Attention-Guided Autoencoder for Automated Progression Prediction of Subjective Cognitive Decline with Structural MRI

Subjective cognitive decline (SCD) is a preclinical stage of Alzheimer's disease (AD) which occurs even before mild cognitive impairment (MCI). Progressive SCD will convert to MCI with the potential of further evolving to AD. Therefore, early identification of progressive SCD with neuroimaging techniques (e.g., structural MRI) is of great clinical value for early intervention of AD. However, existing MRI-based machine/deep learning methods usually suffer the small-sample-size problem which poses a great challenge to related neuroimaging analysis. The central question we aim to tackle in this paper is how to leverage related domains (e.g., AD/NC) to assist the progression prediction of SCD. Meanwhile, we are concerned about which brain areas are more closely linked to the identification of progressive SCD. To this end, we propose an attention-guided autoencoder model for efficient cross-domain adaptation which facilitates the knowledge transfer from AD to SCD. The proposed model is composed of four key components: 1) a feature encoding module for learning shared subspace representations of different domains, 2) an attention module for automatically locating discriminative brain regions of interest defined in brain atlases, 3) a decoding module for reconstructing the original input, 4) a classification module for identification of brain diseases. Through joint training of these four modules, domain invariant features can be learned. Meanwhile, the brain disease related regions can be highlighted by the attention mechanism. Extensive experiments on the publicly available ADNI dataset and a private CLAS dataset have demonstrated the effectiveness of the proposed method. The proposed model is straightforward to train and test with only 5-10 seconds on CPUs and is suitable for medical tasks with small datasets.Comment: 10 pages, 12 figure

Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function

Prior studies have demonstrated that cholera toxin (CT) and other cAMP-inducing factors inhibit interleukin (IL)-12 production from monocytes and dendritic cells (DCs). We show that CT inhibits Th1 responses in vivo in mice infected with Toxoplasma gondii. This correlated with low serum IL-12 levels and a selective reduction in the numbers of CD8α+ conventional DCs (cDCs) in lymphoid organs. CT inhibited the function of interferon (IFN) regulatory factor (IRF) 8, a transcription factor known to positively regulate IL-12p35 and p40 gene expression, and the differentiation of CD8α+ and plasmacytoid DCs (pDCs). Fluorescence recovery after photobleaching analysis showed that exposure to CT, forskolin, or dibutyryl (db) cAMP blocked LPS and IFN-γ–induced IRF8 binding to chromatin. Moreover, CT and dbcAMP inhibited the binding of IRF8 to the IFN-stimulated response element (ISRE)–like element in the mouse IL-12p40 promoter, likely by blocking the formation of ISRE-binding IRF1–IRF8 heterocomplexes. Furthermore, CT inhibited the differentiation of pDCs from fms-like tyrosine kinase 3 ligand–treated bone marrow cells in vitro. Therefore, because IRF8 is essential for IL-12 production and the differentiation of CD8α+ cDCs and pDCs, these data suggest that CT and other Gs-protein agonists can affect IL-12 production and DC differentiation via a common mechanism involving IRF8

A call for citizen science in pandemic preparedness and response : beyond data collection

The COVID-19 pandemic has underlined the need to partner with the community in pandemic preparedness and response in order to enable trust-building among stakeholders, which is key in pandemic management. Citizen science, defined here as a practice of public participation and collaboration in all aspects of scientific research to increase knowledge and build trust with governments and researchers, is a crucial approach to promoting community engagement. By harnessing the potential of digitally enabled citizen science, one could translate data into accessible, comprehensible and actionable outputs at the population level. The application of citizen science in health has grown over the years, but most of these approaches remain at the level of participatory data collection. This narrative review examines citizen science approaches in participatory data generation, modelling and visualisation, and calls for truly participatory and co-creation approaches across all domains of pandemic preparedness and response. Further research is needed to identify approaches that optimally generate short-term and long-term value for communities participating in population health. Feasible, sustainable and contextualised citizen science approaches that meaningfully engage affected communities for the long-term will need to be inclusive of all populations and their cultures, comprehensive of all domains, digitally enabled and viewed as a key component to allow trust-building among the stakeholders. The impact of COVID-19 on people’s lives has created an opportune time to advance people’s agency in science, particularly in pandemic preparedness and response

Protocol for a systematic review assessing the measurement of dietary sodium intake among adults with elevated blood pressure

Daniel Reidpath - ORCID: 0000-0002-8796-0420 https://orcid.org/0000-0002-8796-0420Introduction Accurate sodium intake estimates in adults with elevated blood pressure are essential for monitoring salt reduction progress and preventing cardiovascular diseases. However, sodium assessments are challenging in this high-risk population because many commonly used antihypertensive drugs alter urinary sodium excretion. Despite the high cost and substantial participant burden of gold-standard 24-hour urine collection, the relative performance of existing spot-urine based equations and dietary self-report instruments have not been well studied in this population, who will benefit from salt restriction. This systematic review aims to describe the current methods of assessing dietary sodium intake in adults with elevated blood pressure and determine what method can provide a valid and accurate estimate of sodium intake compared with the gold standard 24-hour urine collection. Methods and analysis Studies assessing sodium intake in adults aged 18 years and above with reported elevated blood pressure will be included. Five electronic databases (MEDLINE, Embase, Global Health, WoS and Cochrane CENTRAL) will be systematically searched from inception to March 2021. Also, a manual search of bibliographies and grey literature will be conducted. Two reviewers will screen the records independently for eligibility. One reviewer will extract all data, and two others will review the extracted data for accuracy. The methodological quality of included studies will be evaluated based on three scoring systems: (1) National Heart, Lung and Blood Institute for interventional studies; (2) Biomarker-based Cross-sectional Studies for biomarker-based observational studies and (3) European Micronutrient Recommendation Aligned Network of Excellence for validation studies of dietary self-report instruments. Ethics and dissemination As the proposed systematic review will collect and analyse secondary data associated with individuals, there will be no ethical approval requirement. Findings will be disseminated in a peer-reviewed journal or presented at a conference.http://dx.doi.org/10.1136/bmjopen-2021-05217512pubpub

Link Between Dietary Sodium Intake, Cognitive Function, and Dementia Risk in Middle-Aged and Older Adults: A Systematic Review

Daniel Reidpath - ORCID: 0000-0002-8796-0420 https://orcid.org/0000-0002-8796-0420Background: A key focus for dementia risk-reduction is the prevention of socio-demographic, lifestyle, and nutritional risk factors. High sodium intake is associated with hypertension and cardiovascular disease (both are linked to dementia), generating numerous recommendations for salt reduction to improve cardiovascular health. Objective: This systematic review aimed to assess, in middle- and older-aged people, the relationship between dietary sodium intake and cognitive outcomes including cognitive function, risk of cognitive decline, or dementia. Methods: Six databases (PubMed, EMBASE, CINAHL, Psych info, Web of Science, and Cochrane Library) were searched from inception to 1 March 2020. Data extraction included information on study design, population characteristics, sodium reduction strategy (trials) or assessment of dietary sodium intake (observational studies), measurement of cognitive function or dementia, and summary of main results. Risk-of-bias assessments were performed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tool. Results: Fifteen studies met the inclusion criteria including one clinical trial, six cohorts, and eight cross-sectional studies. Studies reported mixed associations between sodium levels and cognition. Results from the only clinical trial showed that a lower sodium intake was associated with improved cognition over six months. In analysis restricted to only high-quality studies, three out of four studies found that higher sodium intake was associated with impaired cognitive function. Conclusion: There is some evidence that high salt intake is associated with poor cognition. However, findings are mixed, likely due to poor methodological quality, and heterogeneous dietary, analytical, and cognitive assessment methods and design of the studies. Reduced sodium intake may be a potential target for intervention. High quality prospective studies and clinical trials are needed.https://doi.org/10.3233/JAD-19133976pubpub

Establishing a core outcome set for peritoneal dialysis : report of the SONG-PD (standardized outcomes in nephrology-peritoneal dialysis) consensus workshop

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PURPOSE: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. EXPERIMENTAL DESIGN: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. RESULTS: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. CONCLUSIONS: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).This study was supported by Merck & Co., Inc. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research), the National Institute for Health Research (NIHR) Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), the NIHR Clinical Research Facility (to the Royal Marsden NHS Foundation Trust) and the Cancer Research UK and EPSRC Cancer Imaging Centre. T.A. Yap is the recipient of the 2011 Rebecca and Nathan Milikowsky – PCF Young Investigator Award and is supported by the NIHR. M.O. Leach is an NIHR Senior Investigator.This is the accepted manuscript. The final version is available from AACR at http://clincancerres.aacrjournals.org/content/early/2014/09/19/1078-0432.CCR-14-0868

Discarded livers tested by normothermic machine perfusion in the VITTAL trial:Secondary end points and 5-year outcomes

Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH &gt;7.65 and bicarbonate levels &gt;25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608).</p

Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution

Dietary protein dilution, where protein is reduced and replaced by other nutrient sources without caloric restriction, promotes metabolic health via the hepatokine Fgf21. Here, the authors show that essential amino acids threonine and tryptophan are necessary and sufficient to induce these effects

Intensive Care Unit Admission Parameters Improve the Accuracy of Operative Mortality Predictive Models in Cardiac Surgery

BACKGROUND: Operative mortality risk in cardiac surgery is usually assessed using preoperative risk models. However, intraoperative factors may change the risk profile of the patients, and parameters at the admission in the intensive care unit may be relevant in determining the operative mortality. This study investigates the association between a number of parameters at the admission in the intensive care unit and the operative mortality, and verifies the hypothesis that including these parameters into the preoperative risk models may increase the accuracy of prediction of the operative mortality. METHODOLOGY: 929 adult patients who underwent cardiac surgery were admitted to the study. The preoperative risk profile was assessed using the logistic EuroSCORE and the ACEF score. A number of parameters recorded at the admission in the intensive care unit were explored for univariate and multivariable association with the operative mortality. PRINCIPAL FINDINGS: A heart rate higher than 120 beats per minute and a blood lactate value higher than 4 mmol/L at the admission in the intensive care unit were independent predictors of operative mortality, with odds ratio of 6.7 and 13.4 respectively. Including these parameters into the logistic EuroSCORE and the ACEF score increased their accuracy (area under the curve 0.85 to 0.88 for the logistic EuroSCORE and 0.81 to 0.86 for the ACEF score). CONCLUSIONS: A double-stage assessment of operative mortality risk provides a higher accuracy of the prediction. Elevated blood lactates and tachycardia reflect a condition of inadequate cardiac output. Their inclusion in the assessment of the severity of the clinical conditions after cardiac surgery may offer a useful tool to introduce more sophisticated hemodynamic monitoring techniques. Comparison between the predicted operative mortality risk before and after the operation may offer an assessment of the operative performance