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Biases in medical artificial intelligence (AI) arise and compound throughout the AI lifecycle. These biases can have significant clinical consequences, especially in applications that involve clinical decision-making. Left unaddressed, biased medical AI can lead to substandard clinical decisions and the perpetuation and exacerbation of longstanding healthcare disparities. We discuss potential biases that can arise at different stages in the AI development pipeline and how they can affect AI algorithms and clinical decision-making. Bias can occur in data features and labels, model development and evaluation, deployment, and publication. Insufficient sample sizes for certain patient groups can result in suboptimal performance, algorithm underestimation, and clinically unmeaningful predictions. Missing patient findings can also produce biased model behavior, including capturable but nonrandomly missing data, such as diagnosis codes, and data that is not usually or not easily captured, such as social determinants of health. Expertly annotated labels used to train supervised learning models may reflect implicit cognitive biases or substandard care practices. Overreliance on performance metrics during model development may obscure bias and diminish a model's clinical utility. When applied to data outside the training cohort, model performance can deteriorate from previous validation and can do so differentially across subgroups. How end users interact with deployed solutions can introduce bias. Finally, where models are developed and published, and by whom, impacts the trajectories and priorities of future medical AI development. Solutions to mitigate bias must be implemented with care, which include the collection of large and diverse data sets, statistical debiasing methods, thorough model evaluation, emphasis on model interpretability, and standardized bias reporting and transparency requirements. Prior to real-world implementation in clinical settings, rigorous validation through clinical trials is critical to demonstrate unbiased application. Addressing biases across model development stages is crucial for ensuring all patients benefit equitably from the future of medical AI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cross 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: Patients in the intensive care unit (ICU) are commonly on mechanical ventilation, either through endotracheal intubation or tracheostomy, which usually leaves them nonverbal. Low-technology augmentative and alternative communication (AAC) strategies are simple and effective ways to enhance communication between patients and their communication partners but are underutilised., Aim: The aim of this study was to systematically review current evidence regarding the effectiveness, experience of use, and usability of low-technology AAC with nonverbal patients and their communication partners in the ICU., Methods: This review included quantitative, qualitative, and mixed-methods studies of adult ICU patients aged 18 or older who were nonverbal due to mechanical ventilation and their communication partners. Studies using low-technology AAC, such as communication boards and pen and paper, were included. Six databases were searched, and the review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A convergent segregated approach was used for data synthesis., Results: Thirty-two studies were included. Low-technology AAC improved patient satisfaction, facilitated communication, and met patients' physical and psychological needs. Communication boards with mixed content (e.g., pictures, words, and letters) were preferred but were used less frequently than unaided strategies due to patients' medical status, tool availability, and staff attitudes. Boards should be user-friendly, tailored, include pen/paper, and introduced preoperation to increase patient's comfort when using them postoperatively., Conclusion: Existing evidence support low-technology AAC's efficacy in meeting patients' needs. Better usability hinges on proper implementation and addressing challenges. Further research is crucial for refining communication-board design, ensuring both user-friendliness and sophistication to cater to ICU patients' diverse needs., Registration: The review protocol was registered in the International Prospective Register of Systematic Reviews, with registration number CRD42022331566., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background and Hypothesis: Calcineurin inhibitors affect kidney electrolyte handling and blood pressure through an effect on the distal tubule. The second generation calcineurin inhibitor voclosporin causes hypomagnesemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally., Methods: Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric blood pressure recordings, and analysis of mRNA and protein levels of distal tubular transporters at day 28., Results: Compared to vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased blood pressure, whereas voclosporin caused a gradual but persistent increase in blood pressure which was further characterized by high renin, normal aldosterone, and low endothelin-1., Conclusions: In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two calcineurin inhibitors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Around 700,000 family caregivers provide unpaid care for 900,000 people living with dementia in the United Kingdom. Few family caregivers receive support for their own psychological needs and funding for community respite services has declined. These trends are seen across Europe as demographic and budgetary pressures have intensified due to public spending cuts arising from the 2008 financial crisis and the COVID-19 pandemic. The World Health Organization has prioritized the need to expand the provision of support for caregivers and families of people with dementia by 2025. Web-based interventions have the potential for development as they require modest investment and can be accessed by family caregivers at home. Further cost benefits can be realized by adapting existing interventions with demonstrated effectiveness for new contexts. This paper reports initial findings from the CareCoach study, which is adapting Partner in Balance (PiB), a web-based coaching intervention developed in the Netherlands, for family caregivers in the United Kingdom., Objective: This study aims to work with unpaid family caregivers and staff in adapting the Dutch web-based support tool PiB to improve its acceptability and usability for use in the United Kingdom., Methods: Accelerated Experience-Based Co-Design (AEBCD) was used with caregivers, staff, and core stakeholders. Interviews, workshops, and stakeholder consultations were conducted. Data were analyzed iteratively. Recommendations for the redesign of PiB for use across the United Kingdom were adjudicated by the study Adaptation Working Party., Results: Sixteen caregivers and 17 staff took part in interviews. Thirteen caregivers and 17 staff took part in workshops. Most (n=26) participants were White, female, and retired. All except 4 caregivers (2 male and 2 female) found the PiB's offer of web-based self-help learning acceptable. Caregivers identified complexity and lack of inclusivity in some wording and video resources as problematic. The staff took a stronger perspective on the lack of inclusivity in PiB video resources. Staff and caregivers coproduced new inclusive wording and recommended creating new videos to adapt PiB for the UK context., Conclusions: AEBCD methods facilitated the engagement of caregivers and staff and advanced the adaptation of the PiB complex intervention. An important addition to the AEBCD method in this process was the work of an Adaptation Working Party, which adjudicated and agreed to new wording where this could not be established in consultation with caregivers and staff., Trial Registration: ISRCTN Registry ISRCTN12540555; https://doi.org/10.1186/ISRCTN12540555., (©Fiona Scheibl, Lizzy Boots, Ruth Eley, Christopher Fox, Fergus Gracey, Karen Harrison Dening, Jan Oyebode, Bridget Penhale, Fiona Poland, Gemma Ridel, Juniper West, Jane L Cross. Originally published in JMIR Formative Research (https://formative.jmir.org), 22.05.2024.)

Study Design: Retrospective cohort study., Objective: The aim of this study was to determine the relative importance and predicative power of the Hospital Frailty Risk Score (HFRS) on unplanned 30-day readmission after surgical intervention for metastatic spinal column tumors., Methods: All adult patients undergoing surgery for metastatic spinal column tumor were identified in the Nationwide Readmission Database from the years 2016 to 2018. Patients were categorized into 3 cohorts based on the criteria of the HFRS: Low(<5), Intermediate(5-14.9), and High(≥ 15). Random Forest (RF) classification was used to construct predictive models for 30-day patient readmission. Model performance was examined using the area under the receiver operating curve (AUC), and the Mean Decrease Gini (MDG) metric was used to quantify and rank features by relative importance., Results: There were 4346 patients included. The proportion of patients who required any readmission were higher among the Intermediate and High frailty cohorts when compared to the Low frailty cohort ( Low:33.9% vs. Intermediate:39.3% vs. High:39.2%, P < .001 ). An RF classifier was trained to predict 30-day readmission on all features (AUC = .60) and architecturally equivalent model trained using only ten features with highest MDG (AUC = .59). Both models found frailty to have the highest importance in predicting risk of readmission. On multivariate regression analysis, Intermediate frailty [ OR:1.32, CI(1.06,1.64), P = .012 ] was found to be an independent predictor of unplanned 30-day readmission., Conclusion: Our study utilizes machine learning approaches and predictive modeling to identify frailty as a significant risk-factor that contributes to unplanned 30-day readmission after spine surgery for metastatic spinal column metastases., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Dementia is a complex medical condition that poses significant challenges to healthcare systems and support services. People living with dementia (PLWD) and their carers experience complex needs often exacerbated by social isolation and challenges in accessing support. Social prescribing (SP) seeks to enable PLWD and their carers to access community and voluntary sector resources to support them address such needs. Existing research, however, does not describe what SP interventions are currently in place in dementia care. Little is known about the needs these interventions are designed to address, the reasons that lead PLWD and their carers to participate in them, their effectiveness and the extent to which they could increase positive health outcomes if adopted and how., Methods and Analysis: A complex intervention systematic review of SP for PLWD and/or their carers will be conducted using an iterative logic model approach. Six electronic (MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus and Cochrane/CENTRAL) and two grey literature databases (EThOS and CORE) were searched for publications between 1 January 2003 and June 2023, supplemented by handsearching of reference lists of included studies. Study selection, data extraction and risk of bias assessment, using Gough's Weight of Evidence Framework, will be independently performed by two reviewers. A narrative approach will be employed to synthesise and report quantitative and qualitative data. Reporting will be informed by the Preferred Reporting Items for Systematic Review and Meta-Analysis Complex Interventions extension statement and checklist., Ethics and Dissemination: No ethical approval is required due to this systematic review operating only with secondary sources. Findings will be disseminated through peer-reviewed publications, conference presentations and meetings with key stakeholders including healthcare professionals, patient and carer groups, community organisations (eg, the Social Prescribing Network and the Evidence Collaborative at the National Academy for Social Prescribing), policymakers and funding bodies., Prospero Registration Number: CRD42023428625., Competing Interests: Competing interests: Minor competing interest declared by co-author (EMC) regarding salary costs from the sponsor funded by the NIHR., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design., Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement., Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event., Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD., Competing Interests: Conflict of interest: K. Waeijen-Smit, M. Crutsen, S. Keene, T.J. Ringbæk, F. Fabbian, C-t. Lun, B. Ergan, C. Estebam, J.M. Quintana Lopez, C.L. Chang, R.J. Hancox, E. Shafuddin, H. Ellis, C. Janson, G. Gudmundsson, D. Epstein, A. Lacoma, C. Osadnik, I. Alia, F. Spannella, Z. Karakurt, H. Mehravaran, C. Utens, M.D. de Kruif, F.W.S. Ko, S.P. Trethewey, K. Vermeersch, S. Zilberman-Itskovich, C. Echevarria, R.T.M. Sprooten, P. Faverio, H.J. Prins and S. Houben-Wilke have no grants or personal fees to report. Conflict of interest: M. Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Kamada, Takeda, Zambon, CSL Behring, Specialty Therapeutics, Janssen, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Inhibrx, Ferrer, Menarini, Mereo Biopharma, Spin Therapeutics, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi and Grifols and research grants from Grifols. Conflict of interest: E. Crisafulli has received honoraria for lecturing, scientific advisory boards and participation in clinical studies for AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Qbgroup and Sanofi. Conflict of interest: A. Torres reports speaker/consulting honoraria from Pfizer, MSD, Janssen and Biomerieux. Conflict of interest: C. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the University of Basel, the University Hospital Basel, the KTI, Abbott, Beckman Coulter, BRAHMS, Idorsia, LSI-Medience, Ortho Diagnostics, Novartis, Roche, Siemens, SpinChip and Singulex, as well as speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Idorsia, Novartis, Osler, Roche, SpinChip and Sanofi, all outside the submitted work. Conflict of interest: P. Schuetz has received grants from Nestle, Abbot, bioMerieux and Thermofisher outside the submitted work. Conflict of interest: E. Mekov has received grants and personal fees from Chiesi, and speaker or consulting fees from AstraZeneca and Chiesi. Conflict of interest: T.H. Harries is supported by a National Institute for Health and Care Research Academic Clinical Lectureship. Conflict of interest: J.L. López-Campos has received honoraria during the last 3 years for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetical order): AstraZeneca, Bial, Boehringer, Chiesi, CSL Behring, Faes, Ferrer, Gebro, Grifols, GSK, Megalabs, Menarini and Novartis. Conflict of interest: C.S. Ulrik has received personal fees and grants from AstraZeneca, Chiesi, Boehringer Ingelheim, GSK, Novartis, Sanofi, Menarini, TEVA, ALK-Abello, Takeda, Orion Pharma, TFF Pharmaceuticals and Covis Pharma outside the submitted work. Conflict of interest: J. Dominguez has received honoraria for lectures from Oxford Immunotec (UK) and received payments for license transference from GenID (Germany), and grants from La Fundació La Marató TV3, Instituto de Salud Carlos III (CP03/00112), Catalan Pulmonology Society (SOCAP), Catalan Pulmonology Foundation (FUCAP) and Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). Conflict of interest: A.M. Turner reports research grants outside the submitted work from AstraZeneca, Resmed, Phillips, Chiesi, Grifols, CSL Behring and NIHR, and honoraria from GSK and Boehringer Ingelheim. Conflict of interest: D. Bumbacea has received grants and personal fees in the last 3 years from AstraZeneca, Eli Lilly, Novartis, Sanofi and Synairgen outside of the submitted work. Conflict of interest: PBM has received grants and personal fees from Philips, ResMed, Breas, Chiesi, Fischer & Paykel and, Sanofi outside the submitted work. Conflict of interest: J. Steer has received grants and honoraria, outside the submitted work, from Chiesi, Menarini Group, AstraZeneca and Pfizer. Conflict of interest: S.C. Bourke has received research grants from GSK (BEC COPD IRAS 285200), and additional support from Radiometer for an NIHR-funded study (NIVOW IRAS 313485), Philips, ResMed, and Pfizer Open Air, took part in clinical advisory boards with Philips and AstraZeneca, and has received honoraria from Boehringer Ingelheim, Chiesi, GSK, and AstraZeneca. Conflict of interest: N. Lane reports research grants from Bright Northumbria and The ResMed Foundation; and nonfinancial support from Chiesi and BREAS outside the submitted work. Conflict of interest: J. de Batlle acknowledges receiving financial support from Instituto de Salud Carlos III (Miguel Servet 2019: CP19/00108), co-funded by the European Social Fund, “Investing in your future”. Conflict of interest: R. Russell has received personal fees, outside of the submitted work, from AstraZeneca, Chiesi, Covis, GlaxoSmithKline and Boehringer Ingelheim. Conflict of interest: J.L. Cross has received grants from National Institute of Health Research. Conflict of interest: M.A. Spruit has received grants from the Netherlands Lung Foundation, Stichting Asthma Bestrijding, AstraZeneca, Boehringer Ingeheim, TEVA and CHIESI outside the submitted work. Conflict of interest: S.O. Simons has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Chiesi outside the submitted work. Conflict of interest: F.M.E. Franssen has received grants and personal fees from AstraZeneca, Chiesi, Boehringer Ingelheim, Glaxosmithkline, Novartis and MSD outside the submitted work. Conflict of interest: All authors declare no conflicts of interest in relation to the present study., (Copyright ©The authors 2024.)

Background: Delivering care to growing numbers of patients with increasingly 'complex' needs is currently compromised by a system designed to treat patients within organizational clinical specialties, making this difficult to reconfigure to fit care to needs. Problematic experiences of people with cognitive impairment(s) admitted to hospitals with a hip fracture, exemplify the complex challenges that result if their care is not tailored. This study explored whether a flexible, multicomponent intervention, adapting services to the needs of this patient group, could be implemented in acute hospital settings., Methods: We used action research with case study design to introduce the intervention using a Plan-Do-Study-Act (PDSA) model to three different hospital sites (cases) across England. The qualitative data for this paper was researcher-generated (notes from observations and teleconference meetings) and change agent-generated (action plans and weekly reflective reports of change agents' activities). Normalization Process Theory (NPT) was used to analyze and explain the work of interacting actors in implementing and then normalizing (embedding) the intervention across contexts and times. Data analysis was abductive, generating inductive codes then identified with NPT constructs. Across the three cases, change agents had to work through numerous implementation challenges: needing to make sense of the intervention package, the PDSA model as implementation method, and their own role as change agents and to orientate these within their action context (coherence). They had to work to encourage colleagues to invest in these changes (cognitive participation) and find ways to implement the intervention by mobilising changes (collective action). Finally, they created strategies for clinical routines to continue to self-review, reconfiguring actions and future plans to enable the intervention to be sustained (reflexive monitoring)., Conclusions: Successful implementation of the (PERFECT-ER) intervention requires change agents to recognize and engage with local values, and then to enable its fit with practice and wider contextual goals. A context of constant change fragments normalization. Thus, sustaining practice change over time is fragile and requires change agents to continue a recursive two-way sense-making process. This enables implementation and normalization to re-energize and overcome barriers to change., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Fox 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.)

Objectives: To determine how, and under what circumstances, the PERFECT-ER intervention was implemented in five acute hospital wards and impacted on staff practices and perceptions., Design: Mixed methods process evaluation (undertaken between 2016 and 2018)., Setting: Five acute hospital wards across three different UK regions., Participants: Patients (n=3) admitted to acute wards with hip fracture and cognitive impairment, their relatives (n=29) and hospital staff (n=63)., Interventions: PERFECT-ER, a multicomponent intervention designed to enhance the recovery of patients with hip fracture and cognitive impairment was implemented for 18 months. PERFECT-ER was implemented at ward level ensuring that multiple new and existing practices were undertaken consistently, on the assumption that collectively, small individual advances would improve care delivery for patients., Primary and Secondary Outcome Measures: Implementation of the PERFECT-ER intervention examined through regular intervention scores, service improvement staff reports and action plans, and semi-structured interviews and focus groups., Results: The process evaluation identified points of implementation vulnerability and strength. All wards implemented some elements of PERFECT-ER. Implementation was fragile when ward pressures were high and when ward staff perceived the relative priority of intervention practices to be low. Adaptations to the implementation process may have reduced whole-ward staff engagement with implementation. However, strategical enlistment of senior ward influencers (such as ward managers, orthogeriatricians) combined with service improvement lead in-ward peer pressure tactics facilitated implementation processes., Conclusions: Our study suggests that implementation was expediated when senior staff were on board as opinion leaders and formally appointed internal implementation leaders exerted their power. Within hierarchical settings such as acute wards, key individuals appeared to influence implementation through endorsement and sometimes enforcement. This indicates that whole-ward interventions may not always require cognitive engagement from all ward staff to implement changes. Future ward-level implementation studies could consider how best to engage staff and most importantly, which staff to best target., Trial Registration Number: ISRCTN99336264., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: To systematically review and meta-analyze whether the application of cryotherapy on closed incisions reduces postoperative pain and opioid consumption., Background: Reduction of acute pain and opioid use is important in the postoperative phase of patient care. ''Cryotherapy'' refers to the use of low temperatures for therapeutic purposes., Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Online registries of clinical trial were search until October 2019. RCT that examined postoperative application of cryotherapy over surgical incisions in adults compared to no cryotherapy were eligible. Selection, extraction, and risk of bias appraisal were completed in duplicate. Data were synthesized using random effects meta-analyses. The outcomes of interest were postoperative pain, opioid use, hospital length of stay (LOS) and surgical site infection (SSI)., Results: Fifty-one RCTs (N = 3425 patients) were included. With moderate certainty evidence, patients treated with cryotherapy experienced a reduction in pain on postoperative day 1 (standardized mean differences -0.50, 95% CI -0.71 to -0.29, l 2= 74%) and day 2 (standardized mean differences -0.63, 95% CI -0.91 to -0.35, I 2 = 83%) relative to without cryotherapy application. With moderate certainty of evidence, cryotherapy reduces opioid consumption in morphine milliequivalents and morphine milliequivalents/kg, (mean differences -7.43, 95% CI -12.42, -2.44, I 2 = 96%) and (mean differences -0.89, 95% CI -1.45, -0.33, I 2 = 99%), respectively. With low certainty evidence, cryotherapy does not affect hospital LOS or rate of SSI., Conclusion: Cryotherapy is a pragmatic, noncostly intervention that reduces postoperative pain and opioid consumption with no effect on SSI rate or hospital LOS., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Assess feasibility of a cluster randomised controlled trial (RCT) to measure clinical and cost-effectiveness of an enhanced recovery pathway for people with hip fracture and cognitive impairment (CI)., Design: Feasibility trial undertaken between 2016 and 2018., Setting: Eleven acute hospitals from three UK regions., Participants: 284 participants (208 female:69 male)., Inclusion Criteria: aged >60 years, confirmed proximal hip fracture requiring surgical fixation and CI; preoperative AMTS ≤8 in England or a 4AT score ≥1 in Scotland; minimum of 5 days on study ward; a 'suitable informant' able to provide proxy measures, recruited within 7 days of hip fracture surgery., Exclusion Criteria: no hip surgery; not expected to survive beyond 4 weeks; already enrolled in a clinical trial., Intervention: PERFECT-ER, an enhanced recovery pathway with 15 quality targets supported by a checklist and manual, a service improvement lead a process lead and implemented using a plan-do-study-act model., Primary and Secondary Outcome Measures: Feasibility outcomes: recruitment and attrition, intervention acceptability, completion of participant reported outcome measures, preliminary estimates of potential effectiveness using mortality, EQ-5D-5L, economic and clinical outcome scores., Results: 282 participants were consented and recruited (132, intervention) from a target of 400. Mean recruitment rates were the same in intervention and control sites, (range: 1.2 and 2.7 participants/month). Retention was 230 (86%) at 1 month and 54%(144) at 6 months. At 3 months a relatively small effect (one quarter of an SD) was observed on health-related quality of life of the patient measured with EQ-5D-5L proxy in the intervention group., Conclusion: This trial design was feasible with modifications to recruitment. Mechanisms for delivering consistency in the PERFECT-ER intervention and participant retention need to be addressed. However, an RCT may be a suboptimal research design to evaluate this intervention due to the complexity of caring for people with CI after hip fracture., Trial Registration Number: ISRCTN99336264., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background and Aims: Advice to drink plenty of fluid is common in respiratory infections. We assessed whether low fluid intake (dehydration) altered outcomes in adults with pneumonia., Methods: We systematically reviewed trials increasing fluid intake and well-adjusted, well-powered observational studies assessing associations between markers of low-intake dehydration (fluid intake, serum osmolality, urea or blood urea nitrogen, urinary output, signs of dehydration) and mortality in adult pneumonia patients (with any type of pneumonia, including community acquired, health-care acquired, aspiration, COVID-19 and mixed types). Medline, Embase, CENTRAL, references of reviews and included studies were searched to 30/10/2020. Studies were assessed for inclusion, risk of bias and data extracted independently in duplicate. We employed random-effects meta-analysis, sensitivity analyses, subgrouping and GRADE assessment. Prospero registration: CRD42020182599., Results: We identified one trial, 20 well-adjusted cohort studies and one case-control study. None suggested that more fluid (hydration) was associated with harm. Ten of 13 well-powered observational studies found statistically significant positive associations in adjusted analyses between dehydration and medium-term mortality. The other three studies found no significant effect. Meta-analysis suggested doubled odds of medium-term mortality in dehydrated (compared to hydrated) pneumonia patients (GRADE moderate-quality evidence, OR 2.3, 95% CI 1.8 to 2.8, 8619 deaths in 128,319 participants). Heterogeneity was explained by a dose effect (greater dehydration increased risk of mortality further), and the effect was consistent across types of pneumonia (including community-acquired, hospital-acquired, aspiration, nursing and health-care associated, and mixed pneumonia), age and setting (community or hospital). The single trial found that educating pneumonia patients to drink ≥1.5 L fluid/d alongside lifestyle advice increased fluid intake and reduced subsequent healthcare use. No studies in COVID-19 pneumonia met the inclusion criteria, but 70% of those hospitalised with COVID-19 have pneumonia. Smaller COVID-19 studies suggested that hydration is as important in COVID-19 pneumonia mortality as in other pneumonias., Conclusions: We found consistent moderate-quality evidence mainly from observational studies that improving hydration reduces the risk of medium-term mortality in all types of pneumonia. It is remarkable that while many studies included dehydration as a potential confounder, and major pneumonia risk scores include measures of hydration, optimal fluid volume and the effect of supporting hydration have not been assessed in randomised controlled trials of people with pneumonia. Such trials, are needed as potential benefits may be large, rapid and implemented at low cost. Supporting hydration and reversing dehydration has the potential to have rapid positive impacts on pneumonia outcomes, and perhaps also COVID-19 pneumonia outcomes, in older adults., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Objectives: To establish the evidence for rehabilitation interventions tested in populations of patients admitted to ICU and critical care with severe respiratory illness, and consider whether the evidence is generalizable to patients with COVID-19., Methods: The authors undertook a rapid systematic review. Medline (via OvidSP), CINAHL Complete (via EBSCOhost), Cochrane Library, Cochrane Database of Systematic Reviews and CENTRAL (via Wiley), Epistemonikos (via Epistemonikos.org), PEDro (via pedro.org.au) and OTseeker (via otseeker.com) searched to 7 May 2020. The authors included systematic reviews, RCTs and qualitative studies involving adults with respiratory illness requiring intensive care who received rehabilitation to enhance or restore resulting physical impairments or function. Data were extracted by one author and checked by a second. TIDier was used to guide intervention descriptions. Study quality was assessed using Critical Skills Appraisal Programme (CASP) tools., Results: Six thousand nine hundred and three titles and abstracts were screened; 24 systematic reviews, 11 RCTs and eight qualitative studies were included. Progressive exercise programmes, early mobilisation and multicomponent interventions delivered in ICU can improve functional independence. Nutritional supplementation in addition to rehabilitation in post-ICU hospital settings may improve performance of activities of daily living. The evidence for rehabilitation after discharge from hospital following an ICU admission is inconclusive. Those receiving rehabilitation valued it, engendering hope and confidence., Conclusions: Exercise, early mobilisation and multicomponent programmes may improve recovery following ICU admission for severe respiratory illness that could be generalizable to those with COVID-19. Rehabilitation interventions can bring hope and confidence to individuals but there is a need for an individualised approach and the use of behaviour change strategies. Further research is needed in post-ICU settings and with those who have COVID-19. Registration: Open Science Framework https://osf.io/prc2y., (Copyright © 2021 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin. Voclosporin (VCS), a next-generation calcineurin inhibitor, is reported to cause fewer incidences of NODAT but the reason is unclear. While calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied 2 clinically relevant doses of TAC (10 ng/mL, 30 ng/mL) and VCS (20 ng/mL, 60 ng/mL), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad, and milder, effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery., (Endocrine Society 2020.)

Within health and social care, academic attention is increasingly paid to understanding the nature and centrality of body work. Relatively little is known about how and where body work specifically fits into the wider work relations that produce it in healthcare settings. We draw on ethnographic observations of staff practice in three National Health Service acute hospital wards in the United Kingdom to make visible the micro-processes of patient care sequences including both body work and the work contextualising and supporting it. Our data, produced in 2015, show body work interactions in acute care to be critically embedded within a context of initiating, preparing, moving and restoring and proceeding. Shades of privacy and objectification of the body are present throughout these sequences. While accomplishing tasks away from the physical body, staff members must also maintain physical and cognitive work focussed on producing body work. Thus, patient care is necessarily complex, requiring much staff time and energy to deliver it. We argue that by making visible the micro-processes that hospital patient care depends on, including both body work and the work sequences supporting it, the complex physical and cognitive workload required to deliver care can be better recognised. (A virtual version of this abstract is available at: https://www.youtube.com/channel/UC&#95;979cmCmR9rLrKuD7z0ycA)., (© 2020 Foundation for the Sociology of Health & Illness.)

Background: Despite extensive studies, there are still no clinically available neuroprotective treatments for traumatic brain injury., Objectives: In previous studies we demonstrated beneficial treatment effects of polyarginine peptides R18 (18-mer of arginine; 300 nmol/kg) and R18D (18-mer of D-arginine; 1000 nmol/kg) in a rat model of impact-acceleration closed-head injury., Methods: We examined the efficacy of R18D when intravenously administered at a low (100 nmol/kg) and high (1000 nmol/kg) dose, 30 minutes after a closed-head injury in male Sprague-Dawley rats., Results: At postinjury day 3, treatment with R18D at the high dose significantly reduced axonal injury ( P  = 0.044), whereas the low-dose treatment of R18D showed a trend for reduced axonal injury. Following assessment in the Barnes maze, both doses of R18D treatment appeared to improve learning and memory recovery compared with vehicle treatment at postinjury days 1 and 3, albeit not to a statistically significant level. Rotarod assessment of vestibulomotor recovery did not differ between R18D and the vehicle treatment groups., Conclusions: R18D modestly decreased axonal injury only at the highest dose used but had no significant effect on functional recovery. These findings warrant further studies with additional doses to better understand peptide pharmacodynamics and provide information to guide optimal dosing., (Crown Copyright © 2020 Published by Elsevier Inc.)

Background: Hip fracture is a major injury that causes significant problems for affected individuals and their family and carers. Over 40% of people with hip fracture have dementia or cognitive impairment. The outcomes of these individuals after surgery are poorer than for those without dementia. It is unclear which care and rehabilitation interventions achieve the best outcomes for these people. This is an update of a Cochrane Review first published in 2013., Objectives: (a) To assess the effectiveness of models of care including enhanced rehabilitation strategies designed specifically for people with dementia following hip fracture surgery compared to usual care. (b) To assess for people with dementia the effectiveness of models of care including enhanced rehabilitation strategies that are designed for all older people, regardless of cognitive status, following hip fracture surgery, compared to usual care., Search Methods: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group Specialised Register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 16 October 2019., Selection Criteria: We included randomised and quasi-randomised controlled trials evaluating the effectiveness of any model of enhanced care and rehabilitation for people with dementia after hip fracture surgery compared to usual care., Data Collection and Analysis: Two review authors independently selected trials for inclusion and extracted data. We assessed risk of bias of the included trials. We synthesised data only if we considered the trials to be sufficiently homogeneous in terms of participants, interventions, and outcomes. We used the GRADE approach to rate the overall certainty of evidence for each outcome., Main Results: We included seven trials with a total of 555 participants. Three trials compared models of enhanced care in the inpatient setting with conventional care. Two trials compared an enhanced care model provided in inpatient settings and at home after discharge with conventional care. Two trials compared geriatrician-led care in-hospital to conventional care led by the orthopaedic team. None of the interventions were designed specifically for people with dementia, therefore the data included in the review were from subgroups of people with dementia or cognitive impairment participating in randomised controlled trials investigating models of care for all older people following hip fracture. The end of follow-up in the trials ranged from the point of acute hospital discharge to 24 months after discharge. We considered all trials to be at high risk of bias in more than one domain. As subgroups of larger trials, the analyses lacked power to detect differences between the intervention groups. Furthermore, there were some important differences in baseline characteristics of participants between the experimental and control groups. Using the GRADE approach, we downgraded the certainty of the evidence for all outcomes to low or very low. The effect estimates for almost all comparisons were very imprecise, and the overall certainty for most results was very low. There were no data from any study for our primary outcome of health-related quality of life. There was only very low certainty for our other primary outcome, activities of daily living and functional performance, therefore we were unable to draw any conclusions with confidence. There was low-certainty that enhanced care and rehabilitation in-hospital may reduce rates of postoperative delirium (odds ratio 0.04, 95% confidence interval (CI) 0.01 to 0.22, 2 trials, n = 141) and very low-certainty associating it with lower rates of some other complications. There was also low-certainty that, compared to orthopaedic-led management, geriatrician-led management may lead to shorter hospital stays (mean difference 4.00 days, 95% CI 3.61 to 4.39, 1 trial, n = 162)., Authors' Conclusions: We found limited evidence that some of the models of enhanced rehabilitation and care used in the included trials may show benefits over usual care for preventing delirium and reducing length of stay for people with dementia who have been treated for hip fracture. However, the certainty of these results is low. Data were available from only a small number of trials, and the certainty for all other results is very low. Determining the optimal strategies to improve outcomes for this growing population of patients should be a research priority., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Successful Scholar-Athletes are physically, intellectually, and emotionally committed to high-level achievement in both their academic and sport endeavors. This requires development of an integrated skill-set that includes teamwork, a strong work ethic, commitment, leadership, time management, and physical and emotional health. The identity crosses all perceived boundaries of race, gender, ethnicity, sexual orientation, religion, disability, social, and economic status. A nationwide paradigm shift is urgently needed to recognize and tap into these skills for all scholar-athletes, which are the same tools required to succeed in all professions from science and technology to law, medicine, business and the arts. This article addresses the misperceptions and low expectations that much of our society has for the high school and collegiate Scholar-Athlete. While recognizing the efforts of programs that are working to recalibrate the high school athlete's self perceptions, awaken recognition of their own academic potential, and permit them to achieve successful careers and make invaluable professional contributions to society., (Copyright © 2019 Cross and Fouke.)

Background: older people with frailty are particularly high users of healthcare services, however a lack of standardised recording of frailty in different healthcare electronic datasets has limited investigations into healthcare service usage and demand of the older frail population., Objectives: to investigate the community service demand of frail patients using the electronic frailty index (eFI) as a measure of frailty., Study Design and Setting: a retrospective cohort study using anonymised linked healthcare patient data from primary care, community services and acute hospitals in Norfolk., Participants: patients aged 65 and over who had an eFI assessment score established in their primary care electronic patient record in Norwich based General Practices., Results: we include data from 22,859 patients with an eFI score. Frailty severity increased with age and was associated with increased acute hospital admission within a 6-month window. Patients with a frail eFI score were also more likely to have a community service referral within a 6-month window of frailty assessment, with a RR of 1.84 (1.76-1.93) for mild frailty, 1.96 (1.83-2.09) for moderate frailty and 2.95 (2.76-3.14) for severe frailty scores. We also found that frail patients had more community referrals per patient then those classified as fit and required more care plans per community referral., Conclusions: eFI score was an indicator of community service use, with increasing severity of frailty being associated with higher community healthcare requirements. The eFI may help planning of community services for the frail population., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We have previously demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties, with poly-arginine peptide R18 identified as being highly effective at reducing infarct volume following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. Since peptides synthesised using D-isoform amino acids have greater stability than L-isoform peptides due to increased resistance to proteolytic degradation, they represent potentially more effective peptide therapeutics. Therefore we compared the neuroprotective efficacy of R18 and its D-enantiomer R18D following permanent MCAO in the Wistar rat. Furthermore, as increased peptide stability may also increase peptide toxicity, we examined the effects of R18 and R18D on cultured cortical neurons, astrocytes, brain endothelial cells (bEND.3), and embryonic kidney cells (HEK293) following a 10-minute or 24-hour peptide exposure duration. The in vivo studies demonstrated that R18D resulted in a greater reduction in mean infarct volume compared to R18 (33%, p = 0.004 vs 12%, p = 0.27) after intravenous administration at 300 nmol/kg 30 minutes after MCAO. Both R18D and R18 reduced cerebral hemisphere swelling to a comparable degree (27%, p = 0.03 and 30%, p = 0.02), and improved neurological assessment scores (1.5, p = 0.02 and 2, p = 0.058 vs 3 for vehicle). No abnormal histological findings specific to peptide treatments were observed in hematoxylin and eosin stained sections of kidney, liver, spleen, lung and heart. In vitro studies demonstrated that R18 and R18D were most toxic to neurons, followed by astrocytes, HEK293 and bEND.3 cells, but only at high concentrations and/or following 24-hour exposure. These findings further highlight the neuroprotective properties of poly-arginine peptides, and indicate that R18D at the dose examined is more potent than R18 in Wistar rats, and justify continued investigation of the R18 peptide as a novel neuroprotective agent for stroke.

We examined the neuroprotective efficacy of the poly-arginine peptide R18 and its D-enantiomer R18D in a perinatal hypoxic-ischaemic (HI) model in P7 Sprague-Dawley rats. R18 and R18D peptides were administered intraperitoneally at doses of 30, 100, 300 or 1000 nmol/kg immediately after HI (8% O 2 /92%N 2 for 2.5 h). The previously characterised neuroprotective JNKI-1-TATD peptide at a dose of 1000 nmol/kg was used as a control. Infarct volume and behavioural outcomes were measured 48 h after HI. For the R18 and R18D doses examined, total infarct volume was reduced by 25.93% to 43.80% (P = 0.038 to < 0.001). By comparison, the JNKI-1-TATD reduced lesion volume by 25.27% (P = 0.073). Moreover, R18 and R18D treatment resulted in significant improvements in behavioural outcomes, while with JNKI-1-TATD there was a trend towards improvement. As an insight into the likely mechanism underlying the effects of R18, R18D and JNKI-1-TATD, the peptides were added to cortical neuronal cultures exposed to glutamic acid excitotoxicity, resulting in up to 89, 100 and 71% neuroprotection, respectively, and a dose dependent inhibition of neuronal calcium influx. The study further confirms the neuroprotective properties of poly-arginine peptides, and suggests a potential therapeutic role for R18 and R18D in the treatment of HIE.

Background: Health and social care provision for an ageing population is a global priority. Provision for those with dementia and hip fracture has specific and growing importance. Older people who break their hip are recognised as exceptionally vulnerable to experiencing confusion (including but not exclusively, dementia and/or delirium and/or cognitive impairment(s)) before, during or after acute admissions. Older people experiencing hip fracture and confusion risk serious complications, linked to delayed recovery and higher mortality post-operatively. Specific care pathways acknowledging the differences in patient presentation and care needs are proposed to improve clinical and process outcomes., Methods: This protocol describes a multi-centre, feasibility, cluster-randomised, controlled trial (CRCT) to be undertaken across ten National Health Service hospital trusts in the UK. The trial will explore the feasibility of undertaking a CRCT comparing the multicomponent PERFECTED enhanced recovery intervention (PERFECT-ER), which acknowledges the differences in care needs of confused older patients experiencing hip fracture, with standard care. The trial will also have an integrated process evaluation to explore how PERFECT-ER is implemented and interacts with the local context. The study will recruit 400 hip fracture patients identified as experiencing confusion and will also recruit "suitable informants" (individuals in regular contact with participants who will complete proxy measures). We will also recruit NHS professionals for the process evaluation. This mixed methods design will produce data to inform a definitive evaluation of the intervention via a large-scale pragmatic randomised controlled trial (RCT)., Discussion: The trial will provide a preliminary estimate of potential efficacy of PERFECT-ER versus standard care; assess service delivery variation, inform primary and secondary outcome selection, generate estimates of recruitment and retention rates, data collection difficulties, and completeness of outcome data and provide an indication of potential economic benefits. The process evaluation will enhance knowledge of implementation delivery and receipt., Trial Registration: ISRCTN, 99336264 . Registered on 5 September 2016.

Cationic arginine-rich and poly-arginine peptides (referred to as CARPs) have potent neuroprotective properties in in vitro excitotoxicity and in vivo models of stroke. Traumatic brain injury (TBI) shares many pathophysiological processes as stroke, including excitotoxicity. Therefore, we evaluated our lead peptide, poly-arginine R18, with the COG1410 and APP96-110 peptides, which have neuroprotective actions following TBI. In an in vitro cortical neuronal glutamic acid excitotoxicity injury model, R18 was highly neuroprotective and reduced neuronal calcium influx, while COG1410 and APP96-110 displayed modest neuroprotection and were less effective at reducing calcium influx. In an impact-acceleration closed-head injury model (Marmarou model), R18, COG1410, and APP96-110 were administered intravenously (300 nmol/kg) at 30 minutes after injury in male Sprague-Dawley rats. When compared to vehicle, no peptide significantly improved functional outcomes, however the R18 and COG1410 treatment groups displayed positive trends in the adhesive tape test and rotarod assessments. Similarly, no peptide had a significant effect on hippocampal neuronal loss, however a significant reduction in axonal injury was observed for R18 and COG1410. In conclusion, this study has demonstrated that R18 is significantly more effective than COG1410 and APP96-110 at reducing neuronal injury and calcium influx following excitotoxicity, and that both R18 and COG1410 reduce axonal injury following TBI. Additional dose response and treatment time course studies are required to further assess the efficacy of R18 in TBI., Competing Interests: Conflicts of interest: Bruno P. Meloni and Neville W. Knuckey are the holders of several patents regarding the use of arginine-rich peptides as neuroprotective treatments. The other authors declare no conflict of interest.

Following positive results with the poly-arginine peptide R18 when administered intravenously 30 or 60min after permanent and/or transient middle cerebral artery occlusion (MCAO; 90min) in the rat, we examined the effectiveness of the peptide when administered 2h after MCAO. R18 was administered intravenously (1000nmol/kg via jugular vein) after permanent MCAO or a transient 3-h MCAO or when administered intra-arterially (100nmol/kg via internal carotid artery) immediately after reperfusion following a transient 2-h MCAO. In the transient MCAO studies, the neuroprotective NA-1 peptide was used as a positive control. Infarct volume, cerebral edema and functional outcomes were measured 24h after MCAO. Following permanent or transient MCAO, neither R18 nor NA-1 significantly reduced infarct volume. However, following permanent MCAO, R18 appeared to reduce cerebral edema (p=0.006), whereas following a transient 3-h MCAO, R18 improved the time to remove adhesive tape (p=0.04) without significantly affecting cerebral edema. There was also a trend (p=0.07) towards improved rota-rod performance with R18 in both permanent and transient 3-h MCAO. Following a transient 2-h MCAO, R18 had no significant effects on cerebral edema or neurological score but did lessen the extent of weight loss. Overall, while R18 had no effect on infarct volume, the peptide reduced cerebral edema after permanent MCAO, and improved some functional outcomes after transient MCAO., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine-tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6%, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4%. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2%, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.

Quark nuggets are theoretical objects composed of approximately equal numbers of up, down, and strange quarks and are also called strangelets and nuclearites. They have been proposed as a candidate for dark matter, which constitutes ~85% of the universe's mass and which has been a mystery for decades. Previous efforts to detect quark nuggets assumed that the nuclear-density core interacts directly with the surrounding matter so the stopping power is minimal. Tatsumi found that quark nuggets could well exist as a ferromagnetic liquid with a ~10 12 -T magnetic field. We find that the magnetic field produces a magnetopause with surrounding plasma, as the earth's magnetic field produces a magnetopause with the solar wind, and substantially increases their energy deposition rate in matter. We use the magnetopause model to compute the energy deposition as a function of quark-nugget mass and to analyze testing the quark-nugget hypothesis for dark matter by observations in air, water, and land. We conclude the water option is most promising.

Background: The Rice-Vannucci model of hypoxic-ischaemic encephalopathy (HIE) has been associated with a high degree of variability with respect to the development of cerebral infarction and infarct lesion volume. For this reason, we examined the occurrence of communicational blood flow within the common carotid (CCA), internal (ICA), and external (ECA) carotid arteries following CCA occlusion as a source of variability in the model., New Method: We propose a novel modification to the Rice-Vannucci model, whereby both the CCA and ECA are permanently ligated; mitigating communicational blood flow., Results: Using magnetic resonance angiography, phase-contrast velocity encoding, and pulsed arterial spin labelling, the modified Rice-Vannucci model (CCA/ECA occlusion) was demonstrated to mitigate communicational blood flow, whilst significantly reducing ipsilateral hemispherical cerebral blood flow (CBF). Comparatively, the original Rice-Vannucci model (CCA occlusion) demonstrated anterograde and retrograde blood flow within the ICA and CCA, respectively, with a non-significant reduction in ipsilateral CBF. Furthermore, CCA/ECA occlusion plus hypoxia (8% O 2 /92% N 2 ; 2.5h) resulted in 100% of animals presenting with an infarct (vs 87%), significantly larger infarct volume at 48h (18.5% versus 10.0%; p<0.01), reduced standard deviation (±10% versus ±15%), and significantly worsened functional outcomes when compared to CCA occlusion plus hypoxia., Comparison With Existing Method: We compared a modified Rice-Vannucci model (CCA/ECA occlusion±hypoxia) to the commonly used Rice-Vannucci model (CCA occlusion±hypoxia)., Conclusion: This study demonstrates that CCA/ECA occlusion in the Rice-Vannucci model of HIE reduces infarct volume variability by limiting communicational blood flow., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The concluding statement of the Burns Commission, established to evaluate whether changes are needed to the Freedom of Information Act (FOIA), ruled no major legislative changes were required. As such Freedom of Information (FOI) legislation still enables anyone to obtain information from public authorities. In this brief report article we explore arguments regarding FOI as an instrument for healthcare research using an international research programme as a case study., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

We examined the efficacy of R18 in a transient MCAO model and compared its effectiveness to the well-characterized neuroprotective NA-1 peptide. R18 and NA-1 peptides were administered intravenously (30, 100, 300, 1000nmol/kg), 60min after the onset of 90min of MCAO. Infarct volume, cerebral swelling and functional outcomes (neurological score, adhesive tape and rota-rod) were measured 24h after MCAO. R18 reduced total infarct volume by 35.1% (p=0.008), 24.8% (p=0.059), 12.2% and 9.6% for the respective 1000 to 30nmol/kg doses, while the corresponding doses of NA-1 reduced lesion volume by 26.1% (p=0.047), 16.6%, 16.5% and 7%, respectively. R18 also reduced hemisphere swelling by between 46.1% (1000 and 300nmol/kg; p=0.009) and 24.4% (100nmol/kg; p=0.066), while NA-1 reduced swelling by 25.7% (1000nmol/kg; p=0.054). In addition, several R18 and NA-1 treatment groups displayed a significant improvement in at least one parameter of the adhesive tape test. These results confirm the neuroprotective properties of R18, and suggest that the peptide is a more effective neuroprotective agent than NA-1. This provides strong justification for the continuing development of R18 as a neuroprotective treatment for stroke., (Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)

Background: We recently reported that poly-arginine peptides have neuroprotective properties both in vitro and in vivo. In cultured cortical neurons exposed to glutamic acid excitotoxicity, we demonstrated that neuroprotective potency increases with polymer length plateauing at R15 to R18 (R = arginine resides). In an in vivo study in rats, we also demonstrated that R9D (R9 peptide synthesised with D-isoform amino acids) administered intravenously at a dose of 1000 nmol/kg 30 min after permanent middle cerebral artery occlusion (MCAO) reduces infarct volume. Based on these positive in vitro and in vivo findings, we decided to examine the neuroprotective efficacy of the L-isoform poly-arginine peptides, R12, R15 and R18 when administered at a dose of 1000 nmol/kg 30 min after permanent MCAO in the rat., Results: At 24 h post-MCAO, there was reduced total infarct volume for R12 (12.8 % reduction) and R18 (20.5 % reduction), but this reduction only reached statistical significance for R18. Brain slice analysis revealed significantly reduced injury in coronal slices 4 and 5 for R18, and slice 5 for R12. The R15 peptide had no effect on infarct volume. Peptide treatment did not reveal any statistical significant improvement in functional outcomes., Conclusion: While these findings confirm the in vivo neuroprotective properties of poly-arginine peptides, additional dose studies are required particularly in less severe transient MCAO models so as to further assess the potential of these agents as a stroke therapy.

Background: This paper assessed the validity, internal consistency, responsiveness and floor-ceiling effects of the Norwich Patellar Instability (NPI) Score for a cohort of conservatively managed people following first-time patellar dislocation (FTPD)., Methods: Fifty patients were recruited, providing 130 completed datasets over 12 months. The NPI Score, Lysholm Knee Score, Tegner Level of Activity Score and isometric knee extension strength were assessed at baseline, six weeks, six and 12 months post-injury., Results: There was high convergent validity with a statistically significant correlation between the NPI Score and the Lysholm Knee Score (p<0.001), Tegner Level of Activity Score (p<0.001) and isometric knee extension strength (p<0.002). Principal component analysis revealed that the NPI Score demonstrated good concurrent validity with four components account for 70.4% of the variability. Whilst the NPI Score demonstrated a flooring-effect for 13 of the 19 items, no ceiling effect was reported. There was high internal consistency with a Cronbach Alpha value of 0.93 (95% CI: 0.91 to 0.93). The NPI Score was responsive to change over the 12 months period with an effect size of 1.04 from baseline to 12 months post-injury., Conclusions: The NPI Score is a valid tool to assess patellar instability symptoms in people conservatively managed following FTPD., Level of Evidence: Level II., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: Niemann-Pick disease type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete because of both these factors and because the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and the development of potential therapies, understanding the incidence of NPC and defining at-risk patient populations are important., Method: We evaluated data from four large, massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or nonpathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency., Results: Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1/19,000-1/36,000., Conclusion: We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients.

We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000 nmol/kg) when administered 60 minutes after permanent middle cerebral artery occlusion (MCAO). The TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours after MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical significance at doses of 100 and 1000 nmol/kg. The TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000 nmol/kg, but not to a statistically significant extent, while the 100 nmol/kg dose was ineffective. The reduction in infarct volume with R18 and TAT-NR2B9c peptide treatments was mirrored by improvements in one or more functional outcomes (namely, neurological score, adhesive tape removal, and rota-rod), but not to a statistically significant extent. These findings further confirm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efficacy compared to TAT-NR2B9c in a severe stroke model. The superior neuroprotective efficacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke.

Background: Hip fracture is a major fall-related injury which causes significant problems for individuals, their family and carers. Over 40% of people with hip fracture have dementia or cognitive impairment, and their outcomes after surgery are poorer than those without dementia. It is not clear which care and rehabilitation interventions achieve the best outcomes for these people., Objectives: (a) To assess the effectiveness of models of care including enhanced rehabilitation strategies designed specifically for people with dementia following hip fracture surgery compared to usual care.(b) To assess the effectiveness for people with dementia of models of care including enhanced rehabilitation strategies which are designed for all older people, regardless of cognitive status, following hip fracture surgery compared to usual care., Search Methods: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group Specialised Register, up to and including week 1 June 2014 using the terms hip OR fracture OR surgery OR operation OR femur OR femoral., Selection Criteria: We include randomised and quasi-randomised controlled clinical trials (RCTs) evaluating the effectiveness for people with dementia of any model of enhanced care and rehabilitation following hip fracture surgery compared to usual care., Data Collection and Analysis: Two review authors working independently selected studies for inclusion and extracted data. We assessed the risk of bias of included studies. We synthesised data only if we considered studies sufficiently homogeneous in terms of participants, interventions and outcomes. We used the GRADE approach to rate the overall quality of evidence for each outcome., Main Results: We included five trials with a total of 316 participants. Four trials evaluated models of enhanced interdisciplinary rehabilitation and care, two of these for inpatients only and two for inpatients and at home after discharge. All were compared with usual rehabilitation and care in the trial settings. The fifth trial compared outcomes of geriatrician-led care in hospital to conventional care led by the orthopaedic team. All papers analysed subgroups of people with dementia/cognitive impairment from larger RCTs of older people following hip fracture. Trial follow-up periods ranged from acute hospital discharge to 24 months post-discharge.We considered all of the studies to be at high risk of bias in more than one domain. As subgroups of larger studies, the analyses lacked power to detect differences between the intervention groups. Further, there were some important differences in the baseline characteristics of the participants in experimental and control groups. Using the GRADE approach, we downgraded the quality of the evidence for all outcomes to 'low' or 'very low'.No study assessed our primary outcome (cognitive function) nor other important dementia-related outcomes including behaviour and quality of life. The effect estimates for most comparisons were very imprecise, so it was not possible to draw firm conclusions from the data. There was low-quality evidence that enhanced care and rehabilitation in hospital led to lower rates of some complications and that enhanced care provided across hospital and home settings reduced the chance of being in institutional care at three months post-discharge (Odds Ratio (OR) 0.46, 95% confidence interval (CI) 0.22 to 0.95, 2 trials, n = 184), but this effect was more uncertain at 12 months (OR 0.90, 95% CI 0.40 to 2.03, 2 trials, n = 177). The effect of enhanced care and rehabilitation in hospital and at home on functional outcomes was very uncertain because the quality of evidence was very low from one small trial. Results on functional outcomes from other trials were inconclusive. The effect of geriatrician-led compared to orthopaedic-led management on the cumulative incidence of delirium was very uncertain (OR 0.73, 95% CI 0.22 to 2.38, 1 trial, n = 126, very low-quality evidence)., Authors' Conclusions: There is currently insufficient evidence to draw conclusions about how effective the models of enhanced rehabilitation and care after hip fracture used in these trials are for people with dementia above active usual care. The current evidence base derives from a small number of studies with quality limitations. This should be addressed as a research priority to determine the optimal strategies to improve outcomes for this growing population of patients.

Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs.

Data from massively parallel sequencing or 'Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Introduction: Smith-Lemli-Opitz Syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability., Areas Covered: In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients. We then explore the underlying biochemical defect and pathophysiological alterations that may contribute to the many disease manifestations. Subsequently we explore the epidemiology and succinctly discuss population genetics as they relate to SLOS. The next section presents the diagnostic possibilities. Thereafter, the treatment and management as is standard of care are presented., Expert Opinion: Even though the knowledge of the underlying molecular mutations and the biochemical alterations is being rapidly accumulated, there is currently no efficacious therapy addressing neurological dysfunction. We discuss the difficulty of treating this disorder, which manifests as a combination of a malformation syndrome and an inborn error of metabolism. A very important factor in developing new therapies is the need to rigorously establish efficacy in controlled trials.

The current study assessed the neuroprotective efficacy of magnesium using a FAST-Mag trial treatment protocol alone, and in combination with mild hypothermia, in Sprague Dawley rats subjected to permanent, middle cerebral artery occlusion (MCAO). Treatment with magnesium (MgSO4.7H2O) consisted of an intravenous loading dose (LD: 360 μmol/kg) and a 24 hour infusion (120 μmol/kg/h), while mild hypothermia at 35°C was maintained for 24 hours. Treatment groups consisted of animals receiving: i) saline; ii) magnesium LD/infusion at 1.5 h/2.5 h post-MCAO; iii) magnesium LD/infusion at 1.5 h/2.5 h post-MCAO and hypothermia commencing at 2.5 h post-MCAO; iv) magnesium LD and hypothermia at 1.5 h and magnesium infusion at 2.5 h post-MCAO; v) hypothermia commencing at 1.5 h post-MCAO and magnesium LD/infusion at 2.5 h post-MCAO; and vi/vii) hypothermia commencing at 1.5 h or 2.5 h post-MCAO. No treatment significantly reduced infarct volumes or improved adhesive tape removal time when measured 48 hours after MCAO. These findings indicate that FAST-Mag treatment alone or with mild hypothermia may not provide benefit after ischemic stroke, associated with permanent cerebral artery occlusion.

Background: The SH2-containing inositol-5'-phosphatase 1 (SHIP1) metabolizes PI(3,4,5)P3 to PI(3,4)P2. SHIP1-deficient mice exhibit progressive inflammation. Pharmacological activation of SHIP1 is emerging as a potential therapy for pulmonary inflammatory diseases. Here we characterize the efficacy of AQX-1125, a small-molecule SHIP1 activator currently in clinical development., Experimental Approach: The effects of AQX-1125 were tested in several in vitro assays: on enzyme catalytic activity utilizing recombinant human SHIP1, on Akt phosphorylation in SHIP1-proficient and SHIP1-deficient cell lines, on cytokine release in murine splenocytes, on human leukocyte chemotaxis using modified Boyden chambers and on β-hexosaminidase release from murine mast cells. In addition, pharmacokinetic and drug distribution studies were performed in rats and dogs., Results: AQX-1125 increased the catalytic activity of human recombinant SHIP1, an effect, which was absent after deletion of the C2 region. AQX-1125 inhibited Akt phosphorylation in SHIP1-proficient but not in SHIP1-deficient cells, reduced cytokine production in splenocytes, inhibited the activation of mast cells and inhibited human leukocyte chemotaxis. In vivo, AQX-1125 exhibited >80% oral bioavailability and >5 h terminal half-life., Conclusions: Consistent with the role of SHIP1 in cell activation and chemotaxis, the SHIP1 activator AQX-1125 inhibits Akt phosphorylation, inflammatory mediator production and leukocyte chemotaxis in vitro. The in vitro effects and the pharmacokinetic properties of the compound make it a suitable candidate for in vivo testing in various models of inflammation., (© 2012 Aquinox Pharmaceuticals Inc. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background: The efficacy of AQX-1125, a small-molecule SH2-containing inositol-5'-phosphatase 1 (SHIP1) activator and clinical development candidate, is investigated in rodent models of inflammation., Experimental Approach: AQX-1125 was administered orally in a mouse model of passive cutaneous anaphylaxis (PCA) and a number of rodent models of respiratory inflammation including: cigarette smoke, LPS and ovalbumin (OVA)-mediated airway inflammation. SHIP1 dependency of the AQX-1125 mechanism of action was investigated by comparing the efficacy in wild-type and SHIP1-deficient mice subjected to an intrapulmonary LPS challenge., Results: AQX-1125 exerted anti-inflammatory effects in all of the models studied. AQX-1125 decreased the PCA response at all doses tested. Using bronchoalveolar lavage (BAL) cell counts as an end point, oral or aerosolized AQX-1125 dose dependently decreased the LPS-mediated pulmonary neutrophilic infiltration at 3-30 mg kg⁻¹ and 0.15-15 μg kg⁻¹ respectively. AQX-1125 suppressed the OVA-mediated airway inflammation at 0.1-10 mg kg⁻¹. In the smoke-induced airway inflammation model, AQX-1125 was tested at 30 mg kg⁻¹ and significantly reduced the neutrophil infiltration of the BAL fluid. AQX-1125 (10 mg kg⁻¹) decreased LPS-induced pulmonary neutrophilia in wild-type mice but not in SHIP1-deficient mice., Conclusions: The SHIP1 activator, AQX-1125, suppresses leukocyte accumulation and inflammatory mediator release in rodent models of pulmonary inflammation and allergy. As shown in the mouse model of LPS-induced lung inflammation, the efficacy of the compound is dependent on the presence of SHIP1. Pharmacological SHIP1 activation may have clinical potential for the treatment of pulmonary inflammatory diseases., (© 2012 Aquinox Pharmaceuticals Inc. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background: Manual chest physiotherapy (MCP) techniques involving chest percussion, vibration, and shaking have long been used in the treatment of respiratory conditions. However, methodological limitations in existing research have led to a state of clinical equipoise with respect to this treatment. Thus, for patients hospitalised with an exacerbation of Chronic Obstructive Pulmonary Disease (COPD), clinical preference tends to dictate whether MCP is given to assist with sputum clearance. We standardised the delivery of MCP and assessed its effectiveness on disease-specific quality of life., Methods: In this randomised, controlled trial powered for equivalence, 526 patients hospitalised with acute COPD exacerbation were enrolled from four centres in the UK. Patients were allocated to receive MCP plus advice on airway clearance or advice on chest clearance alone. The primary outcome was a COPD specific quality of life measure, the Saint Georges Respiratory Questionnaire (SGRQ) at six months post randomisation. Analyses were by intention to treat (ITT). This study was registered, ISRCTN13825248., Results: All patients were included in the analyses, of which 372 (71%) provided evaluable data for the primary outcome. An effect size of 0·3 standard deviations in SGRQ score was specified as the threshold for superiority. The ITT analyses showed no significant difference in SGRQ for patients who did, or did not receive MCP (95% CI -0·14 to 0·19)., Conclusions: These data do not lend support to the routine use of MCP in the management of acute exacerbation of COPD. However, this does not mean that MCP is of no therapeutic value to COPD patients in specific circumstances.

In this study we have assessed sodium-calcium exchanger (NCX) protein over-expression on cell viability in primary rat cortical neuronal and HEK293 cell cultures when subjected to oxygen-glucose deprivation (OGD). In cortical neuronal cultures, NCX2 and NCX3 over-expression was achieved using adenoviral vectors, and following OGD increased neuronal survival from ≈20% for control vector treated cultures to ≈80% for both NCX isoforms. In addition, we demonstrated that NCX2 and NCX3 over-expression in cortical neuronal cultures enables neurons to maintain intracellular calcium at significantly lower levels than control vector treated cultures when exposed to high (9mM) extracellular calcium challenge. Further assessment of NCX activity during OGD was performed using HEK293 cell lines generated to over-express NCX1, NCX2 or NCX3 isoforms. While it was shown that NCX isoform expression differed considerably in the different HEK293 cell lines, high levels of NCX over-expression was associated with increased resistance to OGD. Taken together, our findings show that high levels of NCX over-expression increases neuronal and HEK293 cell survival following OGD, improves calcium management in neuronal cultures and provides additional support for NCX as a therapeutic target to reduce ischemic brain injury., (Copyright © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method that adapts flow chemistry to the synthesis of libraries of compounds using a fluorous immiscible solvent as a spacer between reactions. The methodology was validated in the synthesis of two small heterocycle containing libraries. The reactions were performed on a 0.2 mmol scale, enabling tens of milligrams of material to be generated in a single 200 mL reaction plug. The methodology allowed library synthesis in half the time of conventional microwave synthesis while maintaining similar yields. The ability to perform multiple, potentially unrelated reactions in a single run is ideal for making small quantities of many different compounds quickly and efficiently.

CD44 is expressed on T cells where its ability to bind hyaluronan is tightly regulated. Here, we investigated when T cells bind hyaluronan during an immune response. We found that naïve, murine T cells do not bind fluoresceinated hyaluronan but are induced to bind upon antigen-induced T-cell activation in vitro and in vivo. Hyaluronan binding occurred on proliferating T cells and the percentage of hyaluronan-binding cells correlated with the strength of the activation stimulus. A small percentage of hyaluronan-binding cells persisted after in vitro activation and had a memory phenotype (CD122(+) CD44(hi)). This hyaluronan-binding population increased after culture with IL-7 or IL-15 and proliferated more rapidly than nonbinding cells. In vivo, approximately 20-30% of antigen-specific OT-I CD8(+) memory T cells in the spleen and BM bound hyaluronan. Hyaluronan binding identified memory cells that proliferated faster in IL-7 and IL-15, and enriched for CD62L(+) central memory cells. In vivo homeostatic proliferation induced hyaluronan binding on a small percentage of the most rapidly dividing cells after several cell divisions. This study demonstrates that hyaluronan binding is induced upon antigen-induced T-cell activation and occurs on a percentage of the most proliferative activated and memory T cells., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

One of the major instigators leading to neuronal cell death and brain damage following cerebral ischemia is calcium dysregulation. The neuron's inability to maintain calcium homeostasis is believed to be a result of increased calcium influx and impaired calcium extrusion across the plasma membrane. The need to better understand the cellular and biochemical mechanisms of calcium dysregulation contributing to neuronal loss following stroke/cerebral ischemia is essential for the development of new treatments in order to reduce ischemic brain injury. The aim of this paper is to provide a concise overview of the various calcium influx pathways in response to ischemia and how neuronal cells attempts to overcome this calcium overload.

CD44 is a widely expressed cell adhesion molecule with functional similarities to the selectin and integrin adhesion molecules. CD44 has a lectin domain that binds hyaluronan, a component of the extracellular matrix. Interactions between CD44 and hyaluronan promote lymphocyte rolling under flow and cell-cell and cell-matrix adhesion. Attachment of lymphocytes to immobilized CD44 antibodies induces cell adhesion and spreading, which is dependent on Src family kinase activity. Both Lck and Fyn associate with CD44 in T cells. CD4 and CD8 associate with Lck via a zinc-dependent interaction that is inhibited by the divalent metal cation chelator, 1,10-phenanthroline. Here we show that both CD4 and CD44-mediated T cell spreading is abolished in the presence of 1,10-phenanthroline and their association with Lck is significantly reduced. In contrast, the co-immunoprecipitation of Fyn by CD44 was unaffected. The cytoplasmic domain of CD44 was required for divalent cation-dependent association of Lck, but not for its association with Fyn. Mutational analysis of CD44 revealed that cysteine residues were not essential for the interaction nor were the carboxy-terminal 41 amino acids. Progressive deletion of the remaining 31 amino acids of the CD44 cytoplasmic domain revealed the importance of this membrane proximal region for its association with Lck. Using purified recombinant proteins, we demonstrated a direct, zinc-inducible interaction between the cytoplasmic domain of CD44 and Lck but not Fyn. The zinc-inducible interaction required the first 13 amino acids of the cytoplasmic domain of CD44 and the non-catalytic regions of Lck. Taken together, we conclude that CD44 directly associates with Lck in a zinc-inducible manner and this is important for the transmission of CD44-mediated signaling events leading to T cell spreading.

We explored the topical use of resiquimod (R-848), a Toll-like receptor (TLR) 7/8 agonist, in gel formulation, to enhance cross-priming to subcutaneously administered protein antigen in a murine model. Resiquimod application at the time of subcutaneous administration of ovalbumin generated robust antigen-specific CTL as detected by tetramers, IFN-gamma ELISPOT assays and standard cytotoxicity assays. Induced CTL were capable of mediating antigen-specific killing in vivo as measured by in vivo cytotoxicity assays and an ability to protect against B16-OVA tumor challenge. Multiple serial applications of topical resiquimod increased the frequency of antigen-specific CTL when compared to single application. This enhanced frequency was noted despite a marked inhibition of adjuvant mediated pro-inflammatory cytokine release following repeated administration. Topical resiquimod is a potent adjuvant for locally administered subcutaneous vaccines, inducing clinically relevant CTL responses following single application at the time of subcutaneous vaccination.

Objective: We sought to convey lessons learned by the Centers for Disease Control and Prevention's (CDC's) Prevention Research Centers (PRCs) about the value and challenges of private-sector alliances resulting in innovative health promotion strategies. Several PRCs based in a variety of workplace and community settings contributed., Methods: We conducted interviews with principal investigators, a literature review, and a review of case studies of private-sector alliances in a microbusiness model, a macrobusiness model, and as multiparty partnerships supporting public health research, implementation, and human resource services., Results: Private-sector alliances provide many advantages, particularly access to specialized skills generally beyond the expertise of public health entities. These skills include manufacturing, distribution, marketing, business planning, and development. Alliances also allow ready access to employee populations. Public health entities can offer private-sector partners funding opportunities through special grants, data gathering and analysis skills, and enhanced project credibility and trust. Challenges to successful partnerships include time and resource availability and negotiating the cultural divide between public health and the private sector. Critical to success are knowledge of organizational culture, values, mission, currency, and methods of operation; an understanding of and ability to articulate the benefits of the alliance for each partner; and the ability and time to respond to unexpected changes and opportunities., Conclusion: Private-public health alliances are challenging, and developing them takes time and resources, but aspects of these alliances can capitalize on partners' strengths, counteract weaknesses, and build collaborations that produce better outcomes than otherwise possible. Private partners may be necessary for program initiation or success. CDC guidelines and support materials may help nurture these alliances.

Tyrosine phosphorylation is a key means of signal transduction in the immune system, initiating signals from antigen receptors, integrins, and cytokine receptors. Tyrosine phosphorylation is regulated by the balance of tyrosine kinase and tyrosine phosphatase activities. Src family kinases are prevalent in leukocytes and play critical roles in many signaling pathways present in immune cells. For example, they are the key kinases that phosphorylate both immunoreceptor tyrosinebased activation and inhibitory motifs. CD45 is a leukocyte-specific, transmembrane protein tyrosine phosphatase and an important regulator of Src family kinase activity. Here, we briefly review the importance of tyrosine phosphorylation in key signaling pathways in immune cells and then review the accumulating evidence for tyrosine phosphorylation in Toll-like receptor (TLR) signaling leading to proinflammatory cytokine and type I interferon production. We examine how tyrosine phosphorylation directly impacts TLR signaling pathways and review the involvement of specific tyrosine kinases and phosphatases. Finally, we consider how tyrosine phosphorylation signals from other signaling pathways integrate with the TLR signaling pathway to modulate proinflammatory cytokine production.