development. In this study, we aimed to determine if the inability of fostamatinib (a small molecule inhibitor of Syk) to demonstrate sufficient efficacy in phase III of a previous clinical study could have been predicted earlier in the development process. METHODS: Biomarkers of bone, cartilage, and interstitial matrix turnover (C-telopeptide of type I collagen [CTX-I], matrix metalloproteinase-derived types I, II, and III collagen neoepitopes [C1M, C2M, and C3M]) were measured in 450 serum samples from the Oral Syk Inhibition in Rheumatoid Arthritis 1 study (OSKIRA-1, a phase III clinical study of the efficacy of fostamatinib in RA) at baseline and follow-up. Additionally, the same biomarkers were subsequently measured in conditioned media from osteoclast, cartilage, and synovial membrane cultured with the active metabolite of fostamatinib, R406, to assess the level of suppression induced by the drug. RESULTS: In OSKIRA-1 serum samples and osteoclast and cartilage cultures, fostamatinib suppressed the levels of CTX-I and C2M. In OSKIRA-1 serum samples and synovial membrane cultures, fostamatinib did not mediate any clinical or preclinical effect on either C1M or C3M, which have previously been associated with disease response and efficacy. CONCLUSION: These data demonstrate that translational biomarkers are a potential tool for early assessment and decision-making in drug development for RA treatment.

Dissection of Levels II Through V Is Required for Optimal Outcomes in Patients with Lateral Neck Lymph Node Metastasis from Papillary Thyroid Carcinoma.

BACKGROUND: Completeness of surgical resection is an important determinant of outcomes in patients with papillary thyroid carcinoma and regional lymph node metastasis. The extent of therapeutic lateral neck dissection remains controversial. This study aims to assess the impact of modified radical neck dissection of levels II to V in a large patient series. STUDY DESIGN: Retrospective analysis of consecutive patients with papillary thyroid carcinoma who underwent lateral neck dissection at a single institution from June 1, 2006 to December 31, 2014 was performed. RESULTS: A total of 241 lateral neck dissections were performed in 191 patients (118 [62%] women; median age 46 years [range 6 to 87 years]; median follow-up 14.3 months [range 0.1 to 107 months]). Overall, 202 initial neck dissections (195 modified radical neck dissections and 7 less extensive dissections) were performed. Among these initial dissections, 137 (68.8%), 132 (65.7%), 105 (52.0%), and 33 (16.9%) had positive lymph nodes in levels II, III, IV, and V, respectively. Ipsilateral lymph node persistence or recurrence occurred after 22 (10.9%) initial dissections, at level II in 10 (45.5%), level III in 8 (36.4%), level IV in 7 (31.8%), and level V in 3 (13.6%). Thirty-nine reoperative lateral neck dissection were performed, including 18 cases of persistence and recurrence after our initial dissections. In reoperative dissections, positive lymph nodes were confirmed in levels II, III, IV, and V in 18 (46.2%), 10 (25.6%), 13 (33.3%), and 5 (12.8%) dissections, respectively. Temporary nerve injury occurred in 6 (3.0%) initial and 4 (10.3%) reoperative dissections, respectively. There were no permanent nerve injuries. CONCLUSIONS: Omitting levels II and V during lateral neck dissection for papillary thyroid carcinoma potentially misses level II disease in two-thirds of patients and level V disease in one-fifth of patients. Formal modified radical neck dissection is necessary to avoid the morbidity of reoperative surgery.

Comparative effectiveness of budesonide/formoterol combination and tiotropium bromide among COPD patients new to these controller treatments.

BACKGROUND: Inhaled corticosteroid/long-acting ß2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD) exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting ß2-agonist combination) vs tiotropium (long-acting muscarinic antagonist) in the US has not yet been studied. METHODS: Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma) ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs. RESULTS: The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR) of 0.78 (95% CI =[0.70, 0.87], P<0.001), indicating a 22% reduction in risk of COPD exacerbation associated with initiation of BFC versus tiotropium. A post hoc sensitivity analysis found similar effects in those who had a prior asthma diagnosis (HR =0.72 [0.61, 0.86]) and those who did not (HR =0.83 [0.72, 0.96]). BFC initiation was associated with lower COPD-related health care resource utilization and costs ($4,084 per patient-year compared with $5,656 for tiotropium patients, P<0.001). CONCLUSION: In COPD patients new to controller therapies, initiating treatment with BFC was associated with improvements in health and economic outcomes compared with tiotropium.

Engaging stakeholders in rehabilitation research: a scoping review of strategies used in partnerships and evaluation of impacts.

PURPOSE: To describe how stakeholder engagement has been undertaken and evaluated in rehabilitation research. METHODS: A scoping review of the scientific literature using five search strategies. Quantitative and qualitative analyses using extracted data. Interpretation of results was iteratively discussed within the team, which included a parent stakeholder. RESULTS: Searches identified 101 candidate papers; 28 were read in full to assess eligibility and 19 were included in the review. People with disabilities and their families were more frequently involved compared to other stakeholders. Stakeholders were often involved in planning and evaluating service delivery. A key issue was identifying stakeholders; strategies used to support their involvement included creating committees, organizing meetings, clarifying roles and offering training. Communication, power sharing and resources influenced how stakeholders could be engaged in the research. Perceived outcomes of stakeholder engagement included the creation of partnerships, facilitating the research process and the application of the results, and empowering stakeholders. Stakeholder engagement outcomes were rarely formally evaluated. CONCLUSIONS: There is a great interest in rehabilitation to engage stakeholders in the research process. However, further evidence is needed to identify effective strategies for meaningful stakeholder engagement that leads to more useful research that positively impacts practice. Implications for Rehabilitation Using several strategies to engage various stakeholders throughout the research process is thought to increase the quality of the research and the rehabilitation process by developing proposals and programs responding better to their needs. Engagement strategies need to be better reported and evaluated in the literature. Engagement facilitate uptake of research findings by increasing stakeholders' awareness of the evidence, the resources available and their own ability to act upon a situation. Factors influencing opportunities for stakeholder engagement need to be better understood.

Multiple blocks in the engagement of oxidative phosphorylation in putative ovarian cancer stem cells: implication for maintenance therapy with glycolysis inhibitors.

Survival rate in ovarian cancer has not improved since chemotherapy was introduced a few decades ago. The dismal prognosis is mostly due to disease recurrence where majority of the patients succumb to the disease. The demonstration that tumors are comprised of subfractions of cancer cells displaying heterogeneity in stemness potential, chemoresistance, and tumor repair capacity suggests that recurrence may be driven by the chemoresistant cancer stem cells. Thus to improve patient survival, novel therapies should eradicate this cancer cell population. We show that in contrast to the more differentiated ovarian cancer cells, the putative CD44+/MyD88+ ovarian cancer stem cells express lower levels of pyruvate dehydrogenase, Cox-I, Cox-II, and Cox-IV, and higher levels of UCP2. Together, this molecular phenotype establishes a bioenergetic profile that prefers the use of glycolysis over oxidative phosphorylation to generate ATP. This bioenergetic profile is conserved in vivo and therefore a maintenance regimen of 2-deoxyglucose administered after Paclitaxel treatment is able to delay the progression of recurrent tumors and decrease tumor burden in mice. Our findings strongly suggest the value of maintenance with glycolysis inhibitors with the goal of improving survival in ovarian cancer patients.

Functional and toxicological consequences of metabolic bioactivation of methapyrilene via thiophene S-oxidation: Induction of cell defence, apoptosis and hepatic necrosis.

UNLABELLED: Methapyrilene, [N,N-dimethyl-N'-pyridyl-N'(2-thienylmethyl)-1,2-ethanediamine] (MP) was withdrawn from, clinical use due to reported periportal hepatic necrosis and hepatocarcinogenicity in the rat, via S-oxidation of the thiophene group. In this study MP is used as a model hepatotoxin to further characterise the functional consequences of S-oxidation of the thiophene group in vivo, in rat models and in vitro, in freshly isolated rat hepatocyte suspensions. In vivo histological studies revealed the early depletion of glutathione (GSH), which was confined to the damaged periportal area, in contrast to an increase in GSH levels in the centrilobular region. Additionally, the induction of cell defence was demonstrated by an increase in the protein levels of heme-oxygenase 1 (HO-1) and glutamate cysteine ligase, catalytic subunit (GCLC) in vivo. Histological examination demonstrated that cytotoxicity progresses initially via apoptosis before an increase in necrosis over the 3-day administration. An apoptotic-like mechanism was observed in vitro via the measurement of cytochrome c release and caspase activation. CONCLUSION: This study provides evidence for a complex pathway of MP-induced hepatotoxicity which progresses through early adaptation, apoptosis, necrosis and inflammation, all underpinned by the zonal induction and depletion of GSH within the liver.